Ketofan tablets are indicated for the management of pain and also for the treatment of primary dysmenorrhea.

Management of pain and primary dysmenorrhea:
The usual recommended dose is 25 to 50 mg, every 6 to 8 hours as necessary. The total daily dose should not exceed 300 mg.
Special population:
- Patients with impaired renal function and the 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.
-Patients with impaired hepatic function:

These patients should be carefully monitored and kept at the minimal effective daily dosage.
-Children:
The safety and effectiveness of Ketoprofen have not been established.
Administration:
The oral form should be taken with fluids, preferably with food.

Ketoprofen is contraindicated in patients who have a history of hypersensitivity reactions such as asthmatic attacks, or other allergic type reactions to Ketoprofen, acetylsalicylic acid any other ingredients in this medicine, ASA or other NSAIDs. Sever, rarely fatal, anaphylactic reactions have been reported in such patients. Ketoprofen is contraindicated in the following cases: - Active peptic ulcer. - Severe hepatic insufficiency. - Severe renal insufficiency. - Third trimester of pregnancy.

Warnings:
Cardiovascular Risk:
NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction (MI), and stroke, which can be fatal. The risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. NSAIDs are contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.
Gastrointestinal Risk:
NSAIDs cause an increased risk of serious gastrointestinal adverse events including inflammation, bleeding, ulceration, and perforation of the stomach or intestine, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal (GI) events.
Cardiovascular Effects Cardiovascular Thrombotic Events:

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 symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events.
Hypertension:
NSAIDs, including Ketoprofen Immediate-Release Capsules, can lead to onset of new hypertension or worsening of preexisting 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 Ketoprofen Immediate-Release Capsules, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
Congestive Heart Failure and Edema:
Fluid retention and edema have been observed in some patients taking NSAIDs. Peripheral edema has been observed in approximately 2% of patients taking ketoprofen. Ketoprofen Immediate-Release Capsules should be used with caution in patients with fluid retention, or heart failure.
Gastrointestinal effects:
Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 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.
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy,

To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs 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.
Renal Effects:
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greater risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Advanced Renal Disease:
No information is available from controlled clinical studies regarding the use of Ketoprofen Immediate-Release Capsules in patients with advanced renal disease. Therefore, treatment with Ketoprofen Immediate-Release Capsules is not recommended in these patients with advanced renal disease. If Ketoprofen Immediate-Release Capsules therapy must be initiated, close monitoring of the patient's renal function is advisable.
Anaphylactoid Reactions:
As with other NSAIDs anaphylactoid reactions may occur in patients without known prior exposure to Ketoprofen Immediate-Release Capsules.
Ketoprofen Immediate-Release Capsules should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see precautions). Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Skin Reactions:

NSAIDs, including Ketoprofen Immediate-Release Capsules, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
Pregnancy:
In late pregnancy, as with other NSAIDs, Ketoprofen Immediate-Release Capsules should be avoided because it may cause premature closure of the ductus arteriosus.
Precautions:
General:
Ketoprofen Immediate-Release Capsules cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
If steroid dosage is reduced or eliminated during therapy, it should be reduced slowly and the patients observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.
The pharmacological activity of Ketoprofen Immediate-Release Capsules in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Ketoprofen and other non-steroidal anti-inflammatory drugs cause nephritis in mice and rats associated with chronic administration. Rare cases of interstitial nephritis or nephrotic syndrome have been reported in humans with ketoprofen since it has been marketed.
A second form of renal toxicity has been seen in patients with conditions leading to a reduction in renal blood flow or blood volume, where renal prostaglandins have a supportive role in the maintenance of renal blood flow. In these patients, administration of a non-steroidal anti-inflammatory drug results in a dose dependent decrease in prostaglandin synthesis and secondarily, in renal blood flow which may precipitate overt renal failure. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the elderly. Discontinuation of non-steroidal anti-inflammatory drug therapy is typically followed by recovery to the pretreatment state.
Since ketoprofen is primarily eliminated by the kidneys and its pharmacokinetics are altered

by renal failure, patients with significantly impaired renal function should be closely monitored, and a reduction of dosage should be anticipated to avoid accumulation of ketoprofen and/or its metabolites.

