Source: Pharmaceutical Benefits Scheme (AU) Revision Year: 2022 Publisher: sanofi-aventis australia pty ltd, 12-24 Talavera Road, Macquarie Park, NSW 2113, Toll Free Number (medical information): 1800 818 806, Email: medinfo.australia@sanofi.com
Active or a history of gastrointestinal inflammatory disorder or ulceration, haemorrhage, chronic dyspepsia.
History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
Known hypersensitivity to ketoprofen, aspirin or other NSAIDs.
Patients in whom aspirin or other non-steroidal anti-inflammatory agents induce symptoms of asthma, rhinitis or urticaria. Severe, rarely fatal anaphylactic reactions have been reported in such patients.
Third trimester of pregnancy (see Section 4.6 Fertility, pregnancy and lactation).
Severe heart failure.
Severe renal insufficiency.
Severe hepatic impairment.
Treatment of perioperative pain in setting of coronary artery bypass surgery (CABG).
Observational studies have shown that non-selective NSAIDs may be associated with an increased risk of serious CV events including myocardial infarction, stroke and heart failure, which may increase with dose or duration of use. Additionally patients with CV disease, history of atherosclerotic CV disease or risk factors for CV disease may be at greater risk. However, to minimise the potential risk of an adverse CV event, especially in patients with CV risk factors, the lowest effective dose should be used for the shortest possible duration.
There is no consistent evidence to suggest that concurrent use of aspirin mitigates the increased risk of serious CV events associated with NSAID use.
Physicians and patients should remain alert for such CV events, even in the absence of previous CV symptoms. Patients should be informed about signs and/or symptoms of serious CV toxicity and the steps to take if they occur.
An increased risk for arterial thrombotic events has been reported in patients treated with nonaspirin NSAIDS for perioperative pain in the setting of coronary artery bypass surgery (see Section 4.3 Contraindications).
NSAIDs can lead to onset of new hypertension or worsening of pre-existing hypertension. Patients taking antihypertensives along with NSAIDs may have an impaired antihypertensive response and hence NSAIDs should be administered with caution in patients with hypertension. Furthermore, when given to patients with hypertension, blood pressure should be monitored closely during initiation of NSAID treatment and at regular intervals thereafter.
Increased risk of atrial fibrillation has been reported in association with the use of NSAIDs.
Fluid retention and oedema have been observed in some patients taking NSAIDs and NSAIDs should be used with caution in patients with fluid retention or heart failure.
All NSAIDs can cause GI discomfort and serious, potentially fatal GI effects such as ulcers, bleeding and perforation which may increase with dose or duration of use, but can occur at any time without warning. Upper GI ulcers, gross bleeding or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short term therapy is not without risk.
Due to the possibility of severe gastrointestinal lesions, particular attention should be paid to any digestive disturbance and especially to gastrointestinal bleeding. This risk is especially high in patients who continue to receive anticoagulant therapy. Elderly patients are at greater risk for serious GI events. Other risk factors associated with increased risk of developing serious GI events include history of serious GI events, smoking and alcoholism. When gastrointestinal bleeding or ulcerations occur in patients receiving NSAIDs, the medicine should be withdrawn immediately. Doctors should warn patients about the signs and symptoms of serious GI toxicity and what steps to take if they occur. The risk of serious GI events associated with ketoprofen ranged from 0.03 to 1.7% with a higher incidence in elderly.
The concurrent use of NSAIDs and aspirin does increase the risk of serious GI events.
Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors, nicorandil or anti-platelet agents such as aspirin (see Section 4.5 Interactions with other medicines and other forms of interactions).
Because serious GI-tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up.
NSAIDs may very rarely cause serious cutaneous adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome (see Drug Reaction with Eosinophilia with Systemic Symptoms (DRESS)), which can be fatal and occur without warning. These serious adverse events are idiosyncratic and are independent of dose or duration of use. 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. Patients should be advised of the signs and symptoms of serious skin reactions and to consult their doctor at the first appearance of skin rash or any signs of hypersensitivity.
DRESS has been reported in patients using NSAIDs. Some of these events have been fatal or life-threatening. 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. Eosinophilia 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 the NSAID and evaluate the patient immediately.
Withdrawal of concomitant steroid therapy. It is recommended that if steroids are reduced or discontinued during ketoprofen therapy, the dose should be reduced slowly and patients should be observed closely for adverse effects particularly adrenal insufficiency an exacerbation of the symptoms of rheumatoid arthritis.
Masking of symptoms of underlying infections:
Orudis SR can mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection. This has been observed in bacterial community acquired pneumonia and bacterial complications to varicella. When Orudis SR is administered for fever or pain relief in relation to infection, monitoring of infection is advised. In non-hospital settings, the patient should consult a doctor if symptoms persist or worsen.
