P&T News: February 1995, Vol. 15, No. 8

Evolving Controversies in the Interpretation of the Gusto Trial

Alan H. Mutnick, Pharm.D.
Peer Review Status: Internally Peer Reviewed by Virend K. Somers, M.D., Assistant Professor, Division of Cardiovascular Diseases, Department of Internal Medicine

Over the past decade, considerable resources have been devoted to prevention and treatment of AMI. These efforts have resulted in improvements in health care delivery, identification and a reduction in risk factors, positive changes in lifestyle, and new treatment strategies. These factors have contributed to a 20% to 30% reduction in mortality due to AMI from 1979 to 1989. Of particular interest, aggressive thrombolytic strategies represent a significant advance in the ability to dissolve coronary artery thrombi and reduce the incidence of death. Cojunctive agents (e.g., antiplatelets, anticoagulants), adjunctive agents (e.g., beta adrenergic blockers), and invasive cardiovascular interventions have also demonstrated effects on improving prognosis (maintaining coronary artery patency) and reducing the incidence of re-infarction.

The purpose of this article is to present data from the most recently published multicenter clinical trial referred to as GUSTO (Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries) and update the reader on the current controversies surrounding the GUSTO trial.

Background
Previous international large scale clinical trials [i.e., Gruppo Italiano per lo Studio della Streptochinasi nell'lnfarto Miocardico (GISSI-I), Second International Study of Infarct Survival (ISIS-2), GISSI-2, and ISIS-3] have established the benefits of thrombolytics on decreased mortality and further defined patient selection criteria.1-4

The GISSI-I trial was the first placebo controlled study to demonstrate that intravenous streptokinase was effective in lowering mortality in patients with myocardial infarction, while the ISIS-2 trial demonstrated that aspirin alone and in combination with intravenous streptokinase significantly decreased mortality in infarct patients as compared to placebo. The GISSI-2 trial compared the two thrombolytic strategies [t-PA (alteplase, tissue pluminogen activator) and streptokinase] and evaluated the utility of subcutaneous heparin regimen on overall mortality rates.3 The results of this trial demonstrated no significant difference in mortality with respect to choice of thrombolytic or use of subcutaneous heparin. The ISIS-3 trial compared the efficacy of three thrombolytic agents, [streptokinase, anistreplase (APSAC), and double-chain-t-PA/duteplase] along with subcutaneous heparin, and again concluded that there was no significant difference among the three regimens. However, in both the GISSI-2 and ISIS-3 trials, controversy focuses on less than adequate treatment strategies for the resultant equality in outcomes for the different agents evaluated. The use of subcutaneous heparin 4 hours (GISSI-2) and 12 hours (ISIS-3) after thrombolytic treatment has made the study conclusions difficult for many American practitioners to accept and, consequently, difficult to extrapolate the results into clinical practice.

The GUSTO trial was the next logical step in the progression of large clinical studies and was designed to test the open artery hypothesis.5 The premise of the open artery hypothesis is: if a given regimen produces a better patency rate and achieves reperfusion more rapidly, then mortality should also be reduced. It was the intent of GUSTO to incorporate the most aggressive thrombolytic regimens previously used that had also been shown to be safe and effective. The trial was designed to randomize enough patients (greater than 41,000) to be able to detect a one percent mortality difference between the various treatment groups.

Gusto Study Design
Between December 1990 and February 1993, 41,021 patients with chest pain of less than 6 hours in duration and ST segment elevations were randomized into one of four treatment groups (Table 1).5 The study involved over 1,000 hospitals in over 15 countries.

Because the GUSTO trial was independently designed by a balanced international steering committee, streptokinase (SK) was recognized as the standard against which other thrombolytic strategies should be compared. Consequently, two SK arms were included in the study along with two t-PA study arms:

I. t-PA (front-loaded, Neuhaus regimen from TAPS trial) administered with intravenous heparin (also referred to as accelerated t-PA);6

II. t-PA and streptokinase administered with intravenous heparin;

III. Streptokinase administered with intravenous heparin; and

IV. Streptokinase administered with subcutaneous heparin (ISIS-3 regimen).4

TABLE 1: Thrombolytic Therapy Treatment Arms
I	II	III	IV
t-PA Alone	t-PA + SK	SK Alone	SK Alone
IV Heparain + IV t-PA alone t-PA 15 mg bolus 0.75 mg/kg over 30 minutes not greater than 50 mg t-PA 0.50 mg/kg over 60 minutes not greater than 35 mg (Total dose less than or equal to 100 mg)	IV Heparin + IV t-PA + SK t-PA + SK t-PA 1 mg/kg over 60 minutes (10% as bolus; total dose less than or equal to 90 mg) SK 1.0 million units over 60 minutes	IV Heparin + IV SK alone 1.5 million units over 60 minutes	IV SK alone 1.5 million units over 60 minutes + Heparin 12, 500 units subcutaneously every 4 hours after lytic therapy, then 12, 500 units subcutaneously twice daily

