Mobiflex (Tenoxicam)

MOBIFLEX®

Roche

Tenoxicam

Anti-inflammatory – Analgesic

Action And Clinical Pharmacology: Tenoxicam is a nonsteroidal anti-inflammatory agent with analgesic and antipyretic properties. Its mechanism of action, as with other nonsteroidal anti-inflammatory agents, is not yet completely known. Tenoxicam is an inhibitor of prostaglandin biosynthesis both in vitro and in vivo (protects mice against arachidonic acid induced toxicity). In vitro tests of leukocyte peroxidase also suggest that tenoxicam may act as a scavenger for active oxygen at the site of inflammation. These effects probably explain in part, the activity of tenoxicam in the treatment of painful inflammatory and degenerative diseases of the musculoskeletal system. Tenoxicam does not act by pituitary-adrenal stimulation.

After 4, 7, 10 or 14 days of culture with tenoxicam (2.4, 12, 48 µg/mL), there was no significant effect on the amount of cartilage proteoglycans synthesized and released into the culture medium of human chondrocytes, as compared to untreated cultures.

In vitro studies have also shown that tenoxican inhibits the activity of both proteoglycanase and collagenase enzymes obtained from human osteoarthritic cartilage. These in vitro results suggest a positive effect of tenoxicam on the joint cartilage under experimental conditions by slowing down the enhanced catabolism of the osteoarthritic cartilage matrix. The clinical significance of these findings is not yet known and is being investigated.

Pharmacokinetics: Tenoxicam is extensively absorbed following oral administration with an absolute bioavailability of approximately 100%. Following a single oral dose of the 20 mg tablet, peak plasma concentrations (1.46 to 3.31 g/mL) were reached within 0.5 to 6 hours (median: 1.25 hours), and the mean half-life was 72±28 hours (range: 32 to 110 hours) in 8 fasted healthy males. When taken with a meal, tenoxicam is absorbed to the same extent but at a slower rate (peak plasma concentration is attained after 4 hours).

Approximately two thirds of a single 40 mg oral dose of tenoxicam is excreted in the urine, mainly as inactive 5’hydroxy-tenoxicam (20 to 30%). Only small amounts of the unchanged drug (0.5%) were found in the urine.

Following multiple doses of 20 mg once daily, steady state conditions are reached within 10 to 15 days. Maximum steady state plasma concentrations fall within the range of 10 to 15 g/mL.

An average of 17% (4.8 to 45.3%) of a 20 mg oral dose is found in the bile as the C-7 or C-8 0-glucuronide of tenoxicam.

In 14 elderly patients suffering from osteoarthritis or rheumatoid arthritis, the mean peak plasma concentration after a single 20 mg dose of tenoxicam was 2.6 g/mL, and the mean maximum steady state plasma concentration after multiple dosing was 12.4 g/mL.

In 8 male and 4 female patients with renal insufficiency (creatinine clearance 6 to 57 mL/min), peak plasma concentrations were in the range of 1.2 to 5.2 g/mL and the half-life of elimination ranged from 30 to 110 hours after a single 20 mg dose of tenoxicam. Pharmacokinetic parameters in patients with renal insufficiency were not significantly different from those in healthy volunteers.

In 4 male and 2 female patients with liver cirrhosis, the mean peak plasma concentration was 2.6 g/mL and the half-life of elimination ranged between 26 to 84 hours after a single 20 mg dose of tenoxicam.

Tenoxicam is highly bound to the albumin component of plasma proteins (98 to 99%).

The sex-dependent difference in the disposition of tenoxicam was investigated. There was no difference in the maximum plasma concentrations, whereas a difference, at the 0.10 level of significance, was seen for the time to reach maximum drug concentrations, (3.6 hours for males, 1.52 hours for females) and for the half-life of elimination (72.4 hours for males and 61.8 hours for females).

Total tenoxicam concentrations in synovial fluid were determined in 6 patients (3 male, 3 female) after receiving a single 40 mg oral dose of tenoxicam. Peak synovial concentrations (1.82g/mL) were reached after 10 hours. The area under the synovial fluid tenoxicam concentration-time curve was 40 to 50% of the area under the plasma tenoxicam concentration-time curve.

Over a 2-week period of observation 6 healthy volunteers, taking tenoxicam 20 mg daily in a single dose, showed significantly less mean daily fecal blood loss (5.71 mL/week) than they did when taking 1.2 to 3 g of ASA daily (9.41 mL/week).

