Source: Health Products Regulatory Authority (ZA) Revision Year: 2023 Publisher: Kiara Health (Pty) Ltd, 72 Steel Road, Spartan, Kempton Park, 1619, South Africa
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see 4.2 Posology and method of administration and GI and cardiovascular 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.
The elderly has an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation (PUBs) which may be fatal (see 4,2 Posology and method of administration).
NSAIDs, including PIXICAM 20, 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. Epidemiological evidence suggests that PIXICAM 20 may be associated with a high risk of serious gastrointestinal toxicity, relative to other NSAIDs (see4.1 Therapeutic Indications and 4.2 Contraindications)
Patients with significant risk factors for serious GI events should be treated with PIXICAM 20 only after careful consideration (see 4.2 Contraindications)
The possible need for combination therapy with gastro-protective agents (e.g. misoprostol or proton pump inhibitors) should be carefully considered (see 4,2 Posology and method of administration).
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 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 PIXICAM 20 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 PIXICAM 20 treatment. Patients should be asked to report any new or unusual abdominal symptom during treatment. If a gastrointestinal complication is suspected during treatment, PIXICAM 20 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 congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. PIXICAM 20 is contraindicated in patients with moderate to severe heart failure (see Section 4.3 Contraindications).
Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and 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 PIXICAM 20.
Patients with uncontrolled hypertension, mild congestive heart failure, established ischaemic heart disease, and/or cerebrovascular disease should only be treated with PIXICAM 20 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).
Life-threatening cutaneous reactions, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of PIXICAM 20.
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, PIXICAM 20 treatment should be discontinued.
The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect medicine. Early withdrawal is associated with a better prognosis. If the patient has developed SJS or TEN with the use of PIXICAM 20, PIXICAM 20 must not be restarted in this patient at any time.
There have been reports of fixed drug eruption (FDE) with PIXICAM 20. Do not reintroduce PIXICAM 20 in patients with a history of piroxicam-related FDE. There is potential for cross reactivity with other oxicams. Piroxicam should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
PIXICAM 20 should be used only after strict assessment of the benefit-risk ratio in inducible porphyria.
In rare cases, NSAIDs 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 medicinal product may precipitate overt renal insufficiency, 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 those with chronic cardiac insufficiency, liver cirrhosis, nephrotic syndrome or overt renal disease, and patients after recent major surgery. Therefore, such patients should be carefully monitored whilst receiving nonsteroidal anti-inflammatory therapy.
PIXICAM 20 may induce hepatitis and jaundice with fatal outcome. Though rarely, treatment should be discontinued, if abnormal liver values persist or deteriorate, if clinical symptoms suggesting hepatopathy or systemic symptoms (e.g. eosinophilia, exanthema) occur.
Because of reports of adverse eye findings with non-steroidal anti-inflammatory medicinal products, it is recommended that patients who develop visual complaints during treatment with PIXICAM 20 have ophthalmic evaluation.
Patients who are known or suspected to be poor CYP2C9 metabolisers based on previous history/experience with other CYP2C9 substrates should be administered PIXICAM 20 with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.
Patients suffering from hay fever, nasal polyps or chronic obstructive respiratory diseases as well as patients with hypersensitivity to other non-steroidal antiphlogistics/analgesics may use PIXICAM 20 only while heeding certain precautionary measures and under direct medical monitoring, as they are at higher risk of allergic reactions. These can manifest themselves as asthmatic attacks (so-called analgesic asthma), Quincke’s oedema or urticaria.
Special caution is also required in patients with allergic reactions to other substances, as they are also at elevated risk of experiencing hypersensitivity reactions when using PIXICAM 20.
Like other NSAIDs PIXICAM 20 can inhibit thrombocyte aggregation and prolong bleeding time. This has to be considered if evaluating bleeding time.
Longer-term administration of PIXICAM 20 requires regular monitoring of the blood picture (haemoglobin, haematocrit), blood coagulation, as well as hepatic and renal function.