The combination regimen with t-PA and streptokinase was included in the GUSTO trial in anticipation of achieving lower rates of reocclusion after achieving rapid artery patency.7,8

Patients were randomized in a blinded fashion; however, the study was of the open-label design rather than a double-blinded design due to the four very different dosing strategies. The study design also included early administration of aspirin 160 mg followed by daily doses of 160 to 325 mg. Additionally, the intravenous beta blocker atenolol we administered (5 mg initially, repeated in 10 minutes) to all patients, if not contraindicated by preexisting conditions such as hypotension, bradycardia, or bronchospastic disease.

The primary endpoint of the GUSTO trial was 30-day mortality due to any cause. Additionally, one-year and 24-hour mortality were designated as study endpoints. The study also identified several secondary endpoints which included in-hospital adverse events such as bleeding, cardiogenic shock, reinfarction, and recurrent ischemia.

Gusto Results
There was a significant reduction in 30-day mortality with the accelerated t-PA (Treatment Arm I) as compared to any of the other three treatment strategies (p=0.001) (Table 2). There was no significant difference between the two streptokinase groups, and there was no difference in mortality between the combination thrombolytic strategy and the two streptokinase arms. The authors describe an absolute reduction in 30-day mortality with t-PA as compared to the combined streptokinase arms as 1 % (or 1 life saved per 100 patients treated with a risk reduction of 13.6 %), but it was also associated with a higher risk of in-hospital stroke (0.2 vs. 0.3 per 100), a rate which is similar to that seen in GISSI-2 and ISIS-3.4,8 Additionally, mortality rates for the accelerated t-PA arm were lower at 24 hours and at 1 year as compared to the other three treatment arms (Table 2).

TABLE 2. Results for Gusto Mortality Rates
Therapeutic Regimen	24 Hrs (%)	30 Day (%)	1 Year* (%)
I. Accelerated-dose t-PA II. Streptokinase with t-PA III. Streptokinase with IV Heparin IV. Streptokinase with SQ Heparin	2.30 2.80 2.90 2.80	6.30 7.00 7.35 7.24	7.70 8.30 8.90 8.90
____________ *Preliminary data presented, based on 55% of patients with follow-up.

The initial data presentation invokes controversy upon evaluation of the subgroup analysis. In the trial, subgroup analysis evaluated mortality findings based on age, infarct location, and time to treatment. However, due to the small numbers of patients compared in the subgroup analysis and lack of statistical power, it becomes difficult to extrapolate and generalize subgroup findings to the entire patient population.

In an editorial published in the same issue of the original GUSTO paper, Fuster made the following recommendations based on the GUSTO subgroup analysis:9

1. Streptokinase may be the appropriate agent for patients over the age of 75, those with small inferior infarctions, and those presenting more than 4 hours after the onset of symptoms.

2. t-PA is preferable in those under the age 75, who have anterior or large infections, and who present for treatment within 4 hours of the onset of symptoms.

The GUSTO trial did an excellent job of early recruitment of patients into the study. The median time to treatment postchest pain was reported to be approximately 2.5 hours. When the time to treatment was compared, the accelerated t-PA group demonstrated a consistent benefit as compared to the combined streptokinase arms with respect to reduction in 30-day mortality. The authors unequivocally concluded that the subgroup analysis data supported the use of accelerated t-PA in the 0 to 4 hour time frame. However, the raw data from the trial suggest a trend which may favor the streptokinase groups over accelerated t-PA for those patients receiving a thrombolytic 4 to 6 hours after the initial chest pain episode. The small sample size of patients who received thrombolytic treatment beyond 4 hours (23 % of study population) hinders further conclusions. What is clear is that the maximal advantage of the accelerated t-PA regimen over the streptokinase groups on 24-hour mortality is greatest in those patients receiving the agents within 4 hours of the acute event (4.3 % to 5.5% for t-PA vs. 5.4% to 6.7% for streptokinase) as compared to 8.9% to 10.4% for t-PA vs. 9.3% to 8.3% for streptokinase groups in those treated 4 to 6 hours or greater than 6 hours after the onset of chest pain. Of note is the finding that in patients treated greater than 6 hours with a thrombolytic, streptokinase had a greater benefit on mortality rates (8.3% versus 10.4%) when compared to t-PA.