Indications And Clinical Uses: For the symptomatic treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and extra-articular inflammations such as tendinitis, bursitis and periarthritis of the shoulders or hips.

Contra-Indications: Tenoxicam should not be administered to patients with active peptic ulcer or active inflammatory diseases of the gastrointestinal tract. Tenoxicam is contraindicated in patients who have shown hypersensitivity to the drug. It should not be used in patients in whom acute asthmatic attacks, urticaria, rhinitis or other allergic manifestations are precipitated by ASA or other nonsteroidal anti-inflammatory agents. Fatal anaphylactoid reactions have occurred in such individuals.

Before anesthesia or surgery, tenoxicam should not be given to elderly patients, to patients at risk of renal failure, or to patients with increased risk of bleeding, because of an increased risk of acute renal failure and possibility of impaired hemostasis.

Manufacturers’ Warnings In Clinical States: Peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal have been reported during therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) including tenoxicam.

Caution should be exercised when a NSAID such as tenoxicam is used in patients with a history suggestive of peptic ulcer, melena or any gastrointestinal disease. In these cases, the physician must weigh the benefits of treatment against the possible hazards.

Patients taking any NSAID including this drug should be instructed to contact a physician immediately if they experience symptoms or signs suggestive of peptic ulceration or gastrointestinal bleeding. These reactions can occur without warning symptoms or signs and at any time during the treatment.

Elderly, frail and debilitated patients appear to be at higher risk from a variety of adverse reactions from nonsteroidal anti-inflammatory drugs (NSAIDs). As with other nonsteroidal anti-inflammatory drugs, tenoxicam should be used with special caution in these patients.

Pregnancy and Lactation: The safety of tenoxicam during pregnancy and lactation has not been established and therefore its use during pregnancy and lactation is not recommended.

No teratogenic effects were observed in animal reproductive studies. Rats receiving tenoxicam during pregnancy showed delayed delivery. Tenoxicam readily passes into the milk of lactating rats.

Children: Tenoxicam is not recommended for use in patients under 16 years of age as the dose and indications in this population have not been established.

Precautions: Gastrointestinal: If peptic ulceration or gastrointestinal bleeding occur in patients under treatment with tenoxicam, the drug should be immediately withdrawn.

There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow continuation of tenoxicam therapy when and if these adverse reactions appear.

Renal Function: As with other nonsteroidal anti-inflammatory drugs, long-term administration of tenoxicam to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria and occasionally nephrotic syndrome.

A second form of renal toxicity has been seen in patients with prerenal conditions leading to the reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the elderly. Discontinuation of nonsteroidal anti-inflammatory therapy is usually followed by recovery to the pre-treatment state.

Reversible elevation of BUN and serum creatinine have been reported with tenoxicam. The effect is thought to result from inhibition of renal prostaglandin synthesis resulting in changes in medullary and deep cortical blood flow with an attendant effect on renal function. Patients with impaired renal function or on diuretics, as well as elderly patients and those with congestive heart failure or liver ascites, are more at risk.

During long-term therapy, kidney function should be monitored periodically.

Hepatic Function: As with other nonsteroidal anti-inflammatory drugs, borderline elevations of one or more liver tests may occur. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reactions while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with this drug as with other nonsteroidal anti-inflammatory drugs. Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), this drug should be discontinued.

During long-term therapy, liver function tests should be monitored periodically.

Fluid and Electrolyte Balance: Fluid retention and edema have been observed in patients treated with tenoxicam. Therefore, as with many other nonsteroidal anti-inflammatory drugs, the possibility of precipitating congestive heart-failure in elderly patients or those with compromised cardiac function should be born in mind. Tenoxicam should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention.

With NSAID treatment, there is a potential risk of hyperkalemia particularly in patients with conditions such as diabetes mellitus or renal failure; elderly patients and patients receiving concomitant therapy with b-adrenergic blockers, angiotensin converting enzyme inhibitors or some diuretics. Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients at risk.

Hematology: Drugs inhibiting prostaglandin biosynthesis do interfere, with platelet function to some degree; therefore, patients who may be adversely affected by such an action should be carefully observed when tenoxicam is administered.

Blood dyscrasias associated with the use of nonsteroidal anti-inflammatory drugs is rare, but could be with severe consequences.

