THERAPEUTIC INDICATIONS

- Chronic inflammatory rheumatism

- Abarticular rheumatism

- Attack of gout or chrondrocalcinosis

- Acute arthritis and polyarthritis

- Sciatica and low back pain

- Congestive exacerbation in osteoarthritis

POSOLOGY AND METHOD OF ADMINISTRATION

Profenid® E-100 : 1 tablet 2 or 3 times daily or according to physician’s prescription during meal.

Special Populations:

Elderly: It is advisable to reduce the initial dosage and maintain such patients on the minimal effective dose. Individual adjustment may be considered, only after good individual tolerance has been ascertained (see Pharmacokinetics sections).
Children: The safety and effectiveness of ketoprofen tablets, capsules, and suppositories have not been established.
Hepatic impairment: These patients should be carefully monitored and kept at the minimal effective daily dosage (see Precautions section and Pharmacokinetics section).
Renal impairment: It is advisable to reduce the initial dosage and maintain such patients on the minimal effective dose. Individual adjustment may be considered, only after good individual tolerance has been ascertained (see Pharmacokinetics sections).

CONTRA-INDICATIONS

Ketoprofen is contraindicated in patients who have a history of hypersensitivity reactions to ketoprofen, acetylsalicylic acid or other NSAIDs, such as asthmatic attacks or other allergic-type reactions to ketoprofen, ASA or other NSAIDs. Severe, rarely fatal, anaphylactic reactions have been reported in such patients.

Ketoprofen is also contraindicated in the following cases:

o Severe heart failure

o Active or history of peptic ulcer/hemorrhage

o History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy

o Severe hepatic insufficiency

o Severe renal insufficiency

o Third trimester of pregnancy

o Rectitis or proctorrhagia history (rectal administration)

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

Warning

Undesirable effects may be minimized by using the minimum effective dose for the shortest duration necessary to control symptoms

Gastrointestinal reactions : 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 inhibitor or anti-platelet agents such as aspirin or nicorandil;
Gastrointestinal bleeding, ulceration and perforation : GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events
Elderly : the elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.
Cardiovascular recations
Clinical studies and epidemiological data suggest that use of non-aspirin NSAID, particularly at high doses and with long-term treatment, may be associated with an increased risk of arterial thrombotid events (for example myocardial infarction or stroke).
As with existing uncontrolled hypertention, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease, as well as, before initiating long term treatment in patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidemia, diabetes mellitus, smoking).
An increased risk for arterial thrombotic events has been reported in patients treated with non-aspirin NSAIDS for perioperative pain in the setting of coronary artery bypass surgery (CABG)
Skin reactions

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. 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.

~~- Cardiovascular Risk:~~

o NSAIDs may cause in increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. The risk factors for cardiovascular disease may be at greater risk.

~~o Ketoprofen is contraindicated for the treatment of peri-operative pain in the setting of coronary artery by pass graft (CABG) surgery.~~

Precaution:

Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and non selective NSAIDs of up to three years duration have shown an increase risk of serious cardiovascular (CV) thrombotic events, myocardial infractions, and stroke, which can be fatal.
All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAIDs, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptom of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of acetyl salicylic acid mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of acetyl salicylic acid and an NSAID does increase the risk of serious GI events.
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain the first 10-14 days following CABG surgery found an increase incidence of myocardial infraction and stroke.
Hypertension
NSAIDs, including PROFENID® E-100 can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs including PROFENID® E-100, should be use with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment with PROFENID® E-100 and throughout the course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients with taking NSAIDs, including PROFENID® E-100. PROFENID® E-100 should be used with caution in patients with fluid retention or heart failure.
Gastrointestinal (GI) Effect-Risk of GI Ulceration, Bleeding and Perforation
NSAIDs, including PROFENID® E-100 can cause serious gastrointestinal events, including inflammation, 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. Only one in five patients, who develop serious upper GI adverse events of NSAIDs therapy, is symptomatic. 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 with longer duration of use, increasing the like hood of developing a serious GI event at some time, during the course of therapy. However, event short-term therapy is not without risk.
NSAIDs should be prescribes with extreme caution in patients with prior history of ulcer disease of gastrointestinal bleeding. Patients with prior history of ulcer disease and/or gastrointestinal bleeding and who use NSAIDs, have a greater than 10-fol higher risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increased the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general helath status. Most spontaneous report of fatal GI events are in the elderly or debilitated patients, and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event, in patients treated with NSAIDs, the lowest effective dose should be used for the shortestpossible duration. Patients and physicians should remain alert for sign and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.
Patients with past history of peptic ulcer
NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated
At the start of treatment, renal function must be carefully monitored in patients with heart failure, cirrhosis and nephrosis, in patients receiving diuretic therapy or in patients with chronic renal impairment. In these patients, administration of ketoprofen may induce a reduction in renal blood flow caused by prostaglandin inhibition and lead to renal decompensation
Increased risk of atrial fibrillation has been reported in association with the use of NSAIDs.
As with other NSAIDs, in the presence of an infectious disease, it should be noted that the anti-inflammatory, analgesic, and the antipyretic properties of ketoprofen may mask the usual signs of infection progression such as fever
In patients with abnormal liver-function tests, or with history of liver disease, transaminases level should be evaluated periodically, particularly during long term therapy. Rare cases of jaundice and hepatitis have describes with ketoprofen.
If visual disturbances such as blurred vision occur, treatment should be discontinued.
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.