Complications
In the GUSTO trial, there was no significant difference between the accelerated t-PA arm and either streptokinase arms with respect to the endpoint of stroke of "all-types" (p=0.09). In evaluating stroke of all types, the combination thrombolytic arm resulted in an excess of 3 strokes per 1,000 patients treated (p=0.02), and the accelerated t-PA arm resulted in an excess of 2 strokes per 1,000 patients treated (p=0.09) when compared to the combined streptokinase-only arms. Additionally, there was a significant excess of two hemorrhagic strokes per 1,000 patients treated in the accelerated t-PA group as compared to the combined streptokinase-treated arms (p = 0.03).

An important finding of the GUSTO trial was that treatment with thrombolytics did not result in any major complications other than stroke. A rather extensive table is included in the original published paper which depicts the differences among the various treatment arms and the incidence of complications. The GUSTO investigators state, "A consistent pattern of fewer complications was noted in the accelerated t-PA group, particularly with respect to allergic reactions, clinical indicators of left ventricular dysfunction, and arrhythmias."3 In regards to this statement, it is important to note that adjunctive therapy, beyond the use of aspirin, heparin, and atenolol, was left to the discretion of the prescribing physician. Such agents included nitrates, antiarrhythmic drugs, calcium-channel blockers, angiotensin-converting enzyme inhibitors, and digitalis, all which could have influenced complication rates among the different study groups.

The GUSTO paper fails to provide a breakdown of those patients who had left ventricular dysfunction or received additional agents; consequently, it becomes impossible to relate the incidence of major complications to the study arm alone. It would be valuable to know which patients were on digitalis, angiotensin-converting enzyme inhibitors, and other cardiovascular agents, if one is to effectively evaluate the impact of the various thrombolytic arms and the incidence of left ventricular dysfunction.

Open Artery Hypothesis
As previously stated, the major objective of the GUSTO trial was to test the concept of the "Open Artery Hypothesis." An angiographic substudy consisted of the four treatment arms and a total of 2,431 patients. This phase of the study evaluated the relationship between 90-minute patency and mortality.

Overall, the GUSTO 90-minute patency rates are similar to previous patency trials.5 Patency rates (TlMI grade 2 or 3 flow) for the combined streptokinase arms, the accelerated t-PA arm, and the dual thrombolytics arm were 58.2%, 81%, and 73%, respectively.10 This resulted in a significant difference between the accelerated t-PA arms and the combined streptokinase arms (p< 0.001). However, at the 180-minute mark, patency catch-up occurred for the streptokinase arms (Table 3). As can be seen from the Table 3, at 180 minutes, the dual thrombolytic arm had exceeded that of accelerated t-PA, and by 24 hours, 94% of vessels were either TIMI 2 or 3 grades in the dual thrombolytic arm. The investigators suggest that early (90-minute) and sustained patency (TIMI 3 flow) translated into significantly improved left ventricular function. The GUSTO investigators concluded that the data clearly support the open artery hypothesis, and that rapid and complete coronary artery patency (TIMl 3 flow) results in significant improvement in left ventricular function and will reduce mortality. There have appeared conflicting opinions regarding this statement.3,5 Subsequent authors have reported that t-PA patients had a 22 % difference in TIMI-3 flow grades at 90 minutes, but that benefit translated into a mere 1 % difference in overall mortality rates.1 Upon looking at mortality rates from the angiographic substudy, it becomes evident that despite having favorable patency rates at 90 minutes, 180 minutes, and 24 hours, the combined thrombolytic treatment arm had the highest total mortality rates at 30 days (Table 3). Some have speculated on other factors beside thrombolysis as contributors to the mortality benefits (e.g., coronary artery bypass grafting: 9.0% for accelerated t-PA versus 8.3% for streptokinase) reported in the t-PA population.

TABLE 3. Results For Gusto Angiographic Substudy[10]
Therapeutic Regimen	90 Minutes (%)*	180 Minutes (%)*	24 Hours (%)*	30 Day Mortality Rate (%)
I. Accelerated-dose t-PA II. Streptokinase with t-PA III. Streptokinase with IV Heparin IV. Streptokinase with SQ Heparin	81 73 60 54	76 85 74 73	86 94 80 77	5.3 7.8 7.5 6.5
_______ Refers to percent of vessels with TIMI grades and 3 patency rates combined.