Infection: In common with other anti-inflammatory drugs, tenoxicam may mask the usual signs of infection.

Ophthalmology: Blurred and/or diminished vision has been reported with the use of tenoxicam and other nonsteroidal anti-inflammatory drugs. If such symptoms develop this drug should be discontinued and an ophthalmologic examination performed, ophthalmic examination should be carried out at periodic intervals in any patient receiving this drug for an extended period of time.

Hypersensitivity Reactions: As with other NSAIDs, allergic reactions may occur. Manifestation of allergic reactions include urticaria, bronchospasm and anaphylaxis and in rare instances, severe skin reactions such as Stevens-Johnson syndrome and Lyell Syndrome.

Drug Interactions: ASA or Other NSAIDs: Plasma concentrations of tenoxicam are reduced to approximately 80% of their normal concentrations when single doses of tenoxicam are administered in conjunction with ASA (2 600 to 3 900 mg/day). At steady state, simultaneous administration of ASA does not appear to have a significant effect on the plasma concentration of tenoxicam. The use of tenoxicam in conjunction with ASA or another nonsteroidal anti-inflammatory agent is not recommended since data are not available demonstrating that the combination produces greater improvement than that achieved with either drug alone, and the potential for adverse reactions is increased.

Protein-Bound Drugs: As with other NSAIDs, tenoxicam is highly protein-bound, and therefore, might be expected to displace other protein-bound drugs, such as anticoagulants, oral hypoglycemics (sulfonylureas), phenytoin and sulfonamides.

Short-term pharmacodynamic studies have demonstrated that tenoxicam does not potentiate the anticoagulant effect of coumarin-type anticoagulants nor the hypoglycemic effect of sulfonylurea drugs. However, when a NSAID such as tenoxicam is administered concomitantly with anticoagulants, oral hypoglycemics or other highly protein bound drugs, the patients should be monitored and dosage adjustments made, if necessary.

Diuretics/Antihypertensives: As with other nonsteroidal anti-inflammatory drugs, tenoxicam can attenuate the blood pressure lowering effect of hydrochlorothiazide and the peak excretion rates of Naand Clin patients with hypertension. Therefore, close monitoring of patients on this drug combination is advisable. The excretion of electrolytes was not significantly affected when tenoxicam (two-day loading dose of 40 mg daily, followed by 20 mg daily) was administered to normotensive patients receiving furosemide therapy (40 mg daily).

Some NSAIDs have been reported to reduce the antihypertensive effects of certain beta-blockers. The interaction between tenoxicam and beta-blockers has not been studied.

Digoxin: In elderly patients, with normal plasma creatinine levels, plasma digoxin levels were not altered by the concomitant administration of tenoxicam (30 mg daily).

Antacids: The administration of 15 mL of an aluminum hydroxide or an aluminum and magnesium hydroxide antacid just prior to a single 20 mg oral dose of tenoxicam did not affect the bioavailability of tenoxicam.

Cholestyramine: The average half-life of tenoxicam, after a single 20 mg i.v. dose, was reduced from 67.4 hours to 31.9 hours following the administration of cholestyramine (4 g in 200 mL water orally t.i.d.). The apparent drug clearance of tenoxicam increased by 105%.

Lithium: Nonsteroidal anti-inflammatory agents have been reported to increase steady state plasma lithium concentrations. It is recommended that these concentrations be monitored when initiating, adjusting and discontinuing tenoxicam treatment.

Methotrexate: The co-administration of some NSAIDs and methotrexate has been associated with reduced renal tubular secretion of methotrexate, higher plasma concentrations and severe methotrexate toxicity. Therefore, caution should be exercised when NSAIDs such as tenoxicam, are administered concurrently with methotrexate. The interaction between tenoxicam and methotrexate has not been studied.

Adverse Reactions: The most common adverse reactions encountered with nonsteroidal anti-inflammatory drugs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred on occasion, particularly in the elderly.

In approximately 12 000 patients administered tenoxicam 10 to 40 mg/day, (approximately four/fifths receiving 20 mg/day), the incidence of peptic ulceration and the incidence of gastrointestinal bleeding (including hematemesis and melena) was 0.1 to 0.6%.

The approximate incidences of other adverse effects listed by systems are summarized below.