Hepatic Effects:
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Ketoprofen Immediate-Release Capsules. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Ketoprofen Immediate-Release Capsules. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Ketoprofen Immediate-Release Capsules should be discontinued.

In patients with chronic liver disease with reduced serum albumin levels, ketoprofen's pharmacokinetics are altered. Such patients should be closely monitored, and a reduction of dosage should be anticipated to avoid high blood levels of ketoprofen and/or its metabolites.

Hematological Effects:
Anemia is sometimes seen in patients receiving NSAIDs, including Ketoprofen Immediate-Release Capsules. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Ketoprofen Immediate-Release Capsules, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Ketoprofen Immediate-Release Capsules who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Preexisting Asthma:
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Ketoprofen Immediate-Release Capsules should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Not recommended drug associations:
Other NSAIDs, including high dose salicylates, increased risk of gastrointestinal ulceration and bleeding.
Oral anticoagulants, parentral heparin and ticlopidine, increased risk of bleeding caused by platelet aggregation inhibition. If coadministration is unavoidable, patients should be closely monitored (e.g. laboratory tests such as bleeding time).
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 hematologic toxicity of Methotrexate, particularly if administered at high doses (>15 mg/week), possibly related to displacement of protein-bounded methotrexate and to its decreased renal clearance. In patients receiving Ketoprofen therapy previously, 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 should also be observed before initiation of treatment.
Drug associations requiring precautions for use:
Diuretics:
Patients and particularly dehydrated patients taking diuretics are at a 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.
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 the patient is elderly, monitoring should be done more frequently.

Pentoxifylline:
There is an increased risk of bleeding. More frequent clinical monitoring of bleeding time is required.
Drug associations to be taken into account:
Antihypertensive agents (beta-blockers, angiotensin converting enzyme inhibitors, diuretics): risk of decreased antihypertensive potency (inhibition of vasodilator prostaglandins by NSAIDs).

Thrombolytics:
Increased risk of bleeding.
Probenecid:
Concomitant administration of Probenecid may markedly reduce the plasma clearance of Ketoprofen.
Gemeprost:

The efficacy of Gemeprost may be reduced.
IUD:
The efficacy of the IUD may be reduced and result in a pregnancy.

Pregnancy:
There are no adequate studies of Ketoprofen in pregnant women. When used late in pregnancy, it may cause premature closure of the ductus arteriosus and prolong labor and delivery. Ketoprofen is only recommended for use during pregnancy when benefit outweighs risk. Ketoprofen should be avoided near term.
Lactation: There are no data on the excretion of Ketoprofen into human milk. Ketoprofen is not recommended in nursing mothers.

CNS side effects have been observed in some patients. If affected patients should not drive or operate machine.

The incidence of common adverse reactions (above 1%) was obtained from a population of 835 Ketoprofen Immediate-Release Capsules treated patients in double-blind trials lasting from 4 to 54 weeks.
Minor gastrointestinal side effects predominated; upper gastrointestinal symptoms were more common than lower gastrointestinal symptoms. In crossover trials in 321 patients with rheumatoid arthritis or osteoarthritis, there was no difference in either upper or lower gastrointestinal symptoms between patients treated with 75 mg of Ketoprofen Immediate-Release Capsules TID (225 mg/day). Peptic ulcer or GI bleeding occurred in controlled clinical trials in less than 1% of 1,076 patients; however, in open label continuation studies in 1,292 patients the rate was greater than 2%.

The incidence of peptic ulceration in patients on NSAIDs is dependent on many risk factors including age, sex, smoking, alcohol use, diet, stress, concomitant drugs such as aspirin and corticosteroids, as well as the dose and duration of treatment with NSAIDs (see warnings).
Gastrointestinal reactions were followed in frequency by central nervous system side effects, such as headache, dizziness, or drowsiness. The incidence of some adverse reactions appears to be dose related. Rare adverse reactions (incidence less than 1%) were collected from different sources.

Reactions are listed below under body system, then by incidence or number of cases in decreasing incidence.
Incidence Greater than 1% (Probable Causal Relationship)
Digestive: Dyspepsia (11%), nausea, abdominal pain, diarrhea, constipation, flatulence, anorexia, vomiting, stomatitis.
Nervous System: Headache, dizziness, CNS inhibition (i.e., pooled reports of somnolence, malaise, depression, etc.) or excitation (i.e., insomnia, nervousness, dreams, etc.).
Special Senses: Tinnitus, visual disturbance.
Skin and Appendages: Rash.