Cost Effectiveness
It has become apparent during this past year that the use of t-PA in the United States has increased dramatically from under 50% to over 70% since the initial presentation of the GUSTO results in April 1993.3 How the GUSTO study results will change medical practice may evolve in a large part from a financial rather strictly clinical considerations.

A final part of the GUSTO paper centered around a cost-effectiveness discussion which utilized the success/failure rates along with positive/negative outcome results to determine costs per year of life saved. In calculating the cost-effectiveness of t-PA based on drug acquisition costs and life years saved, the survival benefits at 30 days and at 1 year were assumed to be maintained (i.e., the use of accelerated t-PA would save one additional life per 100 patients treaded compared to streptokinase). It has been estimated the each patient saved with front-loaded t-PA will live an additional 8 years. The additional 8 years of life may be population specific, and may increase or decrease based on the population being evaluated. The older the patient and the greater the number of comorbid factors, the smaller tire number of additional years of life expected, and hence the greater the cost per year of life saved for t-PA.

In evaluating the cost-effectiveness from GUSTO, the following equation reflects costs as well as benefits associated with the t-PA and streptokinase (SK) arms of the study: 12

PARAMETERS FROM GUSTO:*, 12 $2,200 per dose t-PA vs. $300 per dose SK; 1% reduction in mortality for t-PA vs. SK; 0.1% reduction in stroke for SK vs. t-PA. Cost-Effectiveness= Cost(t-PA) - Cost(SK) ___________________ Benefits t-PA - SK *Costs and duration of life are used for illustration purposes only, and do not reflect the actual costs from the GUSTO study.

FOR 100 PATIENTS: $220,000 - $30,000 ------------------------ 1 life saved (t-PA) - 0.1 stroke prevented (SK) Cost-effectiveness = $211,111 PER LIFE SAVED

ASSUMING 8 YEARS OF ADDITIONAL LIFE AFTER THROMBOLYTIC USE: $211,111/8 YEARS OF LIFE POST-MI $26,388 PER YEAR OF LIFE SAVED

The above analysis, utilizing the outcome results from GUSTO, reveals the it would cost society an excess of $26,000 per year for each patient surviving an acute myocardial infarction assuming the all patients received t-PA.

The next strategy is to compare the cost per life saved with accelerated t-PA to other well-accepted therapies to determine societies willingness to pay for such a modality. The GUSTO investigators, as well as representatives from the pharmaceutical industry, have compared this number to those for treating severe hypertension ($20,000) per year, dialysis in chronic renal failure ($35,000), bone marrow transplant in breast cancer ($116,000), and cholestyramine to reduce cholesterol ($180,000), and have concluded the accelerated t-PA is definitely a cost-effective modality and society should be willing to pay when compared to other more expensive modalities used to prolong life in other disease conditions.

Clinical Impact from the Gusto Trial
It has been just over 18 months since the initial release of the GUSTO study results in the New England Journal of Medicine, and several notable articles have appeared both against and in support of the GUSTO findings.11,13-15 Much of the criticism for the GUSTO findings center around perceived marketing practices for t-PA which have enabled it to capture media attention as well as the thrombolytic market. Several articles address the more important aspects of GUSTO which can be divided into several key areas:

1. Interpretation of subgroup analyses;14

2. Open-label design of GUSTO; 14,15 and

3. Proof for the open-artery hypothesis.11

The controversy over the GUSTO results will continue, and newer studies need to be developed to pick up where GUSTO left off, so that the strategies for the treatment of acute myocardial infarction can continue to evolve. However, many practitioners have already altered clinical practice based on GUSTO, similar to the response to ISIS-2, GISSI-2, and ISIS-3. We caution against such an approach, as there are still important questions which need to be addressed by those involved in GUSTO. Until these questions involving the contributions of concurrent therapies received by GUSTO patients, interpretation of pre-specified subgroup analyses, and effect of an open-label design are addressed, we offer the following commend from an article entitled, "A Response to 'Holding GUSTO Up to the Light'" by Ridker et al. Ann Intern Med 1994;120:882-5.15

1. Findings from the GISSI-2, ISIS-3, and GUSTO-1 trials indicate that the choice of thrombolytic therapy is much less important to ultimate survival than is the delay in time to onset of treatment.