INTERACTIONS

Not recommended drug associations :

Other NSAIDs (including cyclooxygenase-2 selective inhibitors) and high dose salicylates: Increased risk of gastrointestinal ulceration and bleeding.
Anticoagulants (heparin and warfarin) and platelet aggregation inhibitors (i.e. ticlopidine, clopidogrel): Increased risk of bleeding. If coadministration is unavoidable, patient should be closely monitored.
Lithium: 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.
Methotrexate at doses greater than 15 mg/week: increased risk of haematologic toxicity of methotrexate, particularly if administered at high doses (>15 mg/week), possibly related to displacement of protein-bound methotrexate and to its decreased renal clearance. In patients the first week previously ketoprofen therapy, treatment by ketoprofen should be interrupted for at least 12 hours before administration of methotrexate. When ketoprofen is to be administered following the end of methotrexate therapy, a period of at least 12 hours also be observed before initiation of treatment.

Drug associations requiring precautions for use

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding. 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.
Diuretics: 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 co administration therapy and renal function monitored when the treatment is started
ACE inhibitors and Angiotensin II Antagonists: 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.
Pentoxifylline: there is an increased risk of bleeding. More frequent clinical and bleeding time monitoring is required.
Tenofovir; Concimitant administration of tenofovir disoproxil fumarate and NSAIDs may increase the risk of renal failure.
Nicorandil: In patients concomitantly receiving nicorandil and NSAIDs, there is an increased risk for severe complications such as gastrointestinal ulceration, perforation and hemorrhage.
Cardiac glycosides: A pharmacokinetic interaction between ketoprofen and digoxin has not been demonstrated. However, caution is advised, in particular in patients with renal impairment, since NSAIDs may reduce renal function and decrease renal clearance of cardiac glycoside
Cyclosporin; increased risk of nephrotoxicity
Tacrolimus: Increased risk of nephrotoxicity.

Drug associations to be taken into account:

Antihypertensive agents (beta-blockers, angiotensin converting enzyme inhibitors, diuretics): risk of decrease in antihypertensive potency (inhibition of vasodilatator prostaglandins by NSAIDs).
Thrombolytics: there is an increased risk of bleeding.
Probenecid: concomitant administration of probenecid may markedly reduce the plasma clearance of ketoprofen.
Selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding.
Gemeprost: the efficacy of Gemeprost may be reduced
IUD: the efficacy of IUDs may be reduced and result in a pregnancy

PREGNANCY AND LACTATION

Pregnancy:

During the first and second trimester:

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.

During the third trimester of pregnancy:

All prostaglandin synthetase inhibitors including ketoprofen may induce cardiopulmonary and renal toxicity in the fetus. At the end of the pregnancy, prolonged bleeding time in both the mother and child may occur. Therefore, ketoprofen is contraindicated during the last trimester of pregnancy.

Lactation:

No data are available on excretion of ketoprofen in human milk. Ketoprofen is not recommended in nursing mothers

UNDESIRABLE EFFECTS

Blood and lymphatic system disorders

rare: haemorrhagic anaemia
unknown: agranulocytosis, thrombocytopenia, bone marrow failure, hemolytic anemia, leucopenia
Immune system disorders
unknown: anaphylactic reactions (including shock)
Psychiatric disorders
unknown: depression, hallucinations, confusion, mood altered

Nervous system disorders

uncommon: headache, dizziness, somnolence
rare: paraesthesia
unknown: aseptic meningitis, convulsions, dysgeusia, vertigo

Eye disorders

rare: vision blurred

Ear and labyrinth disorders

rare: tinnitus

Cardiac disorders

unknown: exacerbation of heart failure, atrial fibrillation

Vascular disorders

unknown: hypertension, vasodilatation, vasculitis (including leukocytoclastic vasculitis).

