Piroxicam 10 Mg Capsules Hard

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Piroxicam 10 mg capsules, hard

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 10 mg piroxicam.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Capsule, hard

Opaque blue body/opaque pink cap size 2 capsule marked ‘’PM10’’ and ‘’G’’ containing a white powder.

4.1 Therapeutic indications

Piroxicam is indicated for symptomatic relief of osteoarthritis, rheumatoid arthritis or ankylosing spondylitis in adults and older patients.

Due to its safety profile (see sections 4.2, 4.3 and 4.4), Piroxicam is not a first line option should an NSAID be indicated. The decision to prescribe Piroxicam should be based on an assessment of the individual patient’s overall risks (see sections 4.3 and 4.4).

4.2 Posology and method of administration

Posology

The prescription of piroxicam 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 older patients.

Older people

Older people, 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 older patients who are more likely to be suffering from impaired renal, hepatic or cardiac function.

Paediatric population

The safety and efficacy of Piroxicam has not been established in children and adolescents. Piroxicam use is not recommended in children and adolescents.

Method of administration

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

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• 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.

• Previous skin reactions (regardless of severity) to piroxicam, other NSAIDs and other medication.

• 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.

4.4 Special warnings and precautions for use

Undesirable effects may be minimised by using the minimum effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).

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

Gastrointesinal (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 (see sections 4.3 and below).

The possible need for combination therapy with gastro-protective agents (e.g. misoprostol or proton pump inhibitors) should be carefully considered (see section 4.2).

Serious GI complications

Identification of at-risk subjects

The risk for developing serious GI complications increases with age. Age over 70 years is associated with high risk complications. The administration to patients older than 80 years should be avoided.

Patients taking concomitant oral corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or anti-platelet agents such as low-dose acetylsalicylic acid are at increased risk of serious GI complications (see below and section 4.5). As with other NSAIDs, the use of piroxicam in combination with protective agents (e.g. misoprostol or proton pump inhibitors) must be considered for these at-risk patients.

Patients and physicians should remain alerted for signs and symptoms of GI ulceration and/or bleeding during piroxicam treatment. Patients should be asked to report any new or unusual abdominal symptom during treatment. If a gastrointestinal complication is suspected during treatment, piroxicam should be discontinued immediately and additional clinical evaluation and treatment should be considered.

Cardiovascular and cerebrovascular effects

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.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with piroxicam after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

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 piroxicam.

Respiratory disorders

Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma (see section 4.3), since piroxicam has been reported to cause bronchospasm in such patients.

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 (see section 5.2).

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 (see section 4.8). 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.

Cardiovascular, renal and hepatic impairment

Piroxicam 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 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 non-steroidal anti-inflammatory drug may precipitate overt renal decompensation which is typically followed by recovery to pretreatment state upon discontinuation of non-steroidal anti-inflammatory therapy. Patients at greatest risk of such a reaction are those with congestive heart failure, liver cirrhosis, nephrotic syndrome and overt renal disease, such patients should be carefully monitored whilst receiving non-steroidal antiinflammatory drug 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 piroxicam have ophthalmic evaluation.

Impaired female fertility

The use of piroxicam 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 piroxicam should be considered (see section 4.6).

4.5 Interaction with other medicinal products and other forms of interaction

Antacids: Concomitant administration of antacids had no effect on piroxicam plasma levels.

Anticoagulants: NSAIDs, including piroxicam, may enhance the effects of anticoagulants, such as warfarin. Therefore the use of piroxicam with concomitant anticoagulant such as warfarin should be avoided (see section 4.3).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs):

increased risk of gastrointestinal bleeding (see section 4.4).

Aspirin and other non-steroidal anti-inflammatory drugs: Piroxicam, like other non-steroidal anti-inflammatory drugs decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined.

As with other NSAIDs, the use of piroxicam together with acetylsalicylic acid or concomitant use with other NSAIDs, including other piroxicam formulations, must be avoided, since data are inadequate to show that combinations produce greater improvement that that achieved with piroxicam alone; moreover, the potential for adverse reactions is enhanced (see section 4.4). Human studies have shown that concomitant use of piroxicam and acetylsalicylic acid reduces the plasma piroxicam concentration to about 80% of the usual value.

