PYROCAPS Capsule Ref.[51188] Active ingredients: Piroxicam

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 (CV) risks below).

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 PYROCAPS, can cause serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, which can be fatal.

NSAID exposures of both short and long duration have an increased risk of serious GI events (see section 4.2). Administration of doses of greater than 20 mg per day carries an increased risk of GI side effects. Evidence from observational studies reported suggests that piroxicam may be associated with a high risk of serious gastrointestinal toxicity, relative to other NSAIDs. These serious adverse events can occur at any time, with or without warning symptoms, inpatients treated with NSAIDs.

Patients with significant risk factors for serious GI events should be treated with PYROCAPS only after careful consideration (see sections 4.2, 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 of complications. The administration to patients over 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 as well as those ingesting excessive amounts of alcohol are at increased risk of serious GI complications (see below and section 4.5). As with other NSAIDs, the use of PYROCAPS 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 PYROCAPS treatment. Patients should be asked to report any new or unusual abdominal symptom during treatment. If a gastrointestinal complication is suspected during treatment, PYROCAPS should be discontinued immediately and additional clinical evaluation and treatment should be considered.

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 PYROCAPS after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular (CV) 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. The relative increase of this risk appears to be similar in those with or without known CV disease or CV risk factors. However, patients with known CV disease or CV risk factors may be at greater risk in terms of absolute incidence, due to their increased rate at baseline.

PYROCAPS should be used with caution in patients with a history of bronchial asthma (see also section 4.3).

Poor Metabolisers of CYP2C9 Substrates

Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be administered PYROCAPS 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, PYROCAPS treatment should be discontinued. The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspected medicine. Early withdrawal is associated with a better prognosis.

If the patient has developed SJS or TEN with the use of PYROCAPS, PYROCAPS 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 reported suggests that piroxicam may be associated with a higher risk of serious skin reaction than other non-oxicam NSAIDs.

Patients appear to be at a 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. PYROCAPS should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Cases of fixed drug eruption (FDE) have been reported with piroxicam. Piroxicam should not be reintroduced in patients with history of piroxicam-related FDE. Potential cross reactivity might occur with other oxicams. Piroxicam should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

PYROCAPS should be used with caution in patients with renal, hepatic and cardiac impairment. In rare cases, non-steroidal anti-inflammatory medicines 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 medicine 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 medicines, it is recommended that patients who develop visual complaints during treatment with PYROCAPS have ophthalmic evaluation.

Impaired female fertility

The use of PYROCAPS 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 PYROCAPS should be considered.

Neonatal renal impairment and Oligohydramnios

The use of PYROCAPS around 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Complications of prolonged oligohydramnios include limb contractures and delayed lung maturation, which may require invasive procedures such as exchange transfusion or dialysis. If NSAID treatment is determined necessary, limit use to the lowest effective dose and shortest duration possible.

Additionally it should be avoided at 30 weeks and later in pregnancy because of the additional risk of premature closure of the fetal ductus arteriosus. Consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours. Discontinue the NSAID if oligohydramnios occurs (see Section 4.3. 4.4 and 4.6).

Drug Reaction with Eosinophillia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as PYROCAPS. Some of these events have been fatal or lifethreatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, haematological abnormalities myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophillia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue PYROCAPS and evaluate the patient immediately.

Lactose

PYROCAPS contains lactose. Patients with rare hereditary problems of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption or fructose intolerance should not take PYROCAPS.

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

Anti-coagulants: NSAIDs, including PYROCAPS, may enhance the effects of anticoagulants, such as warfarin. Therefore, the use of PYROCAPS 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: PYROCAPS, like other nonsteroidal anti-inflammatory medicines 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 PYROCAPS 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 than that achieved with PYROCAPS alone; moreover, the potential for adverse reactions is enhanced (see section 4.4). Human studies reported 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 reported 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 PYROCAPS and digoxin, or PYROCAPS and digitoxin, did not affect the plasma levels of either medicine.

Anti-hypertensives including diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists (AIIA)and beta-blockers:

NSAIDs can reduce the efficacy of diuretics and other anti-hypertensive medicines including ACE inhibitors, AIIA and beta-blockers. In patients with impaired renal function (e.g. dehydrated patients or elderly patients with the renal function compromised), the coadministration of an ACE inhibitor or an AIIA and/or diuretics with a cyclo-oxygenase inhibitor can increase the deterioration of the renal function, including the possibility of acute renal failure, which is usually reversible.

The occurrence of these interactions should be considered in patients taking PYROCAPS with an ACE inhibitor or an AIIA and/or diuretics Therefore, the concomitant administration of these medicines should be done with caution, especially in elderly patients. Patients should be adequately hydrated and the need to monitor the renal function should be assessed in the beginning of the concomitant treatment and periodically thereafter.

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

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

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

Antihypertensives – antagonism of the hypotensive effect

Quinolone antibiotics – possible increased risk of convulsions

Mifepristone – NSAIDs could interfere with mifepristone-mediated termination of pregnancy.

Methotrexate – Reduced excretion of methotrexate, possibly leading to acute toxicity. When methotrexate is administered concurrently with NSAIDs, including PYROCAPS, NSAIDs may decrease elimination of methotrexate resulting in increased plasma levels of methotrexate. Caution is advised, especially in patients receiving high doses of methotrexate.

Care should be exercised with the use of PYROCAPS in patients with renal dysfunction. Blood-urea-nitrogen elevation has been observed in some patients. The rise in blood-urea-nitrogen is not associated with elevations in serum creatinine.

PYROCAPS decreases platelet aggregation and prolongs bleeding time. In view of the products inherent potential to cause oedema, heart failure may be precipitated in some compromised patients.

PYROCAPS should not be used in patients on coumarin-type anticoagulants. Changes in different liver function parameters have been observed. Some patients may develop increased serum transaminase levels during treatment with PYROCAPS.

It should be assumed that PYROCAPS will precipitate bronchoconstriction in those patients who are sensitive to aspirin. PYROCAPS increases plasma lithium levels.

Pregnancy

Although no teratogenic effects were reported in animal testing, the safety of piroxicam during pregnancy or during lactation has not yet been established.

PYROCAPS inhibits prostaglandin synthesis and release through a reversible inhibition of the cyclo-oxygenase enzyme. This effect, as with other non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with an increased incidence of dystocia and delayed parturition in pregnant animals when medicine administration was continued in late pregnancy. 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 reported 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 postimplantation loss.

NSAIDs should not be used during the first two trimesters of pregnancy or labour.

Pregnant women should not use PYROCAPS at 20 weeks or later unless specifically advised to do so by a health care professional because it may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Additionally it should be avoided at 30 weeks and later in pregnancy because of the additional risk of premature closure of the fetal ductus arteriosus (see Section 4.3, 4.4 and 4.6).

Breast-feeding

A reported study indicates that piroxicam appears in breast milk at about 1-3% 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 has not been established.

Fertility

Based on the mechanism of action, the use of NSAIDs, including PYROCAPS, 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 PYROCAPS, should be considered.

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

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 Piroxicam administered either in single or divided doses is significantly less irritating to the gastrointestinal tract than aspirin.

Some epidemiological studies reported 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 reported 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 (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. 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).

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 PYROCAPS is important. It allows continued monitoring of the benefit/risk balance of PYROCAPS. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/

None known.