During longer-term high-dosed, improper use of analgesics, headache may occur which must not be treated with elevated doses of the medicinal product. Quite in general, habitual intake of analgesics, particularly in combination with several analgesic agents may lead to permanent renal damage with the risk of renal failure (analgesic nephropathy).
It is recommended when administering PIXICAM 20 in patients with hepatic or renal disease in history to check the hepatic or renal function periodically. Regular monitoring of these functions during treatment is particularly indicated in elderly patients who often exhibit progressive reduction of these functions with age.
PIXICAM 20 contains lactose. Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption or fructose intolerance should not take PIXICAM 20
As with other NSAIDs, the use of PIXICAM 20 together with acetylsalicylic acid or concomitant use with other NSAIDs, including other piroxicam formulations, must be avoided, since data are inadequate to show that such combinations produce greater improvement than that achieved with PIXICAM 20 alone; moreover, the potential for adverse reactions is enhanced (see 4.4 Special warnings and precautions for use). Human studies have shown that concomitant use of PIXICAM 20 and acetylsalicylic acid reduces the plasma PIXICAM 20 concentration to about 80% of the usual value.
Concomitant administration of PIXICAM 20 and glucocorticoids increases the risk of gastrointestinal ulceration or bleeding (see 4.4 Special warnings and precautions for use and 4.8 Undesirable effects).
Concurrent intake of probenecid may result in a delay of excretion of PIXICAM 20.
Concurrent intake of cimetidine may result in a delay of excretion of PIXICAM 20 and thus in an enhancement in its adverse reactions.
Co-administration of PIXICAM 20 and phenytoin or lithium may increase the serum level of these medicinal products.
If PIXICAM 20 and lithium preparations are administered concurrently, monitoring of lithium concentrations in blood is necessary and dose adaption recommended if PIXICAM 20 treatment is initiated, adapted or discontinued.
Co-administration of PIXICAM 20 and potassium-sparing diuretics as well as potassium-containing medicinal products may lead to an increased potassium level in serum.
PIXICAM 20 can attenuate the effect of diuretics and antihypertensives and renal damage may occur.(sufficient fluid intake necessary, blood pressure should be monitored). Patients should be adequately hydrated, and the need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter.
Administration of PIXICAM 20 prior to or following administration of methotrexate may lead to increased methotrexate serum concentration due to reduced excretion of methotrexate and subsequently to increased adverse reactions (combination should be avoided).
NSAIDs, including PIXICAM 20 may enhance the effects of anticoagulants, such as warfarin. Therefore, the use of PIXICAM 20 with concomitant anticoagulants such as warfarin is contraindicated. (see 4.3 Contraindications).
Increased risk of gastrointestinal bleeding (see 4.4 Special warnings and precautions for use).
Co-administration of PIXICAM 20 and ciclosporin may increase the risk of gastrointestinal, renal or hepatic damage (combination should be avoided and the PIXICAM 20 dose reduced, respectively.
Renal and hepatic function should be monitored.
There is a possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
PIXICAM 20 is highly protein-bound and might displace other protein-bound medicinal products thereby increasing their (adverse) effects.
NSAIDs are reported to increase the blood concentration of these medicinal products. However, this was not observed in a study with PIXICAM 20.
Cholestyramine may increase PIXICAM 20 elimination.
Concomitant administration may lead to fluctuations of blood glucose levels. Therefore, blood glucose levels should be monitored intensively.
When PIXICAM 20 is given in combination with quinolone antibiotics, there is a possible increased risk of convulsions.
NSAIDs, including PIXICAM 20, may interfere with mifepristone-mediated termination of pregnancy.
Based on the mechanism of action of NSAIDs, the use of PIXICAM 20 may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Consider withdrawal of NSAIDs, including PIXICAM 20, in women who have difficulties conceiving or who are undergoing investigation of infertility (see Section 4.4 Special warnings and precautions for use).