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Ciclosporin, tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with ciclosporin or tacrolimus.

Cimetidine: Results of two separate studies indicate a slight but significant increase in absorption of piroxicam following cimetidine administration but no significant changes in elimination rate constants or half-life. The small increase in absorption is unlikely to be clinically significant.

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

Digoxin, digitoxin: Concurrent therapy with piroxicam and digoxin, or piroxicam and digitoxin, did not affect the plasma levels of either drug.

Diuretics: Non-steroidal anti-inflammatory drugs may cause sodium, potassium and fluid retention and may interfere with the natriuretic action of diuretic agents. These properties should be kept in mind when treating patients with compromised cardiac function or hypertension since they may be responsible for the worsening of those conditions.

Highly protein-bound drugs: Piroxicam is highly protein-bound and therefore might be expected to displace other protein-bound drugs. The physician should closely monitor patients for change when administering Piroxicam to patients on highly protein-bound drugs.

Lithium: Non-steroidal anti-inflammatory drugs, including piroxicam, have been reported to increase steady state plasma lithium levels. It is recommended that these levels are monitored when initiating, adjusting and discontinuing Piroxicam

Piroxicam, like other non-steroidal anti-inflammatory drugs, may interact with the following drugs / classes of therapeutic agents:

Antihypertensives - antagonism of the hypotensive effect

Methotrexate - reduced excretion of methotrexate, possibly leading to acute toxicity Quinolone antibiotics - possible increased risk of convulsions

Mifepristone - NSAIDs could interfere with mifepristone-mediated termination of pregnancy. NSAIDs should not be used for 8 - 12 days after administration of mifepristone.

4.6 Fertility, pregnancy and lactation

Pregnancy

While no teratogenic effects were seen in animal testing, the safety of piroxicam during pregnancy has not yet been established. Piroxicam inhibits prostaglandin synthesis and release through a reversible inhibition of the cyclo-oxygenase enzyme. This effect, as with other non-steroidal antiinflammatory drugs has been associated with an increased incidence of dystocia and delayed parturition in pregnant animals when drug administration was continued into late pregnancy. Congenital abnormalities have been reported in association with piroxicam administration in man; however, these are low in frequency and do not appear to follow any discernible pattern.

In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the ductus arteriosus), use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (see section 4.3).

Inhibition of prostaglandin synthesis might adversely affect pregnancy. Data from epidemiological studies suggest an increased risk of spontaneous abortion after use of prostaglandin synthesis inhibitors in early pregnancy. In animals, administration of prostaglandin synthesis inhibitors has been shown to result in increased pre- and post- implantation loss.

NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

Breastfeeding

A study indicates that piroxicam appears in breast milk at about 1% to 3% of the maternal plasma concentrations. No accumulation of piroxicam occurred in milk relative to that in plasma during treatment for up to 52 days.

Piroxicam is not recommended for use in nursing mothers as clinical safety in neonates has not been established.

Fertility

Based on the mechanism of action, the use of NSAIDs, including piroxicam may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of NSAIDs, including, piroxicam should be considered.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Where the frequency of the adverse reaction has been determined, the following convention for frequency is used:

common (>1/100,<1/10); uncommon (>1/1000 to <1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data).

	Common	Uncommon	Rare	Very rare	Not known
Blood and lymphatic system disorders	Anaemia Leucopenia Eosinophilia Thrombocytopenia				Aplastic anaemia, Haemolytic anaemia
Immune system disorders					Hypersensitivity reactions such as anaphylaxis Serum sickness
Metabolism and nutrition disorders	Anorexia Hyperglycaemia	Hypoglycaemia			Fluid retention
Psychiatric disorders					Insomnia, Depression, Nervousness, Hallucinations, Mood alterations, Dream abnormalities, Mental confusion
Nervous system disorders	Somnolence Dizziness Headache Vertigo				Paraesthesia
Eye disorders		Blurred vision			Swollen eyes Eye irritations
Ear and labyrinth disorders	Tinnitus				Hearing impairment
Cardiac disorders		Palpitations			Cardiac failure Arterial thrombotic events (for example myocardial infarction or stroke)
Vascular disorders					Hypertension Vasculitis
Respiratory, thoracic and mediastinal disorders					Bronchospasm Dyspnoea Epistaxis
*Gastrointestinal disorders	Epigastric distress, Nausea, Vomiting, Constipation, Abdominal Discomfort, Flatulence, Diarrhoea, Abdominal pain and indigestion.	Stomatitis			Pancreatitis Gastritis Gastrointestinal bleeding (including hematemesis and melena) Perforation Ulceration

