P&T News: September 1998

Troglitazone

Sara Schroeder, Pharm.D. and Jacqueline D. Joss, Pharm.D.
Peer Review Status: Internally Peer Reviewed by John H. MacIndoe, M.D., Professor, Division of Endocrinology-Metabolism, Department of Internal Medicine

Pharmacology
The most recent information on the metabolic effects of troglitazone shows that troglitazone increases insulin-mediated peripheral glucose disposal, primarily in skeletal muscle, as well as having a small effect on the liver and adipose tissue. At higher doses (greater than or equal to 600 mg/day), it has been shown to cause a small decrease hepatic glucose production . Troglitazone has antihyperglycemic effects only in the presence of insulin; however, it does not stimulate insulin production itself. For this reason, hypoglycemia is expected to be less likely in patients treated with troglitazone monotherapy. Because its mechanism of action is dependent on insulin, troglitazone is not effective in patients with Type I diabetes.1

In addition to the effects troglitazone has on fasting plasma glucose, it provides additional benefits to patients with Type 2 diabetes. In a 48-week study by Ghazzi et al , troglitazone produced significant reductions in insulin levels from 112.32 ± 98.76 pmol/1 at baseline to 82.68 ± 65.64 pmol/1 (p is less than 0.05), triglycerides decreased from 279 ± 346 mg/dl to 190 ± 122 mg/dl (p less than 0.05), and HDL was increased from 39 ± 12 mg/dl at baseline to 46 ± 13 mg/dl. These improvements are in metabolic parameters characteristically increased (TGs) and decreased (HDL) in patients with insulin resistance. In this study, troglitazone was also shown to significantly increase LDL from 135 ±36 mg/dl to 146 ± 38 mg/dl (p less than 0. 05) and total cholesterol from 218 ± 48 mg/dl to 229 ± 44 mg/dl (p less than 0. 05).

Efficacy
Troglitazone has been evaluated in several studies as monotherapy and in combination with insulin, a sulfonylurea, or metformin in patients with Type 2 diabetes. These studies are summarized in Tables 1- 3; the most significant findings are discussed below.

Combination Therapy with Insulin
Schwartz et al studied 350 patients ages 18 to 72 years with poorly controlled Type 2 diabetes (HbA1c, 8 to 12%) who were receiving 30 or more units/day of insulin and had fasting serum glucose (FSG) concentrations 140 or more mg/dl.5 The patients were obese, with an average body mass index (BMI) of 34.8 to 35.1 kg/m2 within the three patient groups. Patients were randomized to receive either 200 mg of troglitazone, 600 mg of troglitazone, or placebo daily for 26 weeks after a two week screening period and an eight-week single- blind, placebo base line period. The patients also received instruction on appropriate diet. Insulin doses were reduced if the FSG was less than or equal to 90 mg/dl at one office visit, was 90 to 109 mg/dl on two consecutive office visits, or was less than or equal to 100 mg/dl on two consecutive days during home monitoring. The mean glycosylated hemoglobin values (HbA1c), fasting serum glucose concentrations and daily insulin doses all decreased in a dose-related manner in the troglitazone groups compared to placebo. The HbA1c, which reached its nadir around 16 weeks, decreased significantly in the 200 mg (-0.8%) and 600 mg (-1.4%) troglitazone groups compared to placebo (-0.1%), (p is less than 0.001). Fasting serum glucose concentrations significantly decreased by 16% in the 200 mg troglitazone group (-35 mg/dl), and by 23 % in the 600 mg troglitazone, group (49 mg/dl) compared to placebo (+ 0.8 mg/dl), (p less than 0. 00 1). The daily insulin dose decreased by 11 % and 29 % in the 200 and 600 mg troglitazone groups, respectively, and increased by 1% in the placebo group (p less than 0.001). The incidence and types of adverse events were similar in all three groups, with 94 % of patients in the troglitazone groups and 97% of patients on placebo reporting at least one adverse event. Symptoms of hypoglycemia occurred in 41% of the patients on placebo, 45% of those on 200 mg of troglitazone, and in 62% of those taking 600 mg of troglitazone. Eight patients (two in the 200 mg, three in the 600 mg and three in the placebo group) had serum aminotransferase concentrations greater than three times the upper limit of normal. Two of these patients in the 600 mg group discontinued therapy because of jaundice and hyperbilirubinemia in one and because of congestive heart failure in the other. For the other troglitazone patients, the liver function tests (LFTs) returned to normal after therapy was interrupted, and in the placebo group the LFTs returned to base line without interruption of treatment.

