Roxifen Forte

Roxifen Forte is indicated for symptomatic relief of osteoarthritis, rheumatoid arthritis or ankylosing spondylitis.

Due to its safety profile , Roxifen Forte is not a first line option should an NSAID be indicated. The decision to prescribe Roxifen Forte should be based on an assessment of the individual patient's overall risks.

Roxifen Forte gel is a non-steroidal anti-inflammatory agent indicated for a variety of conditions characterised by pain and inflammation, or stiffness. It is effective in the treatment of osteoarthritis of superficial joints such as the knee, acute musculoskeletal injuries, periarthritis, epicondylitis, tendinitis, and tenosynovitis.

The prescription of Roxifen Forte should be initiated by physicians with experience in the diagnostic evaluation and treatment of patients with inflammatory or degenerative rheumatic diseases.

The maximum recommended daily dose is 20 mg.

Undesirable effects may be minimised by using the minimum effective dose for the shortest duration necessary to control symptoms. The benefit and tolerability of treatment should be reviewed within 14 days. If continued treatment is considered necessary, this should be accompanied by frequent review.

Given that piroxicam has been shown to be associated with an increased risk of gastrointestinal complications, the need for possible combination therapy with gastro-protective agents (e.g. misoprostol or proton pump inhibitors) should be carefully considered, in particular for elderly patients.

Use in the elderly

Elderly, frail or debilitated patients may tolerate side-effects less well 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.

For oral administration. To be taken preferably with or after food.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

Roxifen Forte Gel is for external use only. No occlusive dressings should be employed.

Apply 1g of gel, corresponding to 3cm, and rub into the affected site three to four times daily leaving to residual material on the skin. Therapy should be reviewed after 4 weeks.

Use in Children: Dosage recommendations and indications for use of Roxifen Forte Gel in children have not been established.

Use in the elderly: No special precautions are required.

History of gastro-intestinal ulceration, bleeding or perforation.

Patient history of gastrointestinal disorders that predispose to bleeding disorders such as ulcerative colitis, Crohn's disease, gastrointestinal cancers or diverticulitis.

Patients with active peptic ulcer, inflammatory gastrointestinal disorder or gastrointestinal bleeding.

Concomitant use with other NSAIDs, including COX-2 selective NSAIDs and acetylsalicylic acid at analgesic doses.

Concomitant use with anticoagulants.

History of previous serious allergic drug reaction of any type, especially cutaneous reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Hypersensitivity to the active substance or the excipients, previous skin reaction (regardless of severity) to piroxicam, other NSAIDs and other medications.

Patients in whom aspirin and other non-steroidal anti-inflammatory drugs induce the symptoms of asthma, nasal polyps, angioedema or urticaria.

Severe heart failure.

During the last trimester of pregnancy.

Roxifen Forte Gel should not be used in those patients who have previously shown hypersensitivity to Roxifen Forte in any of its forms, or any of the other ingredients. The potential exists for cross sensitivity to aspirin and other non-steroidal anti-inflammatory agents.

Roxifen Forte Gel should not be given to patients in whom aspirin and other non-steroidal anti-inflammatory agents induce the symptoms of asthma, nasal polyps, angioneurotic oedema or urticaria.

The clinical benefit and tolerability should be re-evaluated periodically and treatment should be immediately discontinued at the first appearance of cutaneous reactions or relevant gastrointestinal events.

Gastrointestinal (GI) Effects, Risk of GI Ulceration, Bleeding, and Perforation

NSAIDs, including piroxicam, can cause serious gastrointestinal events including bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs.

NSAID exposures of both short and long duration have an increased risk of serious GI event. Evidence from observational studies suggests that piroxicam may be associated with a high risk of serious gastrointestinal toxicity, relative to other NSAIDs.

Patients with significant risk factors for serious GI events should be treated with piroxicam only after careful consideration.

The possible need for combination therapy with gastro-protective agents (e.g. misoprostol or proton pump inhibitors) should be carefully considered.

Serious GI Complications

Identification of at-risk subjects

The risk for developing serious GI complications increases with age.).).

Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be administered piroxicam with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.

Skin reactions

Life-threatening cutaneous reactions (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) have been reported with the use of piroxicam.

Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.

If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, piroxicam treatment should be discontinued. 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 piroxicam, piroxicam must not be re-started in this patient at any time.

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. Evidence from observational studies suggests that piroxicam may be associated with a higher risk of serious skin reaction than other non-oxicam 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. Piroxicam should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Roxifen Forte should be used with caution in patients with renal, hepatic and cardiac impairment. In rare cases, non-steroidal anti-inflammatory drugs may cause interstitial nephritis, glomerulitis, papillary necrosis and the nephrotic syndrome. Such agents inhibit the synthesis of the 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 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 with congestive heart failure, liver cirrhosis, nephrotic syndrome and overt renal disease; such patients should be carefully monitored whilst receiving NSAID therapy. Because of reports of adverse eye findings with non-steroidal anti-inflammatory drugs, it is recommended that patients who develop visual complaints during treatment with Roxifen Forte have ophthalmic evaluation.

Impaired female fertility

The use of Roxifen Forte may impair female 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 Roxifen Forte should be considered.

Roxifen Forte 0.5% Gel is not suitable for use in children under 12 years of age.

The gel should not be used for any condition other than those specified.

Life-threatening cutaneous reactions (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) have been reported with the systemic administration of Roxifen Forte. These reactions have not been associated with topical Roxifen Forte, but the possibility of occurring with topical Roxifen Forte cannot be excluded.

Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.

If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, Roxifen Forte treatment should be discontinued.

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 Roxifen Forte, Roxifen Forte must not be re-started in this patient at any time.

If local irritation develops, the use of the gel should be discontinued and appropriate therapy instituted as necessary.

Keep away from the eyes and mucosal surfaces. Do not apply to any sites affected by open skin lesions, dermatoses or infection.

NSAIDs, including Roxifen Forte, may cause interstitial nephritis, nephrotic syndrome and renal failure. There have also been reports of interstitial nephritis, nephrotic syndrome and renal failure with topical Roxifen Forte, although the causal relationship to treatment with topical Roxifen Forte has not been established. As a result, the possibility that these events may be related to the use of topical Roxifen Forte cannot be ruled out.

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

None known.

Gastrointestinal: These are the most commonly encountered side-effects but in most instances do not interfere with the course of therapy.

Objective evaluations of gastric mucosa appearances and intestinal blood loss show that 20mg/day of Roxifen Forte administered either in single or divided doses is significantly less irritating to the gastrointestinal tract than aspirin.

Some epidemiological studies have suggested that piroxicam is associated with higher risk of gastrointestinal adverse reactions compared with some NSAIDs, but this has not been confirmed in all studies. Administration of doses exceeding 20mg daily (of more than several days duration) carries an increased risk of gastrointestinal side effects, but they may also occur with lower doses.

Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment. The possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should therefore be borne in mind.

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).

Liver function: Changes in various liver function parameters have been observed. Although such reactions are rare, if abnormal liver function tests persist or worsen, if clinical symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g.eosinophilia, rash etc.), Roxifen Forte should be discontinued.

Other: Routine ophthalmoscopy and slit-lamp examination have revealed no evidence of ocular changes.

The systemic absorption of Roxifen Forte 0.5% Gel is very low. In common with other topical NSAIDs, systemic reactions occur infrequently. Mild to moderate local irritation, erythema, pruritus, and dermatitis may occur at the application site.

Gastrointestinal: nausea, dyspepsia, abdominal pain and gastritis have been reported.

Respiratory, thoracic and mediastinal disorders: There have been isolated reports of bronchospasm and dyspnoea.

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported very rarely.

Contact dermatitis, eczema and photosensitivity skin reaction have also been observed from post-marketing experience.

Reporting of suspected adverse reactions

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 (Website: www.mhra.gov.uk/yellowcard).

In the event of overdosage with Roxifen Forte, supportive and symptomatic therapy is indicated. Studies indicate that administration of activated charcoal may result in reduced re-absorption of piroxicam, thus reducing the total amount of active drug available.