Hepatobiliary disorders				Fatal hepatitis Jaundice
Skin and subcutaneous tissue disorders	Skin rash Pruritus		Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.4).	Dermatitis exfoliative Erythema multiforme Angioedema Nonthrombocytopenic purpura (Henoch-Schoenlein) Onycholysis Alopecia, Urticaria Vesiculo bullous reactions Photoallergic reactions.
Renal and urinary disorders		Interstitial nephritis, nephrotic syndrome, renal failure, renal papillary necrosis.
Reproductive system and breast disorders				Female fertility decreased
General disorders and administration site conditions	Oedema (mainly of the ankle)			Malaise
Investigations	Increased serum transaminase levels Weight increase			Positive ANA Weight decrease Decreases in haemoglobin and haematocrit, unassociated with obvious gastrointestinal bleeding

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 20 mg/day of piroxicam administered either in single or divided doses is significantly less irritating to the gastro-intestinal 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 20 mg daily (of more than several days duration) carries an increased risk of gastro-intestinal side-effects, but they may also occur with lower doses, see section 4.2.

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.

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.), piroxicam should be discontinued.

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

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 www.mhra.gov.uk/yellowcard.

4.9 Overdose

In the event of overdosage with Piroxicam, 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-inflammatory and anti-rheumatic products, non-steroids, oxicams, ATC code: M01AC01

Mechanism of action

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 cyclooxygenase 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.

5.2 Pharmacokinetic properties

Absorption

Piroxicam is well absorbed following oral 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 20 mg/day for periods of 1 year produces similar blood levels to those seen once steady state is first achieved.

Distribution

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

Treatment with a loading dose regimen of 40 mg daily for the first 2 days followed by 20 mg 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 20 mg daily dose regimen.

Piroxicam is extensively bound to proteins (about 99%).

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 piroxicam 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 piroxicam FDDF were nearly superimposable. There were no significant differences between the mean steady state Cmax values, Cmin values, T/, or Tmax values. This study concluded that piroxicam 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.

Biotransformation and Elimination

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.

Special populations

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 metaboliser 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.

5.3 Preclinical safety data

There are no preclinical safety data of relevance to the prescriber which are additional to that already included in other sections of the SmPC.

6.1 List of excipients

The capsules contain:

-Maize Starch -Talc.

The capsules shell contains: -Gelatin

-Erythrosine (E127)

-Indigo carmine (E132) -Titanium Dioxide (E171) -Patent Blue (E131).

The printing ink contains: -Shellac

-Iron Oxide black (E172) -Propylene Glycol - Ammonium Hydroxide (E527).

6.2. Incompatibilities

None.

6.3. Shelf Life

60 months.

6.4 Special precautions for storage

Store below 25 °C.

Blisters: Store in the original package in order to protect from moisture.

Bottles: Keep the bottle tightly closed in order to protect from moisture

6.5 Nature and contents of container

Piroxicam capsules are available either in polypropylene containers with polyethylene caps (with optional polyethylene ullage filler) or PVC/aluminium foil blisters. The pack sizes available in both pack types are 5, 7, 10, 14, 15, 20, 21, 25, 28, 30, 56, 60, 84, 90, 100, 112, 120, 168 and 180, additionally

pack sizes of 250, 500 and 1000 are available in polypropylene containers only.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Generics [UK] Ltd t/a Mylan

Station Close

Potters Bar

Herts

EN6 1TL

8 MARKETING AUTHORISATION NUMBER(S)

PL 04569/0150

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

27/02/2009

10 DATE OF REVISION OF THE TEXT

07/07/2016