Product Monograph - Surgam
ACTIONS AND CLINICAL PHARMACOLOGY
SURGAM (tiaprofenic acid), a propionic acid derivative, is a nonsteroidal anti-inflammatory agent with analgesic and antipyretic properties. Its mechanism of action, as with other nonsteroidal anti-inflammatory agents, is not yet completely known. Tiaprofenic acid is an inhibitor of prostaglandin synthetase enzymes which are known to be associated with inflammation and pain. The therapeutic effect of SURGAM does not result from pituitary-adrenal stimulation.
In vitro and ex vivo studies in different experimental models with cartilage and cultures of human chondrocytes obtained from biopsy specimens have shown that exposure to tiaprofenic acid did not depress the biosynthesis of proteoglycans nor alter the differentiation of proteoglycans secreted. The degradation of proteoglycan aggregates was inhibited. In vivo data in osteoarthritis patients showed a significant reduction in stromelysin (proteoglycanase) activity further to pre-treatment with tiaprofenic acid. These results support tiaprofenic acid as an effective inhibitor of stromelysin and also suggest a positive effect on the joint cartilage under experimental conditions in patients receiving therapeutic doses. The clinical significance of these findings is under further investigation.
Pharmacokinetics
SURGAM (tiaprofenic acid) given orally is rapidly absorbed at the gastric and duodenal levels. Peak serum levels are achieved in 30-90 minutes. It is extensively plasma protein bound (98%). Following a single dose of 200 mg the plasma half-life is approximately 1.7 hours. Food delays the absorption and the time to reach peak plasma concentrations by 10%.
SURGAM is largely eliminated in the urine as unaltered tiaprofenic acid with its two metabolites (II & III) accounting for less than 10%. These metabolites have almost no activity.
Chronic administration of SURGAM at the dosage of 200 mg t.i.d. confirmed rapid elimination and absence of accumulation. Steady state was reached after one day's treatment and plasma levels approached zero within 24 hours of the last dose.
In two groups of arthritic patients treated with SURGAM 200 mg t.i.d. and 300 mg b.i.d. receiving the drug for 7 days or more, the times to reach mean peak serum levels were respectively 78 and 50 minutes; in synovial fluid, the mean time to peak levels was approximately 4 hours for both dosages. Following a 200 mg dose, peak serum and synovial fluid levels reached 26 mcg/mL and 5.3 mcg/mL respectively and 50 mcg/mL and 7.7 mcg/mL after a 300 mg dose. At 8 hours serum blood levels were lower than those of synovial fluids but by 11 hours these levels were approximately the same.
In another study rheumatoid arthritis patients were given SURGAM 200 mg t.i.d. for 7 days. After the first dose, a fall in the synovial PGE2 level occurred inversely to a rise in drug level. The level of PGE2 remained low after one week's continuous medication. These results indicate that SURGAM reaches its target organ and is retained within the joint. It also suggests that reduction in PGE2 production is one of the ways in which tiaprofenic acid acts. The clinical significance of the relative serum and synovial fluid levels has, however, not been elucidated.
The results of a 3-month study in elderly osteoarthritis patients receiving SURGAM 300 mg b.i.d. showed no significant differences for all pharmacokinetic parameters (Cmax, Tmax, C9, AUC0-9h, t1\2) measured at weeks 0, 4, 8 and 12, thus suggesting a lack of accumulation.
Feacal blood loss at usual clinical dose was less than with usual clinical doses of ASA.
Following repeated administration of 2 capsules of SURGAM SR 300 mg once daily, Cmax was reached 4 to 8 hours later, with a significantly higher concentration at 6 hours than that obtained with the regular SURGAM tablets. Steady state was reached 12 hours after the first dose. There were no significant differences in Cmax, Cmin and AUC0-24h between the regular and the sustained release formulations.
In patients with rheumatoid arthritis treated with repeated doses of SURGAM SR 600 mg once daily, the time to synovial fluid Cmax was 8 hours and the synovial fluid AUC0-24h was approximately 36% of the plasma AUC0-24h. Twenty-four hours after the last dose, the tiaprofenic acid concentration was higher in the synovial fluid than in the plasma. The elimination half-life from synovial fluid (median: 8.6 h) was at least twice that from plasma (median: 4.2 h).
In a pharmacokinetics study in elderly patients, no accumulation of tiaprofenic acid was found following repeated once daily administration of SURGAM SR capsules. The mean half-life was 4.4 hours.
The effect of food on the bioavailability of SURGAM SR capsules is not known as no studies have been carried out.