Other significant changes over the 26 weeks of the study included an increase in total cholesterol by 7 mg/dl in the 200 mg group (p less than 0. 05) and by 12 mg/dl in the 600 mg group (p less than 0. 05). The LDL increased by 9 mg/dl in the 200 mg group and by 14 mg/dl in the 600 mg group. HDL was significantly increased only in the 600 mg group from 38 ±9 mg/dl to 41 ± 11 mg/dl. The mean body weight increased significantly after 26 weeks in the troglitazone groups compared to placebo. Weight changes from 100.5 to 102.0 kg, 98.6 to 100.5 kg and 100.9 to 104.5 kg occurred in the placebo, 200 ing and 600 ing groups of troglitazone, respectively (p less than 0.001).5

Table 1. Summary of Clinical Trials: Combination Therapy with Insulin
Study Population	Troglitazone Dose	Concomitant Therapy	Monitoring Variable	Results
350 NIDDM patients with baseline MAI, of 8 to 12% despite 30 or more units of insulin daily 5	200 mg or 600 mg qd or placebo for 26 weeks	Insulin (insulin doses were adjusted if fasting glucose less than 90 mg/dl at one or between 90 and 109 mg/dl at two consecutive office visits, or if less than 100 mg/dl on 2 consecutive days at home).		All variables decreased significantly with both troglitazone doses vs placebo:
			Fasting blood glucose	Placebo +0.8 mg/dl 200 mg -35 mg/dl (16%) 600 mg -49 mg/dl (23%)
			HbA1c	Placebo -0.1% 200 mg -0. 8% 600 mg -1.4%
			Daily insulin dose	Placebo +1% 200 mg -11% 600 mg -29%
350 NIDDM patients with baseline MAI, of 9.42% on average of 73 units of insulin per day1	200 mg or 600 mg troglitazone qd or placebo for 6 months	Insulin (insulin doses were adjusted if 2 consecutive blood glucose readings less than 100 mg/dl)	HbA1c, (mean change from baseline)	Placebo - 0.12% 200 mg -0.84 % 600 mg -1.41%
			Daily insulin dose (mean change from baseline)	200 mg -15% 600 mg - 41% These changes were statistically significant (p is less than 0. 0001)
222 NIDDM patients with baseline MAI, of 9.2 % on 30 to 150 units of insulin per day. Patients had failed oral antidiabetic agents before insulin initiation17	200 mg or 400 mg troglitazone qd or placebo for 26 weeks. This was followed by an open label extension of 200 mg troglitazone qd titrated to 400 mg based on reponse	Insulin (insulin doses were reduced 25% when fasting blood glucose [per patient diary] was reduced 5% from baseline)	50% or more reduction in insulin dose and a 15 % reduction in fasting blood glucose or blood glucose level less than 140 mg/dl	Number of patients reaching defined goal: Placebo 5 (7%) 200 mg 16 (22%)# 400 mg 20 (27%)#
# p is less than 0.01 vs placebo