There have been sporadic reports of decreased haematocrit and haemoglobin values without progressive deterioration on prolonged administration of the medicine. Anaemia is commonly observed in rheumatoid arthritis patients and is sometimes aggravated by non-steroidal antiinflammatory medicines which may produce fluid retention or significant gastrointestinal blood loss in some patients. Patients on long-term treatment with NSAIDs including ketoprofen, should have their haemoglobin or haematocrit checked if they develop signs or symptoms of anaemia.
Inhibition of renal prostaglandin synthesis by NSAIDs may interfere with renal function, especially in the presence of existing renal disease. As with other NSAIDs, ketoprofen should be used with caution in patients with renal impairment. At the start of treatment and periodically, renal function must be carefully monitored in patients with heart failure, cirrhosis and nephrosis, in patients receiving diuretic therapy, in patients with chronic renal impairment, particularly if the patient is elderly. In these patients, administration of ketoprofen may induce a reduction in renal blood flow caused by prostaglandin inhibition and lead to renal decompensation. Abnormalities in LDH and BUN have occurred in patients on Orudis therapy.
Hyperkalaemia may occur, especially in patients with underlying diabetes, renal failure, and/or concomitant treatment with hyperkalaemia promoting agents. Potassium levels must be monitored under these circumstances (see Section 4.5 Interactions with other medicines and other forms of interactions).
Impaired hepatic function. Serious hepatic adverse events appear to be rare with ketoprofen. Rare cases of jaundice and hepatitis have been described with ketoprofen. With NSAIDs abnormal liver function test (such as elevation of AST, ALT and SAP) may occur in upto 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may resolve with continued therapy. Meaningful elevations (three times the upper limit of normal) of ALT or AST occurred in controlled clinical trials in less than 1% of patients.
Physicians and patients should remain alert for the hepatotoxicity. Patients should be informed about the signs and/or symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritis, jaundice, abdominal tenderness in the right upper quadrant and “flu-like” symptoms) and the steps to take should these signs and/or symptoms occur. If an abnormal liver function test occurs liver function should be monitored until it returns to normal. If a significant abnormality persists, Orudis should be discontinued. It is recommended that in those patients with a history of liver dysfunction periodic liver function test be carried out.
Plasma protein binding medicines. Orudis is highly protein bound. Concomitant use of other protein binding medicines, e.g. anticoagulants, sulphonamides and hydantoins, might necessitate modification of dosage in order to avoid increased levels of such medicines resulting from competition for plasma protein binding sites.
Adverse ophthalmological effects have been observed with non-steroidal anti-inflammatory agents; accordingly, in patients who develop visual disturbances during treatment with Orudis, treatment should be discontinued pending a complete ophthalmological examination.
Use of NSAIDs, including Orudis, from about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.
Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, it should be managed under medical supervision and limit Orudis use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if Orudis treatment extends beyond 48 hours. Discontinue Orudis if oligohydramnios occurs and follow up according to clinical practice (see Section 4.6 Fertility, pregnancy and lactation).
See Section 4.3 Contraindications, and Section 4.4 Special warnings and precautions for use – Hepatic Function.
See Section 4.3 Contraindications, Section 4.4 Special warnings and precautions for use – Renal Function and Use in the elderly, Section 4.5 – Interactions with other medicines and other forms of interactions – Digoxin and Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory medicines and thiazide diuretics.
In pharmacokinetic studies, ketoprofen clearance was reduced in older patients receiving ketoprofen, compared with younger patients. Peak ketoprofen concentrations and free drug AUC were increased in older patients. The glucuronide conjugate of ketoprofen, which can serve as a potential reservoir for the parent drug, is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. It is recommended that the initial dosage of ketoprofen should be reduced for patients over 75 years of age and it may be useful to monitor renal function. In addition, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Elderly patients may be more sensitive to the anti-prostaglandin effects of NSAIDS (on the gastrointestinal tract and kidneys) than younger patients. In particular, elderly or debilitated patients who receive NSAID therapy seem to tolerate gastrointestinal ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population. Therefore, caution should be exercised in treating the elderly, and when individualizing their dosage, extra care should be taken when increasing the dose.
See Section 4.2 Dose and method of administration.
Ketoprofen is not recommended for children under 12 years since safety and efficacy in this age group have not been established.
No data available.
The following interactions have been studied using conventional ketoprofen at a dose of 200 mg daily.
The risk of hyperkalaemia can be enhanced when ketoprofen is administered concomitantly with potassium salts, potassium-sparing diuretics, ACE inhibitors and angiotensin II antagonists, NSAIDs, heparins (low molecular-weight or unfractioned), ciclosporin, tacrolimus and trimethoprim (see Section 4.4 Special warnings and precautions for use).
Concomitant administration of magnesium hydroxide and aluminium hydroxide hydrate does not interfere with the rate or extent of the absorption of ketoprofen.