INDICATIONS AND CLINICAL USE
SURGAM (tiaprofenic acid) is indicated for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis (degenerative joint disease).
CONTRAINDICATIONS
The following are contraindicated to the use of SURGAM (tiaprofenic acid):
- 1. Active peptic ulcer, a history of recurrent ulceration or active inflammatory disease of the gastrointestinal system.
- 2. Known or suspected hypersensitivity to the drug or other non-steroidal anti-inflammatory drugs (NSAIDs). The potential for cross-reactivity between different NSAIDs must be kept in mind.
- 3. SURGAM is contraindicated in patients with a history of asthma, whether or not induced by aspirin or non-steroidal anti-inflammatory drugs.
- 4. SURGAM should not be used in patients with the complete or partial syndrome of nasal polyps, or in whom asthma, anaphylaxis, urticaria, rhinitis or other allergic manifestations are precipitated by ASA or other nonsteroidal anti-inflammatory agents. Fatal anaphylactoid reactions have occurred in such individuals. As well, individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse effects.
- 5. Significant hepatic impairment or active liver disease.
- 6.
Severely impaired or deteriorating renal function (creatinine clearance <30 mL/min).
Individuals with lesser degrees of renal impairment are at risk of deterioration of their renal function when prescribed NSAIDs and must be monitored.
- 7. SURGAM is not recommended for use with other NSAIDs because of the absence of any evidence demonstrating synergistic benefits and the potential for additive side effects.
- 8. Pregnancy (See Warnings).
WARNINGS
- Gastrointestinal system (GI)
Serious GI toxicity, such as peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal can occur at any time, with or without symptoms in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) including SURGAM (tiaprofenic acid).
Minor upper GI problems, such as dyspepsia, are common, usually developing early in therapy. Physicians should remain alert for ulceration and bleeding in patients treated with non-steroidal anti-inflammatory drugs, even in the absence of previous GI tract symptoms.
In patients observed in clinical trials of such agents, symptomatic upper GI ulcers, gross bleeding, or perforation appear to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of patients treated for one year. The risk continues beyond one year and possibly increases.
The incidence of these complications increases with increasing dose.
- SURGAM should be given under close medical supervision to patients prone to gastrointestinal tract irritation particularly those with a history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal tract such as ulcerative colitis and Crohn's disease. In these cases the physician must weigh the benefits of treatment against the possible hazards.
- Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and instruct them to contact a physician immediately if they experience persistent dyspepsia or other symptoms or signs suggestive of gastrointestinal ulceration or bleeding.
- Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients by checking their hemoglobin periodically and by being vigilant for the signs and symptoms of ulceration and bleeding and should inform the patients of the importance of this follow-up.
- If ulceration is suspected or confirmed, or if GI bleeding occurs, SURGAM should be discontinued immediately, appropriate treatment instituted and the patient monitored closely.
- No studies, to date, have identified any group of patients not at risk of developing ulceration and bleeding. A prior history of serious GI events and other factors such as excess alcohol intake, smoking, age, female gender and concomitant oral steroid and anti-coagulant use have been associated with increased risk.
- Studies to date show that all NSAIDs can cause GI tract adverse events. Although existing data does not clearly identify differences in risk between various NSAIDs, this may be shown in the future.
Genitourinary tract
Some NSAIDS are known to cause persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of therapy with a NSAID. Some cases have become severe on continued treatment. Tiaprofenic acid appears to have a greater propensity than other NSAIDS to generate reports of cystitis. Although the reaction is generally reversible, non-recognition has led to extensive investigations and even surgical intervention, in some patients. Should urinary symptoms occur, treatment with SURGAM must be stopped immediately to obtain recovery. This should be done before any urological investigations or treatments are carried out. Before starting treatment with SURGAM, the patient should be asked to inform his/her physician of any urinary symptoms, even if the patient is familiar with these symptoms from the patient’s medical history.
Use in the Elderly
Patients older than 65 years and frail or debilitated patients are most susceptible to a variety of adverse reactions from nonsteroidal anti-inflammatory drugs (NSAIDs): the incidence of these adverse reactions increases with dose and duration of treatment. In addition, these patients are less tolerant to ulceration and bleeding. Most reports of fatal GI events are in this population. Older patients are also at risk of lower esophageal ulceration and bleeding.
For such patients, consideration should be given to a starting dose lower than the one usually recommended, with individual adjustment when necessary and under close supervision. See "Precautions" for further advice.