Monotherapy
Maggs et al studied 93 patients with Type 2 diabetes treated with diet therapy only or had just discontinued their oral antidiabetic therapy .3 Metabolic studies were done before patients were randomly assigned to one of five treatment groups: 100, 200, 400, or 600 mg of troglitazone daily or placebo. Follow-up metabolic studies were repeated after 6 months of therapy. Baseline characteristics of patients were similar among the 5 groups with an average glucose level of 180 to mg/dl and an average BMI of 31 to 34 kg/Mm2. After 6 months, it was found that dosages of 400 to 600 mg/day of troglitazone decreased plasma glucose levels by as much as 20%. It also decreased fasting triglyceride levels (p=0.012) independent of dose as well as fasting insulin levels (p less than 0.001). Significant predictors of a favorable decline in plasma glucose were higher troglitazone doses (p less than 0.001), elevated pretreatment fasting C-peptide level greater than 2.7 ng/ml (normal = 0.5 to 2.5 ng/ml) (p less than 0.016), and a lower pretreatment body mass index (p less than 0.05).

Table 2. Summary of Clinical Trials: Monotherapy
Study Population	Troglitazone Dose	Concomitant Therapy	Monitoring Variable	Results
93 NIDDM patients with baseline glucose levels of 180-213 mg/dl 3	100 mg, 200 mg, 400 mg, 600 mg qd or placebo for 6 months	None (previously diet treated or off previous therapy for 2 weeks)	Fasting and postprandial plasma glucose	-20%
229 NIDDM patients with baseline glucose levels of 126 to 270 mg/dl (mean not reported) 10	400 mg or 800 mg qd or 200 mg or 400 mg bid or placebo for 12 weeks	None (previously diet treated or off previous therapy for 3 weeks)	Fasting blood glucose	Placebo 228 mg/dl 400 mg qd 181 mg/dl 800 mg qd 169 mg/dl 200 mg bid 187 mg/dl 400 mg bid 169 mg/dl (all troglitazone groups: p less than 0.001 vs placebo)
			HbA1c	Placebo 8.9% 400 mg qd 8.2% 800 mg qd 7.8% 200 mg bid 8.5% 400 mg bid 8.0% (all p less than 0.05 except 200 mg bid NS vs placebo)
			Insulin levels	Decreased significantly in all troglitazone groups by 27 to 34%
792 NIDDM patients with baseline HbA1c, of 7 to 11 %, mean baseline blood glucose 233 to 242 mg/dl11	200, 400, 600 or 800 mg qd or placebo for 12 weeks	None	Fasting blood glucose	Placebo +6% 200 mg -11% 400 mg -14% 600 mg -15% 800 mg -19%
			Insulin levels	Decreased by 5 to 21%
			Responders (30 or more mg/dl decrease in fasting blood glucose)	Placebo 18% 200 mg 38% 400 mg 54% 600 mg 60% 800 mg 65%
NS = Not statistically significant.

Combination Therapy with Metformin
In a study published by Inzucchi et al, 29 patients with Type 2 diabetes, a HbA1c, above the upper limit of normal, and a plasma C-peptide concentration 1.5 or more ng/ml on diet or sulfonylurea therapy were randomly assigned to receive either 1000 mg twice daily of metformin or 400 mg once daily of troglitazone for 3 months .2 The randomization was performed after a two-week washout period in which any previous drug therapy was discontinued. The three months of monotherapy was followed by a combination of the two regimens for the next three months. Patients had an average BMI of 33.7 and 34.0 kg /m2 and an average HbA1c of 9.8 ±1.7% and 9.3 ±1.9% in the metformin and troglitazone groups, respectively. Fasting and postprandial plasma glucose concentrations, HbAl, and routine hematologic and chemical values were measured at base line and monthly thereafter. The average fasting plasma glucose after a two-week washout period was 287 mg/dl in the metformin group and 275 mg/dl in the patients assigned to troglitazone. After 3 months of therapy, both groups produced a 20% decrease in fasting plasma glucose, but neither group produced a significant change in HbAlc from the two-week washout period. During combination therapy, mean fasting plasma glucose levels fell an additional 41 mg/dl (-18%), with a total mean decrease in fasting plasma glucose concentration over the six month study of 98 mg/dl (a 35% reduction). The mean HbA1c decreased over the 3 months of combination therapy by 1.2% from base line (p less than 0.001). There was no significant change in weight in either group and no adverse reactions attributed to troglitazone therapy. In summary, in this small group of patients, metformin and troglitazone had identical efficacy as monotherapy, with the combination further reducing both fasting and postprandial glucose concentrations. The lack of drop in HbA1c in either group during monotherapy may be attributed to the loss of blood glucose control during the two-week washout period that occurred prior to initiation of the study.