Urogenital: Impairment of renal function (edema, increased BUN)1, signs or symptoms of urinary-tract irritation.
Adverse events occurring in 3 to 9% of patients. Incidence Less than 1% (Probable Causal Relationship)

Body as a Whole: Chills, facial edema, infection, pain, allergic reaction, anaphylaxis.
Cardiovascular: Hypertension, palpitation, tachycardia, congestive heart failure, peripheral vascular disease, vasodilation.
Digestive: Appetite increased, dry mouth, eructation, gastritis, rectal hemorrhage, melena, fecal occult blood, salivation, peptic ulcer, gastrointestinal perforation, hematemesis, intestinal ulceration, hepatic dysfunction, hepatitis, cholestatic hepatitis, jaundice.
Hemic: Hypocoagulability, agranulocytosis, anemia, hemolysis, purpura, thrombocytopenia.
Metabolic and Nutritional: Thirst, weight gain, weight loss, hyponatremia.

Musculoskeletal: Myalgia.
Nervous System: Amnesia, confusion, impotence, migraine, paresthesia, vertigo.
Respiratory: Dyspnea, hemoptysis, epistaxis, pharyngitis, rhinitis, bronchospasm, laryngeal edema.
Skin and Appendages: Alopecia, eczema, pruritus, purpuric rash, sweating, urticaria, bullous rash, exfoliative dermatitis, photosensitivity, skin discoloration, onycholysis, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson Syndrome.
Special Senses: Conjunctivitis, conjunctivitis sicca, eye pain, hearing impairment, retinal hemorrhage and pigmentation change, taste perversion.

Urogenital: Menometrorrhagia, hematuria, renal failure, interstitial nephritis, nephrotic syndrome.
Incidence Less than 1% (Causal Relationship Unknown)
The following rare adverse reactions, whose causal relationship to ketoprofen is uncertain, are being listed to serve as alerting information to the physician.
Body as a Whole: Septicemia, shock.
Cardiovascular: Arrhythmias, myocardial infarction.
Digestive: Buccal necrosis, ulcerative colitis, microvesicularsteatosis, pancreatitis.
Endocrine: Diabetes mellitus (aggravated).
Nervous System: Dysphoria, hallucination, libido disturbance, nightmares, personality disorder, aseptic meningitis.

Cases of overdose have been reported with doses up 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.

Cases of overdose have been reported with doses up 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 ketoprofenoverdosages. 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.

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

Absorption

Ketoprofen immediate-release formulations are rapidly and well-absorbed, with peak plasma levels occurring within 0.5 to 2 hours.
When Ketoprofen is administered with food, its total bioavailability (AUC) is not altered; however, the rate of absorption is slowed.
Food intake reduces Cmax by approximately one-half and increases the mean time to peak concentration (tmax) from 1.2 hours for fasting subjects (range, 0.5 to 3 hours) to 2.0 hours for fed subjects (range, 0.75 to 3 hours). The fluctuation of plasma peaks may also be influenced by circadian changes in the absorption process.

Metabolism
The metabolic fate of Ketoprofen is glucuronide conjugation to form an unstable acyl-glucuronide. The glucuronic acid moiety can be converted back to the parent compound. Thus, the metabolite serves as a potential reservoir for parent drug. There are no known active metabolites of Ketoprofen. Ketoprofen has been shown not to induce drug-metabolizing enzymes.

Elimination
The elimination half-life of Ketoprofen has been reported to be from 2 to 4 hours administration of Ketoprofen immediate release formulations.
In a 24 hour period, approximately 80% of an administered dose of Ketoprofen is excreted in the urine, primarily as the glucuronide metabolite.

None

Calcium phosphate tribasic.
- Lactose monohydrate.
- Maize starch.
- Povidone K25.
- Cross carmellose sodium.
- Talc powder.
- Magnesium stearate

Not applicable.

2 years

Store below 25ºC

A chromo-duplex carton box containing a pamphlet and two blisters each of (10 KETOFAN tablets).

No special requirements.