Gastrointestinal (10.4 to 23.0%): dyspepsia (0.1 to 9.7%), nausea (2.0 to 6.7%), constipation (0.5 to 2.9%), abdominal pain (0.7 to 3.3%), diarrhea (0.5 to 2.3%), flatulence (0.04 to 1.9%), vomiting (0.2 to 1.1%), ulcerative stomatitis (0.1 to 0.7%), gastritis (0.1 to 0.8%), esophagitis (0.2%), abdominal discomfort (1.4 to 2.2%), pyrosis (1.3 to 1.9%), epigastric discomfort (0.2 to 0.4%), epigastric pain (1.8 to 2.5%), hyperacidity (0.02 to 0.4%), anorexia (0.05 to 0.4%), indigestion (0.1 to 0.2%), meteorism (0.2 to 0.4%), gastric pressure (0.5 to 1.0%), mouth dryness (0.1 to 0.3%). Glossitis, stomatitis, dysphagia and reflux esophagitis were each reported in less than 0.1% of the patients.

Dermatologic (1.6 to 3.9%): rash (0.2 to 1.4%), pruritus (0.3 to 1.3%), sweating (0.06 to 0.3%), exanthema (0.2 to 0.3%), itching (0.05 to 0.4%). Photosensitivity reaction, seborrhea, urticaria, eczema and nail disorder were each reported in 0.1% or less of the patients. One case of angioedema was also reported.

CNS (2.0 to 9.1%): headache (0.9 to 4.3%), dizziness (0.8 to 3.3%), malaise (0.04 to 0.8%), paresthesia (0.02 to 0.5%), somnolence (0.1 to 0.7%), vertigo (0.2 to 0.4%), confusion (0.2%), fatigue (0.1 to 0.9%), depression (0.6%), insomnia (0.1 to 0.2%). Leg cramps, nervousness, fever and paresis were each reported in 0.1% of the patients.

Cardiovascular: hypertension (0.02 to 0.3%), palpitations (0.02 to 0.2%), flushing (0.02 to 0.03%), purpura (0.02 to 0.2%). Tachycardia was reported in less than 0.1% of the patients.

Hematologic: anemia (0.04 to 0.3%), leukopenia (0.04 to 0.4%). Thrombocytopenia was reported in 0.1% or less of the patients.

Renal: hematuria (0.02 to 0.2%), edema (0.2 to 1.3%), micturition frequency (0.02 to 0.3%), polyuria (0.03 to 0.1%). Dysuria, cystitis, increased BUN, increased creatinine and albuminuria were each reported in less than 0.1% of the patients. Isolated cases of abnormal renal function and one case of renal failure were reported.

Hepatic (0.06 to 0.4%): abnormal hepatic function (0.3%). Jaundice, increased AST (SGOT), ALT (SGPT), gamma GT and bilirubin were each reported in less than 0.1% of the patients. Hepatitis, hepatic coma and hepatic failure were each reported once.

Respiratory (0.02 to 0.65%): dyspnea (0.2%), bronchospasm (0.1%).

Eyes, Ears, Nose, Throat: vision abnormal (0.02 to 0.3%). Diplopia, conjunctivitis, tinnitus, deafness, epistaxis and abnormal lacrimation were each reported in 0.1% or less of the patients.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Cases of overdose with tenoxicam have not been reported. In the event of overdosage, supportive and symptomatic therapy is indicated.

Dosage And Administration: A single daily dose of 20 mg should be taken orally at the same time each day. Higher doses should be avoided as they do not usually achieve a significantly greater therapeutic effect, but may be associated with a higher risk of adverse events.

In some patients a 10 mg daily dose may be sufficient. The smallest effective dose should be prescribed.

Geriatrics: As with other NSAIDs, tenoxicam should be used with special caution in elderly patients since they may be less able to tolerate side effects than younger patients. They are also more likely to be receiving concomitant medication or to have impaired hepatic, renal or cardiovascular function.

Availability And Storage: Each yellow, film-coated, oblong tablet, single scored on one side, imprinted ROCHE, contains: tenoxicam 20 mg. Nonmedicinal ingredients: cornstarch, hydroxypropyl methylcellulose, iron oxide, lactose, magnesium stearate, talc and titanium dioxide. White, opaque high density polyethylene bottles of 100. Store at 15 to 30°C. (Shown in Product Recognition Section)

MOBIFLEX® Roche Tenoxicam Anti-inflammatory – Analgesic

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