Although there are no studies to date, haemodialysis is probably not useful in enhancing elimination of piroxicam since the drug is highly protein-bound.

Overdose is unlikely to occur with this topical preparation.

Piroxicam is a non-steroidal anti-inflammatory agent which also possesses analgesic and antipyretic properties. Oedema, erythema, tissue proliferation, fever and pain can all be inhibited in laboratory animals by the administration of piroxicam. It is effective regardless of the aetiology of the inflammation. While its mode of action is not fully understood, independent studies in vitro as well as in vivo have shown that piroxicam interacts at several steps in the immune and inflammation responses through:

Inhibition of prostanoid synthesis, including prostaglandins, through a reversible inhibition of the cyclo-oxygenase enzyme.

Inhibition of neutrophil aggregation.

Inhibition of polymorphonuclear cell and monocyte migration to the area of inflammation.

Inhibition of lyosomal enzyme release from stimulated leucocytes.

Reduction of both systemic and synovial fluid rheumatoid factor production in patients with seropositive rheumatoid arthritis.

It is established that piroxicam does not act by pituitary-adrenal axis stimulation. In-vitro studies have not revealed any negative effects on cartilage metabolism.

Pharmacotherapeutic group: Anti-inflammatory preparations, non-steroids for topical use (ATC code M02AA07).

Roxifen Forte inhibits the enzyme cyclo-oxygenase. This is a basic characteristic of non-steroidal anti-inflammatory drugs, which allows them to influence many physiological processes.

Depending on the site of action, NSAID may;

- reduce the vascular phase of inflammation,

- decrease sensitisation of nociceptors to stimulation,

- act as an antipyretic,

- inhibit the secondary phase of platelet aggregation,

- affect the motility of bronchi and of the uterus,

- cause a dose dependent decrease in renal blood flow particularly in patients with renal impairment,

- lead to the activation of free radicals by neutrophils,

- affect the permeability of the foetal umbilical arterial canal,

- interfere with the renal resorption of uric acid,

- affect the gastric mucosa leading to ulceration of the muscularis mucosa.

Roxifen Forte's pharmacological profile is based on the inhibition of prostaglandin synthesis from arachidonic acid in vitro, of collagen-induced aggregation of human and animal platelets in vitro, of the release of lysosomal enzymes, of the generation of the reactive superoxide anion, of chemostaxis/migration of neurophils, macrophages, monocytes, platelets, of the carrageenin-induced foot oedema in rats, of the benzoquinone-induced writhing in mice, of E.coli-induced fever in rats and of urate crystal-induced synovitis.

Piroxicam is well absorbed following oral or rectal administration. With food there is a slight delay in the rate but not the extent of absorption following administration. The plasma half-life is approximately 50 hours in man and stable plasma concentrations are maintained throughout the day on once-daily dosage. Continuous treatment with 20mg/day for periods of 1 year produces similar blood levels to those seen once steady state is first achieved.

Drug plasma concentrations are proportional for 10 and 20mg doses and generally peak within 3 to 5 hours after medication. A single 20mg dose generally produces peak piroxicam plasma levels of 1.5 to 2 mcg/ml while maximum plasma concentrations, after repeated daily ingestion of 20mg piroxicam, usually stabilise at 3 to 8 mcg/ml. Most patients approximate steady state plasma levels within 7 to 12 days.

Treatment with a loading dose regimen of 40mg daily for the first 2 days followed by 20mg daily thereafter allows a high percentage (approximately 76%) of steady state levels to be achieved immediately following the second dose. Steady state levels, area under the curves and elimination half-life are similar to that following a 20mg daily dose regimen.

A multiple dose comparative study of the bioavailability of the injectable forms with the oral capsule has shown that after intramuscular administration of piroxicam, plasma levels are significantly higher than those obtained after ingestion of capsules during the 45 minutes following administration the first day, during 30 minutes the second day and 15 minutes the seventh day. Bioequivalence exists between the two dosage forms.