Respiratory, thoracic and mediastinal disorders

rare: asthma
unknown: bronchospasm (particularly in patients with known hypersensitivity to ASA and other NSAIDs)

Gastrointestinal disorders

common: dyspepsia, nausea, abdominal pain, vomiting
uncommon: constipation, diarrhoea, flatulence, gastritis
rare: stomatitis, peptic ulcer
unknown: exacerbation of colitis and Crohn’s disease, gastrointestinal haemorrhage and perforation

Hepatobiliary disorders

rare: hepatitis, transaminases increased

Skin and subcutaneous disorders

uncommon: rash, pruritis
unknown: photosensitivity reaction, alopecia, urticaria, angioedema, bullous eruption including Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis.

Renal and urinary disorders

unknown: renal failure acute, tubulointerstitial nephritis, nephritic syndrome, renal function tests abnormal

General disorders and administration site conditions

uncommon: oedema

Metabolism and nutritional disorders

Unknown: hyponatremia, hyperkalemia

Investigations

rare: weight increased

OVERDOSAGE

Cases of overdose have been reported with doses upt to 2.5 g of ketoprofen. In most instances, the symptoms observed have been benign and limited to lethargy, drowsiness, nausea, vomiting and epigastric pain.

There are no specific antidotes to ketoprofen overdosages. In cases of suspected massive overdosages, a gastric lavage is recommended and symptomatic and supportive treatment should be instituted to compensate for dehydration, to monitor urinary excretion and to correct acidosis, if present.

If renal failure is present, hemodialysis may be useful to remove circulating drug.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties :

Ketoprofen is a non-steroidal anti-inflammatory arylcarboxylic acid derivative belonging to the propionic acid group of NSAIDs. Ketoprofen has anti-inflammatory, antipyretic properties and has central and peripheral analgesic activity. However, its mode of action is not fully explained. It inhibits prostaglandin synthetase and platelet aggregation.

PHARMACOKINETIC PROPERTIES

General characteristics

Absorption:

Ketoprofen is rapidly and completely absorbed from the gastrointestinal tract. Maximal plasma levels are reached within 60 to 90 minutes after oral administration (45 to 60 minutes after rectal administration). When ketoprofen is administered with food, the rate of absorption is slowed, resulting in delayed and reduced peak concentration (Cmax); however, its total bioavailibility is not altered.

Distribution:

The drug is 99% bound to plasma protein. Ketoprofen diffuses into synovial fluid and in intraarticular, capsular, synovial and tendon tissues. Ketoprofen crosses the blood brain barrier and the placenta barrier. The plasma elimination half-life is approximately 2 hours.

The volume of distribution is approximately 7 L.

Metabolism:

The biotransformation of ketoprofen is characterised by two main processes, hydroxylation and conjugation with glucuronic acid, the latter being the main pathway in man.

Excretion of ketoprofen as unchanged drug is very low (less than 1%). Almost all administered ketoprofen is excreted as metabolites in urine, of which 65 to 85% of administered dose is excreted as a glucuronide metabolite.

Elimination:

50% of the administered dose is excreted in the urine within 6 hours following drug administration. Within five days following the oral administration, approximately 75 to 90% of the dose are mainly excreted in the urine. Fecal excretion is very low (1 to 8%).

Special populations:

- Elderly patients: absorption of ketoprofen is not modified; there is an increased half-life (3 h) and decreased renal and plasma clearance.

- Patient with renal insufficiency: There is a decreased renal and plasma clearance and increased half-life correlated with severity of renal failure.

- Patient with hepatic insufficiency: There are no significant changes in the plasma clearance and elimination half-life. However, the unbound fraction is approximately doubled.

Presentation

Box of 100 enteric coated tablet (10 blisters @ 10 tablets)

Reg No.: DKL0121201015B1

Manufactured by

PT Aventis Pharma, Jakarta Indonesia

Date of revision: 7 April 2016

Date of revision 5 Feb 2018 (Based on approval 01 August 2017)

This information is intended for Health Care Professional only. See local product information for full details information

PROFENID E-100