2. Any potential differences in efficacy among thrombolytic agents are at most small in absolute benefit and are unlikely to pertain to most patients with myocardial infarction who present more than 4 hours after the onset of pain.

3. All thrombolytic agents appear effective when given up to 12 hours after the onset of symptoms; clinical strategies must, therefore, be adopted to increase thrombolytic use among persons arriving later regardless of which agent is chosen.

4. Due to the in-hospital delay of almost 90 minutes for thrombolytic therapy, local programs in emergency departments designed to decrease the time delay in a more effective way to save lives as compared to determining which thrombolytic agent is needed.

5. Underutilization of thrombolytic therapy in the U.S. is the most important clinical issue confronting practitioners in the medical treatment of myocardial infarction. Small differences amongst agents in terms of safety, efficacy, and ease of administration is far less important than is the wider use of this class of agents to the many patients who are not exposed to Them despite their proven clinical benefit.

Summary
The GUSTO trial was a well-controlled and balanced clinical trial which evaluated four clinical strategies for thrombolysis in acute myocardial infarction. The results of the angiographic study, though still controversial, did provide additional merit to the support for the open artery hypothesis. The comparison of intravenous vs. subcutaneous heparin with streptokinase provided no significant difference, and the dual thrombolytic arm produced disappointing results, perhaps due to the lack of accelerated t-PA. Though the GUSTO investigators suggest that accelerated t-PA combined with intravenous heparin is the best thrombolytic strategy for patients with acute myocardial infarction, they also suggest that there are different margins of benefit in certain sub-groups which will require further analysis. A multitude of health interventions must be evaluated comparatively with respect to outcomes and associated costs.

An additional concern, beyond the findings from GUSTO and all its controversies, centers around not only the high cost of thrombolytic agents, but rather healthcare practitioners' reception to pharmaceutical industry tactics which may affect one's choice of agents. The GUSTO trial cost approximately $60 million, and approximately $55 million were contributed by the manufacturer of t-PA. Therefore, it becomes even more crucial for each practitioner to review all available information on this study prior to finalizing one's treatment plan for patients in need of this therapy.

References

1. Lancet 1986;1:397-402.

2. Lancet 19S8;2:349-60.

3. Lancet 1990;336:65-71.

4. Lancet 1993;339:753-70.

5. N Engl J Med 1993;329:673-82.

6. J Am Coll Cardiol 1992;19:885-91.

7. Circulation 1988;77:1100-7.

8. Circulation 1991;84:540-9.

9. N Engl J Med 1993;329:723-4. Editorial.

10. N Engl J Med 1993;329:1615-22.

11. Ann Pharmacother 1994;28:97-8.

12. J Myocardial Ischmia 1993;5:10-1. Editorial.

13. N Engl J Med 1994;330:504-6.

14. Ann Intern Med 1994;120:876-81.

15. Ann Intern Med 1994;120:882-5.

Through October 1994, 25 cases of tendon rupture have been reported. The majority of these cases have occurred outside of this country. Seventeen of the cases were unilateral or bilateral rupture of the Achilles tendon; the remainder occurred in hand or should joints. Only seven of the cases invoked patients in whom fluoroquinolone levels exceeded the therapeutic range.

Current labeling for fluoroquinolones warns against their use in children, adolescents, pregnant women, and lactating women. These agents have caused arthropathies and produced erosion of the cartilage of weight bearing joints in immature animals in most tested species. The doses used in these studies were near the therapeutic range in humans. It has been suggested that the disruption of extracellular matrix of cartilage and the depletion of collagen seen in animals may be similar to the degradation that causes tendon ruptures in humans.

Fluoroquinolones currently available in this country include: oral and injectable ciprofloxacin, oral enoxacin, oral norfloxacin, oral norfloxacin, and oral and injectable ofloxacin.

________
Abstracted from: N Engl J Med 1995;332:193. Letter.

• Salmeterol inhalation aerosol should not be initiated in patients with significantly worsening or acutely deteriorating asthma, which mall be a life-threatening condition. Serious acute respiratory events, including fatalities, have been reported, both in the United States and worldwide, when salmeterol inhalation aerosol has been initiated in this situation. Although it is not possible from these reports to determine whether salmeterol inhalation aerosol contributed to these adverse events or simply failed to relieve the deteriorating asthma, the use of salmeterol inhalation aerosol in this setting is inappropriate.
• Salmeterol inhalation aerosol should not be used to treat acute symptoms. It is crucial to inform patients of this and prescribe a short-acting inhaled beta2-agonist for this purpose as well as warn them that increasing inhaled beta2-agonist use is a signal of deteriorating asthma.
• Salmeterol inhalation aerosol is not a substitute for inhaled or oral corticosteroids. Corticosteroids should not be stopped or reduced when salmeterol inhalation aerosol is initiated.
  