Ketoprofen may present an additive effect with other NSAIDs (increased risk of gastrointestinal ulcer and/or haemorrhage). Therefore, concomitant administration is not advised.
Ketoprofen does not alter aspirin absorption. However, in a study of 12 normal subjects, concurrent administration of aspirin decreased ketoprofen protein binding and increased ketoprofen plasma clearance from 0.07 L/kg/hour without aspirin to 0.11 L/kg/hour with aspirin. The clinical significance of these changes has not been adequately studied. Therefore, concurrent use of aspirin and ketoprofen is not recommended.
Hydrochlorothiazide given concomitantly with ketoprofen produces a reduction in urinary potassium and chloride excretion compared to hydrochlorothiazide alone. Patients and particularly dehydrated patients, taking diuretics are at greater risk of developing renal failure secondary to a decrease in renal blood flow caused by prostaglandin inhibition. Such patients should be rehydrated before initiating coadministration therapy and renal function monitored when the treatment is started.
In a study of 12 patients with congestive heart failure where ketoprofen and digoxin were concomitantly administered, ketoprofen did not alter the serum levels of digoxin. However, caution is advised, in particular in patients with renal impairment, since NSAIDS may reduce renal function and decrease renal clearance of cardiac glycosides.
There is a risk of elevation of lithium plasma levels, sometimes reaching toxic levels, due to decreased lithium renal excretion. Where necessary, plasma lithium levels should be closely monitored and the lithium dosage levels adjusted during and after NSAIDs therapy.
Increased risk of bleeding. If concomitant use is unavoidable, patient should be closely monitored including laboratory test results (bleeding time).
Increased risk of bleeding. If coadministration is unavoidable, patient should be closely monitored.
Concurrent use of NSAIDs and warfarin has been associated with severe, sometimes fatal haemorrhage. The exact mechanism of the interaction between NSAIDs and warfarin is unknown, but may involve enhanced bleeding from NSAID-induced gastrointestinal ulceration, or an additive effect of anticoagulation by warfarin and inhibition of platelet function by NSAIDs. Ketoprofen should be used in combination with warfarin only if absolutely necessary, and patients taking this combination of medicines should be closely monitored.
Probenecid increases both free and bound ketoprofen through reducing the plasma clearance of ketoprofen to about one-third as well as deceasing its protein binding. Therefore, the combination of ketoprofen and probenecid is not recommended.
Methotrexate at doses greater than 15 mg/week: Methotrexate is highly protein bound and may be displaced by NSAIDs including ketoprofen. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in severe haematologic and gastrointestinal toxicity which may lead to death.
Methotrexate at doses lower than 15 mg/week: During the first weeks of combination treatment, full blood count should be monitored weekly. If there is any alteration of the renal function, or if patient is elderly, monitoring should be more frequent.
There is increased risk of nephrotoxicity.
There is an increased risk of bleeding. More frequent clinical monitoring and monitoring of bleeding time is required.
Concomitant administration of tenofovir disoproxil fumarate and NSAIDs may increase the risk of renal failure.
In patients concomitantly receiving nicorandil and NSAIDS, there is an increased risk for severe complications such as gastrointestinal ulceration, perforation and haemorrhage (see Section 4.4 Special warnings and precautions for use – Gastrointestinal Events).
There is a risk of decrease in antihypertensive potency (inhibition of vasodilator prostaglandins by NSAIDs).
In patients with compromised renal function (e.g. dehydrated patients or elderly patients), the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure.
Concomitant use of a renin-angiotensin system inhibiting medicine (ACE-inhibitor or angiotensin receptor antagonist), an anti-inflammatory medicine (NSAID, including COX-2 inhibitor) and a thiazide diuretic may increase the risk of renal impairment. This includes use in fixed-combination products containing more than one class of medicine. The combination of these agents should be administered with caution, especially in the elderly and in patients with pre-existing renal impairment. Renal function (serum creatinine) should be monitored after initiation of concomitant therapy, and periodically thereafter.
There is an increased risk of bleeding.
The efficacy of gemeprost may be reduced.
The efficacy of IUDs may be reduced and result in a pregnancy.
Increased risk of gastrointestinal ulceration or bleeding (see Section 4.4 Special warnings and precautions for use – Gastrointestinal Events and Steroid Therapy).
Increased risk of gastrointestinal bleeding (see Section 4.4 Special warnings and precautions for use – Gastrointestinal Events).
The use of NSAIDs 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 the NSAID should be considered.
Pregnancy Category C – Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.
Data from epidemiological studies suggest an increased risk of miscarriage after the use of a prostaglandin synthesis inhibitor in early pregnancy.
Use of NSAIDs, including Orudis, from about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment (see Section 4.4 Special warnings and precautions for use).