Combination Therapy with Sulfonylureas
The efficacy of troglitazone, in combination with sulfonylureas has also been studied. Iwamoto and colleagues studied 291 patients with Type 2 diabetes and poor glycemic control on sulfonylurea therapy (FPG 150 or more mg/dl).6 Baseline patient characteristics include an average BMI of 23 kg /m2 , an average FPG of 195 mg/dl and 189 mg/dl, and an average HbA1c, of 9.2% and 9.0% in the troglitazone and placebo groups, respectively. Patients were randomly allocated to troglitazone 200 mg bid or to placebo for a duration of 12 weeks, while the sulfonylurea was continued at the same dose in both groups. FPG and HbA1c, were measured every 4 weeks, starting 4 weeks prior to randomization. The average FPG at week 8 and 12 in the troglitazone group decreased significantly by 15% (30 mg/dl) compared to placebo (2% increase p less than 0.001). HbA1c, levels in the troglitazone group fell from 9.2 ±1.4% to 8.5 ±1.5% at the end of treatment, while the placebo group maintained its HbA1c of 9.0 ± 1.5% at baseline and 9.2 ±1.6% at the end of 12 weeks. Patients were classified as responders if their FPG decreased by greater than 20% or their HbA1c, dropped by greater than 1%. Of the patients randomized to troglitazone, 51.6% were considered responders, while 11.9% of the placebo-treated patients showed similar decreases in FPG and HbA1cc. Possible hypoglycernic symptoms were observed by 3.6% of the patients in the troglitazone group, and in no patients on placebo. Eight cases in the troglitazone group and two cases in the placebo group had an increase in the enzyme lactate dehydrogenase. The severity of these enzyme elevations and the outcomes of the patients were not specified.

Table 3. Summary of Clinical Trials: Comparative or Combination Therapy with Oral Agents
Study Population	Troglitazone Dose	Concomitant Therapy	Monitoring Variable	Results
146 NIDDM patients with mean fasting blood glucose 192 mg/dl (HbA1c, 8.9%) dl 12	200 or 400 mg daily for 12 weeks (open label study)	None or sulfonylureas or sulfonylureas with biguanides (previous therapy was continued)	Fasting blood glucose	Decreased by 37 mg/dl vs baseline (p less than 0.01)
			HbA1c	Decreased by 0.8% vs baseline (p less than 0.01)
552 NIDDM patients with fasting blood glucose of more than 140 mg/dl and less than 300 mg/dl on maximal doses of sulfonylureas.16 After the 4-week washout period, the baseline HbA1c was reported at 9.5%.#	Micronized glyburide 12 mg qd (G12) or Troglitazone (T) 200, 400 or 600 mg qd or G12 & T200, G12 & T 400 or G12 & T600.	None or sulfonylurea	HbA1c	Mean difference from control (G12): T200 1.02%* T400 -0.05% T600 0.03% G12/T200 -1.60**% G12/T400 -1.81**% Gl2/T600 -2.65**%
			Fasting blood glucose	Mean difference from control (G12): T200 19.8 mg/dl T400 -1.8 mg/dl T600 -10.8 mg/dl G12/T200 -54 mg/dl** G 12/T400 -61 mg/dl** G12/T 600 -79 mg/dl**
291 NIDDM patients with baseline HbA1c of 9.2% (troglitazone group) and 9.0% (placebo group)6 while on sulfonylurea therapy	200 mg bid or placebo for 12 weeks	Sulfonylurea	Fasting blood glucose	30 mg/dl (15 %) decrease vs 4 mg/dl increase with placebo
			HbA1c	0.7% decrease vs 0.2% increase with placebo
			Responders (more than 20 % decrease in fasting blood glucose or more than 1% decrease in HbA1c)	51.6% vs 11. 9% for placebo
29 NIDDM patients with baseline HbA1c of 9.3% (troglitazone group) and 9.8% (metformin group) 2	3 months of metformin or troglitazone monotherapy followed by combination therapy for 3 months	Metformin 1000 mg bid	Fasting blood glucose	Metformin -58 mg/dl (20%) Troglitazone -54 mg/dl (20%) Combination-41 mg/dl (18%)
			HbA1c	Decreased 1.2% from baseline with combination therapy
* p is less than or equal to 0. 001 ** p is less than or equal to 0. 0001 #Note: There was a 42% withdrawal rate. Results were based on an intent to treat analysis based on the last observation carried forward.