Cross-sensitivity
Patients sensitive to any of the non-steriodal anti-inflammatory drugs may be sensitive to any one of the other NSAIDs also. There is a risk of cross-sensitivity among aspirin and non-steroidal anti-inflammatory drugs, including the group to which tiaprofenic acid belongs. These pseudo-allergic reactions may include symptoms such as rash, urticaria, angiodema or more potentially severe manifestations (e.g. laryngeal oedema, bronchoconstriction, shock). The risk of pseudo-allergic reactions is greater in patients with recurrent rhino sinusitis, nasal polyposis or chronic urticaria. Asthmatic patients are particularly at risk of dangerous reactions. Therefore, tiaprofenic acid must not be administered to patients with asthma.
Aseptic Meningitis
In occasional cases, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissues diseases, etc.) seem to be pre-disposed. Therefore, in such patients, the physician must be vigilant to the development of this complication.
Use in pregnancy and lactation
The safe use of tiaprofenic acid in pregnancy and lactation has not been established. Although no teratogenic effects were seen in animal studies, parturition was delayed and prolonged, and there was an increase in the number of stillbirths. There is also the possible risk of premature closure of the ductus arteriosus, and development of a bleeding tendency or renal risk in the neonate. Tiaprofenic acid crosses the placental barrier and is secreted in breast milk. The use of this drug is not, therefore, recommended during pregnancy and lactation.
Use in children
The safety and efficacy of SURGAM (tiaprofenic acid) has not been established in children and its use in this age group is therefore not recommended.
Infection
In common with other anti-inflammatory drugs, tiaprofenic acid may mask the usual signs of infection. If SURGAM is used against symptoms of inflammation accompanying infectious disorders, effective anti-infective therapy is mandatory.
Fluid Balance
SURGAM may cause sodium and water retention with oedema. At the start of therapy, urine volume and renal function should be carefully monitored in patients with cardiac insufficiency, liver cirrhosis, or nephrotic syndrome and in patients on diuretics (See also Precautions).
PRECAUTIONS
Gastrointestinal system
There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow the continuation of SURGAM (tiaprofenic acid) therapy when and if these adverse reactions appear.
Renal function
Long term administration of nonsteroidal anti-inflammatory drugs to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome.
A second form of renal toxicity has been seen in patients with prerenal conditions leading to the reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and may precipitate overt renal decompensation. 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 nonsteroidal anti-inflammatory therapy is usually followed by recovery to the pre-treatment state.
SURGAM and its metabolites are eliminated primarily by the kidneys, therefore the drug should be used with great caution in patients with impaired renal function. In these cases utilization of lower doses of SURGAM should be considered and patients carefully monitored.
During long-term therapy kidney function should be monitored periodically.
Hepatic function
As with other NSAIDs, borderline elevations of one or more liver function tests may occur. Though these have been seen in up to 15% of patients treated with other NSAIDS, they have been reported in less than 1% of patients treated with SURGAM during clinical trials (See Adverse Reactions). These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. 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 more severe hepatic reaction while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with NSAIDs.
Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), this drug should be discontinued.
During long-term therapy, liver function tests should be monitored periodically. If there is a need to prescribe this drug in the presence of impaired liver function, it must be done under strict observation.
Fluid and electrolyte balance
Fluid retention and oedema have been observed in patients treated with SURGAM. Therefore, as with many other NSAIDs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. SURGAM should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention.
With NSAID treatment, there is a potential risk of hyperkalemia particularly in patients with conditions such as diabetes mellitus or renal failure; elderly patients; or in patients receiving concomitant therapy with beta-adrenergic blockers, angiotensin-converting-enzyme inhibitors or some diuretics. Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients who are at risk.
Hematology
Drugs inhibiting prostaglandin biosynthesis do interfere with platelet function to varying degrees; therefore, patients who may be adversely affected by such an action should be carefully observed when SURGAM is administered.
Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of NSAIDs are rare, but could occur with severe consequences.
Ophthalmology
Blurred and/or diminished vision has been reported with the use of SURGAM and other NSAIDs. If such symptoms develop this drug should be discontinued and an ophthalmologic examination performed; ophthalmologic examination should be carried out at periodic intervals in any patient receiving this drug for an extended period of time.
Central nervous system:
Some patients may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of SURGAM. If patients experience these side effects, they should exercise caution in carrying out activities that require alertness.
Use in elderly
SURGAM should be used with caution in the elderly, and the dosage adjusted individually.
Drug interactions
Acetylsalicylic acid (ASA) or other NSAIDs:
The use of SURGAM in addition to any other NSAID, including those over the counter ones (such as ASA and Ibuprofen) is not recommended due to the possibility of additive side effects.