In mice and rats there is no evidence of teratogenic or embryotoxicity. In the rabbit slight embryotoxicity likely related to maternal toxicity has been reported. As the safety of ketoprofen in pregnant women has not been evaluated, the use of ketoprofen during the first and second trimester of pregnancy should be avoided.
NSAIDs have an inhibitory effect on prostaglandin synthesis and, when given during the latter part of pregnancy, may cause cardiopulmonary (closure of the fetal ductus arteriosus) and renal toxicity. When given at term, they prolong labour and delay parturition and prolonged bleeding time in both mother and child may occur. Therefore, ketoprofen is contraindicated during the last trimester of pregnancy.
No data are available on excretion of ketoprofen in human milk. In rats, ketoprofen at doses of 9 mg/kg (54 mg/m²/day; approximately 0.3 times the maximum recommended human therapeutic dose) did not affect perinatal development. Upon administration to lactating dogs, the milk concentration of ketoprofen was found to be 4 to 5% of the plasma drug level. As with other medicines that are excreted in milk, ketoprofen is not recommended for use in nursing mothers.
Patients should be warned about the potential for somnolence, dizziness or convulsions, and advised not to drive or operate machinery if these symptoms occur.
The following adverse events have been observed with ketoprofen.
Gastrointestinal: Dyspepsia (11.5%), nausea*, abdominal pain*, diarrhoea*, constipation*, flatulence*, anorexia, vomiting, stomatitis, gastralgia.
Central nervous system: Headache*, dizziness, CNS inhibition or excitation*.
Special senses: Tinnitus, visual disturbance.
Dermatological: Rash.
Urogenital: Impairment of renal function (oedema, increased BUN)*, signs or symptoms of urinary tract irritation.
* Incidence greater than 3%
Gastrointestinal: Appetite increase, dry mouth, gastralgia, dyspepsia, abdominal pain, nausea, vomiting, diarrhoea, constipation, flatulence, eructation, gastritis, stomatitis, rectal haemorrhage, melaena, faecal occult blood, salivation, peptic ulcer, gastrointestinal perforation, haematemesis, intestinal ulceration, gastrointestinal bleeding, exacerbation of colitis and Crohn’s disease, pancreatitis.
Central Nervous System: Amnesia, confusion, impotence, migraine, paraesthesia, vertigo, fatigue, tension, anxiety, drowsiness, convulsions, depression, hallucinations, aseptic meningitis, mood disorder.
Aseptic meningitis has been reported as a potential rare adverse effect from the administration of several anti-inflammatory medications, including selective and non-selective COX inhibitors.
Special senses: Conjunctivitis, conjunctivitis sicca, eye pain, hearing impairment, retinal haemorrhage and pigmentation change, taste perversion.
Dermatological: Alopecia, eczema, pruritus, purpuric rash, sweating, urticaria, angio-oedema, bullous rash including Stevens-Johnson, toxic epidermal necrolysis, exfoliative dermatitis, photosensitivity discolouration, onycholysis, flushing, acute generalized exanthematous pustulosis.
Body as a whole: Chills, oedema, pain, allergic reaction, anaphylactic reactions (including shock).
Cardiovascular: Hypertension, palpitation, tachycardia, congestive heart failure, peripheral vascular disease, vasodilation, vasculitis (including leukocytoclastic vasculitis), bruising, exacerbation of heart failure, atrial fibrillation.
Haematological: Hypocoagulability, agranulocytosis, anaemia, haemolysis, purpura, thrombocytopenia, bone marrow aplasia, hemolytic anemia, leucopenia.
Metabolic and nutritional: Thirst, weight gain, weight loss, hepatic dysfunction, hyponatraemia, hyperkalaemia, elevations of transaminases levels, rare cases of hepatitis.
Mouth: Mouth ulcers, sore tongue, inflammation of the mouth and gum have been reported.
Infections and Infestations: Orudis SR can mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of infection (including bacterial community-acquired pneumonia and bacterial complications to varicella (Section 4.4 Special warnings and precautions for use).
Musculoskeletal: Myalgia.
Respiratory: Dyspnoea, haemoptysis, epistaxis, pharyngitis, rhinitis, laryngeal oedema, asthmatic attack, bronchospasm, (particularly in patients with hypersensitivity to aspirin and other NSAIDs).
Urogenital: Menometrorrhagia, haematuria, renal failure, abnormal renal function tests, interstitial nephritis, nephrotic syndrome.
Anorectal: These include local pain, burning, pruritus, tenesmus, rarely rectal bleeding, which have been reported in approximately 16% of patients. In clinical trials 5% of patients discontinued rectal therapy for these reasons.
Hypersensitivity reactions: Dermatological reactions, rash, pruritus, urticaria, angioedema.
Unknown: Oligohydramnios, neonatal renal impairment
Unknown: Drug Reaction with Eosinophilia with Systemic Symptoms (DRESS)
Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