Efficacy Summary
Troglitazone has been shown to be effective in patients with Type 2 diabetes by decreasing fasting blood glucose by 20% monotherapy ,3 16 to 23% in patients poorly controlled on insulin,5 an additional 18% when used in combination with metformin 2 and by an additional 15 %6 or more16 when added to sulfonylurea therapy. In patients on insulin, the daily insulin dose could be decreased by 11 to 15% with 200 mg troglitazone and up to 41% with 600 mg of troglitazone. Troglitazone is not effective in all patients as was shown in the study by Iwamoto et al, for when troglitazone was added to a sulfonylurea, only 51% of patients were considered to have responded to the therapy, where responders were defined as having a decrease in FPG of at least 20% or a reduction in HbA1c of at least 1%.6 The reductions in HbA1c with troglitazone ranged from 0. 4 to 1.1% with monotherapy and from 0.7 to 2.65 % with combination therapy (see Tables 2 and 3).

Pharmacokinetic Properties
Troglitazone is rapidly absorbed following oral administration, with the time to peak occurring within 2 to 3 hours of taking the dose. Food increases the extent of absorption by 30 to 85%; therefore, troglitazone should be taken with a meal. Its half-life is 16 to 34 hours, allowing steady state blood levels to be reached in 3 to 5 days. Eighty-five percent of the administered dose is extensively metabolized by the liver, with only 3% of the drug excreted unchanged in the urine.

Adverse Effects
In general, troglitazone has been well tolerated during clinical trials, with the type and incidence of adverse reactions similar to placebo.9 The adverse events reported 10 or more percent of the troglitazone patients include infection (18%), headache (11%) and pain (10%), which was similar to the occurrence rates in placebo, which were 22%, 11%, and 14%, respectively.1 Other reported adverse effects include small decreases in hemoglobin, hematocrit and neutrophil count. These hematologic effects may be related to a reported increase in plasma volume of 6-8% found in healthy volunteers. Although the clinical significance of this effect is unknown, it is recommended not to use troglitazone in patients with NYHA stage III or IV heart failure, unless the expected benefit is believed to outweigh the potential risk.1