Concomitant administration of acetylsalicylic acid results in decreased peak serum concentrations of SURGAM and slight increases in both clearance and apparent half-life. The clinical significance of these changes is unknown.
Drugs Affecting Blood Formation and Coagulation:
Numerous studies have shown that the concomitant use of NSAIDs and anticoagulants increases the risk of GI adverse events such as ulceration and bleeding.
SURGAM is not recommended for co-administration with vitamin K antagonists, ticlopidine, and heparin due to increased risk of hemorrhage. The possibility of interaction with thrombolytics must be taken into account.
Diuretics
SURGAM can reduce the activity of diuretics (i.e. both their diuretic and antihypertensive effects).
Anti-hypertensives
Nonsteroidal anti-inflammatory drugs can reduce the antihypertensive effect of propranolol and other beta-blockers as well as other antihypertensive agents. Co-administration of NSAIDs and ACE-inhibitors can promote impairment of renal function and/or hyperkalemia. Glucocorticoids:
Numerous studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increases the risk of GI side effects such as ulceration and bleeding. This is especially the case in older (>65 years of age) individuals.
In patients receiving concomitant steroid therapy, any reduction in steroid dosage should be gradual to avoid the possible complications of sudden steroid withdrawal.
Lithium
SURGAM can reduce the renal excretion of lithium.
Methothrexate
SURGAM can interfere with the plasma protein binding and renal clearance of methothrexate.
Other Drug Interactions
SURGAM is extensively bound to serum albumin (98%). This may lead to interaction with sulfonylurea, hypoglycemic agents, sulfonamides, phenytoin, Therefore caution should be observed when these drugs are used concurrently.
Laboratory and Diagnostic Tests
No interference known.
ADVERSE REACTIONS
The most common adverse reactions encountered with NSAIDs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred, particularly in the elderly.
In clinical trials with SURGAM (tiaprofenic acid) encompassing 1361 patients, the detailed break-down of side effects was as follows:
CLINICAL TOLERANCE
Percentage of Incidence
Short term Long Term (up to 8 wks) (3-36 mths)
! GASTROINTESTINAL (16%)
Indigestion 3.1 13.5 Nausea 5.8 8.2 Heartburn 3.3 6.0 Epigastric pain 2.5 5.3 Vomiting 1.1 4.1 Abdominal pain 2.4 3.1 Constipation 2.9 2.7 Flatulence 1.5 2.2 Diarrhea 2.9 2.2 Less than 1%
Enterocolitis 0.4 0.2 Melena 0.4 0.0
Although not seen in this series there have been
rare incidents of gastric or duodenal ulceration.
! CENTRAL NERVOUS SYSTEM (6.2%)
Dizziness 2.4 3.9 Drowsiness 0.4 3.1 Headache 2.9 3.4 Depression 0.8 1.9
Less than 1% (range 0.2 - 0.7%)
Disorientation, tinnitus, insomnia, anxiety, tiredness/weakness.
! CUTANEOUS (2.1%)
Rash, erythema, pruritus 1.7 7.2
Less than 1% (range 0.2 - 0.8%)
Dry skin, onycholysis.
! CARDIOVASCULAR (1.1%)
Hot flushes 1.0 1.4
Less than 1% (range 0.3 - 0.5%)
Chest pain, angina, bruising.
! RENAL (1.1%)
Oedema 1.2 1.9 Less than 1% (range 0.1 - 0.5%)
Incontinence, polyuria, oliguria.
! HEPATIC - Less than 1% (see LABORATORY & BIOCHEMICAL TOLERANCE)
! MISCELLANEOUS (2.2%)
Dry mouth/tongue, stomatitis 1.1 2.4 Nosebleeds 0.1 1.4
Less than 1% (range 0.1-0.5%)
Eye itching/conjunctivitis/red eyes, minor eye ulcers, blurred vision, anorexia, weight gain, cramps, dyspnea, intermenstrual bleeding/vaginal spotting, paresthesia of fingers, sneezing, sweating.
LABORATORY AND BIOCHEMICAL TOLERANCE
Combined decrease of hematocrit and hemoglobin: 2.8% of patients. Decrease of hemoglobin: 2.8% of patients. Increased white blood cell count 0.6%; decreased count 0.3%.
Increased gammaglutamic transferase and ASAT: less than 1%. Increased alkaline phosphatase from previously normal levels: less than 1%. In patients with initially high alkaline phosphatase the levels remained high or increased.