A multiple dose comparative study of the pharmacokinetics and the bioavailability of Roxifen Forte FDDF with the oral capsule has shown that after once daily administration for 14 days, the mean plasma piroxicam concentration time profiles for capsules and Roxifen Forte FDDF were nearly superimposable. There were no significant differences between the mean steady state C_max values, C_min values, T½, or T_max values. This study concluded that Roxifen Forte FDDF (Fast Dissolving Dosage Form) is bioequivalent to the capsule after once daily dosing. Single dose studies have demonstrated bioequivalence as well when the tablet is taken with or without water.

Piroxicam is extensively metabolised and less than 5% of the daily dose is excreted unchanged in urine and faeces. Piroxicam metabolism is predominantly mediated via cytochrome P450 CYP 2C9 in the liver. One important metabolic pathway is hydroxylation of the pyridyl ring of the piroxicam side-chain, followed by conjugation with glucuronic acid and urinary elimination.

Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be administered piroxicam with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.

Pharmacogenetics:

CYP2C9 activity is reduced in individuals with genetic polymorphisms, such as the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from two published reports showed that subjects with heterozygous CYP2C9*1/*2 (n=9), heterozygous CYP2C9*1/*3 (n=9), and homozygous CYP2C9*3/*3 (n=1) genotypes showed 1.7-, 1.7-, and 5.3-fold higher piroxicam systemic levels, respectively, than the subjects with CYP2C9*1/*1 (n=17, normal metabolizer genotype) following administration of an oral single dose. The mean elimination half life values of piroxicam for subjects with CYP2C9*1/*3 (n=9) and CYP2C9*3/*3 (n=1) genotypes were 1.7- and 8.8-fold higher than subjects with CYP2C9*1/*1 (n=17). It is estimated that the frequency of the homozygous*3/*3 genotype is 0% to 5.7% in various ethnic groups.

A study in man examining skin biopsies following Roxifen Forte gel administration concluded that Roxifen Forte rapidly permeates through the stratum corneum into the epidermis/dermis after application of the gel with plasma levels being low.

A separate study in man demonstrated mean plasma concentrations of Roxifen Forte gel to be approximately 5% of those observed after equivalent doses of oral or intramuscular Roxifen Forte. In healthy subjects or patients following the administration of a single oral dose, the pharmacokinetics of Roxifen Forte are linear, with maximum plasma concentration usually being obtained in about 2 h, but this can vary from 1-6 h in different subjects. It has a low clearance rate of approximately 45 h, but the half-life can vary from 30-60 h. After repeated doses of 20 mg daily, steady - state concentrations are generally achieved in 7-12 days; with a peak plasma concentration ranging from 4.5-2.2 mg/l.

In humans it penetrates into the synovial fluid of patients with rheumatoid arthritis, osteoarthritis, and reactive synovitis where mean concentrations are approximately 40% of those in plasma; it is also demonstrable in synovial tissues. Concentrations of Roxifen Forte in breast milk are about 1% of those in the maternal plasma at the same time. Overall, Roxifen Forte is 99% bound to plasma protein. Pharmacokinetics of the drug do not appear to be age related, and renal function has only a limited influence on its elimination, but plasma concentrations are increased in patients with severe liver dysfunction.

Roxifen Forte is eliminated by biotransformation in the liver. The major route is by hydroxylation, with the resultant products being excreted alone or as a glucuronide in urine and faeces. The metabolites of Roxifen Forte have little or no anti-inflammatory activity in animal models. Approximately 10% of an oral dose is excreted as unchanged drug in 10 days.

None stated.

There are no preclinical data of relevance to the prescriber which are additional to those included elsewhere in the SPC.

None stated.

The metabolism of Roxifen Forte is inhibited by cimetidine and it itself can inhibit antipyrine metabolism.

No special requirements.

Pierce the tube by reversing the cap and screwing down to break the seal on the tube. Apply 3cm (1¼” approximately) of the gel on the affected area. Rub the gel into the skin until the gel disappears. Do this three or four times a day. For muscle sprains and strains, you should start to feel better within one week. If the pain has not got any less after a week, tell your pharmacist or doctor. Replace the cap after use.

Wash hands after each application unless it is the hand that is being treated.