  Salmeterol is indicated for long-term, twice daily (morning and evening) administration in the maintenance treatment of asthma and in the prevention of bronchospasm in patients 12 years of age and older with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma, who require regular treatment with inhaled, short-acting beta2-agonists. It should not be used in patients whose asthma can be managed by occasional use of short-acting, inhaled beta2-agonists.
• Due to the slower onset of this beta2 agonist in comparison to albuterol, patients should be counseled to use albuterol or a similar short acting product during acute asthma attacks. Patients without a short acting product should be counseled to contact their doctor to have one prescribed.

______

1. N Engl J Med. 1994 331:1314. Letter

2. Glaxo Laboratories Serevent Product Information. Research Triangle Park, NC. December 1994.

Roche Laboratories has recently revised the product information regarding ketorolac (Toradol(R)). These revisions include updated safety information (including eight new contraindications), new dosing guidelines, and intravenous administration guidelines.

The updated safety guidelines are a result of postmarketing adverse drug reaction reports. As of October 1, 1993, the FDA had reported 146 deaths and 2,119 adverse drug reactions worldwide since 1990.1 Recent literature cites additional case reports of adverse drug reactions related to ketorolac therapy. The following table, taken from the manufacturer's package insert, overviews the contraindications and dosing revisions.2 NOTE: oral ketorolac is not stocked at UIHC.

Toradol, a nonsteroidal anti-inflammatory drug (NSAID), is indicated for the short-term (up to 5 days) management of moderately severe, acute pain, that requires analgesia at the opioid level. It is NOT indicated for minor or chronic painful conditions. Toradol is a potent NSAID analgesic, and its administration carries many risks. The resulting NSAID-related adverse events can be serious in certain patients for whom Toradol is indicated, especially when the drug is used inappropriately. Increasing the dose of Toradol beyond the label recommendations will not provide better efficacy but will result in increasing the risk of developing serious adverse events. Gastrointestinal Effects Toradol can cause peptic ulcers, gastrointestinal bleeding, and/or perforation. Therefore, Toradol is contraindicated in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding. Renal Effects Toradol is contraindicated in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion. Risk of Bleeding Toradol inhibits platelet function and is, therefore, contraindicated in patients with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete hemostasis, and those at high risk of bleeding. Toradol is contraindicated as prophylactic analgesic before any major surgery, and is contraindicated intra-operatively when hemostasis is critical because of the increased risk of bleeding. Hypersensitivity Hypersensitivity reactions, ranging from bronchospasm to anaphylactic shock, have occurred and appropriate counteractive measures must be available when administering the first dose of ToradolIV/IM. Toradol is contraindicated in patients with previously demonstrated hypersensitivity to ketorolac tromethamine or allergic manifestations to aspirin or other nonsteroidal anti inflammatory drugs (NSAIDs). Intrathecal or Epidural Administration Toradol is contraindicated for intrathecal or epidural administration due to its alcohol content. Labor, Delivery, Nursing The use of Toradol in labor and delivery is contraindicated because it may adversely affect fetal circulation and inhibit uterine contractions. The use of Toradol is contraindicated in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates. Concomitant Use with NSAlDs Toradol is contraindicated in patients currently receiving ASA or NSAIDs because of the cumulative risk of inducing serious NSAID-related side effects. Dosage and Administration ToradolORAL ToradolORAL is indicated only as continuation therapy to ToradolIV/IM, and the combined duration of use of ToradolIV/IM and ToradolORAL is not to exceed 5 (five) days because of the increased risk of serious adverse events. The recommended total daily dose of ToradolORAL (maximum 40 mg) is significantly lower than for ToradolIV/IM (maximum 120 mg). Special Populations Dosage should be adjusted for patients 65 years or older, for patients under 50 kg (110 lbs) of body weight, and for patients with moderately elevated serum creatinine. Doses of ToradolIV/IM are not to exceed 60 mg (total dose per day) in these patients.

_____________
1. F.D.C. "The Pink Sheet," November 1, 1993.

2. Roche Laboratories. Toradol Product Information. Nutley, NJ. December 1994.

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