Increase in blood urea nitrogen (BUN): 2.5% of total patients (11.8% in the elderly). Increase in BUN and creatinine: 0.4% of patients.
Hyperkalemia: 2.4% of patients.
In addition, the following side effects have been reported in clinical and postmarket use of tiaprofenic acid:
Gastrointestinal: Disorders of intestinal transit, ulcer, perforation, overt or occult gastrointestinal haemorrhage resulting in anaemia.
Muco-cutaneous: Purpura, urticaria, very rarely erythema multiforme and bulbous eruptions (Stevens-Johnson syndrome or exceptionally toxic epidermal necrolysis); very rarely photosensitivity reactions.
Hypersensitivity Reactions: Asthmatic attacks, especially in subjects allergic to aspirin and other non-steroidal anti-inflammatory agents, angio-oedema, anaphylactic shock.
Haematological: thrombocytopenia, prolongation of bleeding time.
Urinary System: Urinary symptoms (bladder pain, dysuria, and frequency), haematuria or cystitis may occur. When treatment with tiaprofenic acid has been continued for months after onset of the urinary symptoms, inflammatory changes to the urinary tract, sometimes severe, have been observed and a few patients have undergone surgical procedures. Therefore, should any urinary symptom occur, treatment with tiaprofenic acid must be discontinued immediately, Complete recovery after discontinuation is the rule (See Warnings).
Nervous System: Vertigo, tinnitus, tremor.
Renal: Sodium and water retention (see Warnings). As with other NSAIDS, isolated cases of acute interstitial nephritis have been reported with tiaprofenic acid.
Hepatic: Liver test abnormalities.
Other: Palpebral oedema, palpitations.
SYMPTOMS AND TREATMENT OF OVERDOSAGE
There have been no reports of overdosage. No specific antidote is known, therefore treatment should be symptomatic and supportive. Early gastric lavage is indicated.
DOSAGE AND ADMINISTRATION
SURGAM 200 and 300 mg TABLETS
Rheumatoid arthritis
The usual initial and maintenance dose is 600 mg daily in 3 divided doses. Some patients may do well on 300 mg twice daily. The maximum daily dose is 600 mg.
Osteoarthritis
The usual initial and maintenance dose is 600 mg daily in 2 or 3 divided doses. In rare instances patients may be maintained on 300 mg daily in divided doses. The maximum maintenance daily dose is 600 mg.
SURGAM SR 300 mg SUSTAINED RELEASE CAPSULES
Rheumatoid arthritis or osteoarthritis
The initial and maintenance dose is two (2) sustained release capsules of 300 mg once daily. SURGAM SR capsules should be swallowed whole.
PHARMACEUTICAL INFORMATION
DRUG SUBSTANCE
Proper name: Tiaprofenic acid
Chemical name: Alpha-(5-benzoyl-2-thienyl) propionic acid or
5-benzoyl-alpha-methyl-2 thiophene acetic acid.
Molecular formula: C14H12O3S
Structural formula:
Molecular weight: 260.3
Physical form: White, microcrystalline powder
Solubility: Readily soluble in alcohol, chloroform and acetone; sparingly soluble in water
pKa: About 3.0
Melting point: About 95°C
COMPOSITION
SURGAM 300 mg tablets
Non-medicinal ingredients: Maize starch, Pluronic F68, magnesium stearate, talc.
SURGAM SR 300 mg capsules
Non-medicinal ingredients: Glyceryl monostearate, microcrystalline cellulose, talc.
Capsule shell: Gelatin
Cap: FD&C Blue No.2, FD&C Red No. 3, titanium dioxide
Body: FD&C Blue No.2, FD&C Red No. 3
STABILITY AND STORAGE RECOMMENDATIONS
SURGAM 300 mg tablets, SURGAM SR 300 mg capsules
Store between 15/ and 30/C. Protect from excessive heat, light and humidity.
AVAILABILITY OF DOSAGE FORM
SURGAM (tiaprofenic acid) is available as 300 mg white to creamy-white biconvex tablets, embossed with the Roussel logo on one side; the reverse side is scored with a break-line, one half embossed "SURGAM" and the other half "300".
SURGAM tablets are available in amber white opaque polyethylene bottles of 100 tablets.
SURGAM SR (tiaprofenic acid) is available as 300 mg hard gelatin capsules with a transparent pink body and opaque maroon cap printed in black with "SURGAM SR" on one side and the Roussel logo on the other, each containing off-white spheroidal pellets.
SURGAM SR is available in white opaque polyethylene bottles of 60 capsules.