Safety during pregnancy and lactation has not yet been established. Use of PIXICAM 20 is contraindicated in the last trimester of pregnancy (see Section 4.3 Contraindications). Regular use of non-steroidal anti-inflammatory drugs such as PIXICAM 20 during the third trimester of pregnancy, may result in premature closure of the foetal ductus arteriosus in utero, and possibly, in persistent pulmonary hypertension of the new-born. The onset of labour may be delayed, and its duration increased.
Piroxicam is distributed into breast milk. Since clinical safety has not been established, PIXICAM 20 is not recommended for use in nursing mothers.
The effects of PIXICAM 20 on the ability to drive and use machines have not been investigated. If central nervous side effects such as fatigue, dizziness, drowsiness, and vertigo occur during administration of PIXICAM 20 at higher dose, the ability to drive and/or to use machines can be impaired in the individual case. This applies to a higher extent in combination with alcohol. If affected, patients should not drive or operate machinery.
The evaluation of undesirable effects is based on the following information on frequency:
Frequent: (≥1/10), (≥1/100 up to <1/10)
Less frequent: (≥1/1 000 up to <1/100), (≥1/10 000 up to <1/1 000), (<1/10 000)
Not known: cannot be estimated from the available data
Frequent: Anaemia, eosinophilia, leucopenia, thrombocytopenia
Not known: Aplastic anaemia, haemolytic anaemia
Not known: Anaphylaxis, serum sickness
Frequent: Anorexia, hyperglycaemia
Less frequent: Hypoglycaemia
Not known: Fluid retention
Not known: Depression, dream abnormalities, hallucinations, insomnia, mental confusion, mood alterations, nervousness
Frequent: Dizziness, headache, somnolence, vertigo
Not known: Paraesthesia
Less frequent: Blurred vision
Not known: Eye irritations, swollen eyes
Frequent: Tinnitus
Not known: Hearing impairment
Less frequent: Palpitations.
Not known: Cardiac failure**
Not known: Vasculitis, hypertension**, arterial thrombotic events**
Not known: Bronchospasm, dyspnoea, epistaxis
Frequent: Abdominal discomfort, abdominal pain, constipation, diarrhoea, epigastric distress, flatulence, nausea, vomiting, indigestion
Less frequent: Stomatitis
Not known: Gastritis, gastrointestinal bleeding (including melaena and haematemesis), pancreatitis, perforation, ulceration, exacerbation of colitis and Crohn’s disease, ulcerative stomatitis
Not known: Fatal hepatitis*** or jaundice***
Frequent: Pruritis, skin rash
Less frequent: Severe cutaneous adverse reactions (SCARs), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (see Section 4.4 Special warnings and precautions for use
Not known: Alopecia, angioedema, dermatitis exfoliative, erythema multiforme, nonthrombocytopenic purpura (Henoch-Schoenlein), onycholysis, photoallergic reactions, urticaria, vesiculo bullous reactions, fixed drug eruption (see Section 4.4 Special warnings and precautions for use)
Not known: Nephrotic syndrome, glomerulonephritis, interstitial nephritis****, renal failure.
Not known: Female fertility decreased
Frequent: Oedema (mainly of the ankle)**
Not known: Malaise
Frequent: Reversible elevations of BUN, increased serum transaminase levels***, weight increase
Less frequent: Reversible elevations of creatinine
Not known: Positive ANA, weight increase, decreases in haemoglobin and haematocrit unassociated with obvious gastrointestinal bleeding
* The most commonly observed adverse events are gastrointestinal in nature.
** Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.
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 4.4 Special warnings and precautions for use).
*** Changes of several liver function parameters have been observed. As with most other nonsteroidal anti-inflammatory medicinal products in some patients increased serum transaminase levels during treatment with PIXICAM 20 may occur (see 4.4 Special warnings and precautions for use).
**** In rare cases, NSAIDs may cause acute interstitial nephritis. 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, such as in severe congestive heart failure, dehydration, nephrotic syndrome, cirrhosis of the liver, or pre-existing renal disease.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. 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/Publications/Index/8.
Not applicable.
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