The most serious adverse effect due to troglitazone therapy is hepatotoxicity, often signaled by the elevation of liver enzymes. As of December 1997, approximately 150 adverse events were reported to the FDA, including 3 deaths from liver failure linked to the use of troglitazone in Japan (these deaths occurred before the recommendation for liver enzyme testing took effect there). Distribution of the medication was halted in the United Kingdom in November 1997 on the basis of these hepatic dysfunction reports. Recent case reports were published that revealed severe hepatotoxicity caused by troglitazone after 138 days and 35 days of exposure to standard doses of the medication. 13 Two patients had acute hepatocellular necrosis with bridging necrosis and fibrosis and cholestasis. A third patient developed massive loss of liver parenchyma and liver failure after using troglitazone for 3.5 months, which required liver transplantation. 14 As a result, the manufacturer of troglitazone has recently made the monitoring requirements more stringent than the liver enzyme monitoring recommendations originally implemented in November 1997. 15 These guidelines were developed in consultation with the FDA and specify that patients with moderately elevated ALT levels at the start of therapy (greater than 1.5 times the upper limit of normal) should not receive troglitazone. Patients who are started on troglitazone should have ALT levels measured at baseline and monthly for eight months, then every two months for the remainder of the first year of therapy, then periodically thereafter. Patients whose ALT levels are found to be moderately elevated (greater than 1.5 to 2 times the upper limit of normal) during therapy with troglitazone should have ALT levels retested within a week and then weekly until they either return to normal or rise above 3 times the upper limit of normal, at which point troglitazone should be discontinued. Liver function tests should also be obtained for patients at the first symptoms suggestive of hepatic dysfunction, such as nausea, vomiting, abdominal pain, or dark urine.1

During the clinical trials of troglitazone in North America, elevations in liver enzymes more than three times normal were detected in 1.9% (48 of 2510) of patients. The onset of the serum alanine aminotransferase elevations was typically delayed, with only one patient having an elevation during the first month of therapy. In most patients, the peak values occurred between the third and seventh month of therapy .

Drug Interactions
Troglitazone may induce CYP3A4, reducing the efficacy of other drugs also metabolized in the liver by this enzyme. Examples of drugs metabolized by CYP3A4 include astemizole, calcium channel blockers, cisapride, corticosteroids, cyclosporine, HMG-CoA reductase inhibitors, tacrolimus, triazolam and trimetrexate. Drugs that have been studied and found to be altered with concomitant troglitazone use include oral contraceptives, cholestyramine, and terfenadine. The addition of troglitazone to oral contraceptives produced a 30% decrease in plasma concentration, leading to decreased efficacy of the oral contraceptive. Cholestyramine, if taken at the same time as troglitazone, decreases the absorption of troglitazone by approximately 70%, while coadministration of troglitazone with terfenadine decreased the concentration of terfenadine and its metabolite by 50 to 70%.1

Troglitazone has been shown not to interact when it is coadministered with acetarninophen, glyburide, digoxin or warfarin.

Dose and Cost Comparison Information
Troglitazone is marketed in 200 mg, 300 mg, and 400 mg tablets, and should be taken with a meal. The initial dose is 200 mg per day when used in combination therapy. If there is an inadequate response after 2 to 4 weeks, the dose may be increased to 400 mg once daily (average daily dose), with a maximum dose of 600 mg once daily. When used as monotherapy, the drug should be started at 400 mg/day. If the patient is not responding after 6 to 8 weeks of therapy, the dose may be increased to 600 mg/day.1 (See Table 4 for detailed dosing guidelines.) Troglitazone is significantly more costly than the sulfonylureas, metformin and acarbose, ranging from $89 per month (average wholesale price) for 200 mg per day dose to $284 for 600 mg per day (Table 5).

Table 4. Dosing and Liver Function Test Monitoring Guidelines for Troglitazone1

DOSING GUIDELINES: Monotherapy: Initial dose - 400 mg once daily with a meal For patients not responding to 400 mg once daily, increase dose to 600 mg once daily after one month. Discontinue therapy if patient is not responding to 600 mg per day after one month. Combination Therapy: Initial dose - 200 mg once daily with a meal For patients not responding adequately, increase dose by 200 mg per day at 2 to 4 week intervals to a maximum of 600 mg once daily. Usual dose is 400 mg once daily. If using Insulin: Initially maintain current insulin dose. Decrease insulin dose by 10 to 25 % when fasting plasma glucose decreases to 120 mg/dl. Further adjustments should be individualized based on response. LIVER FUNCTION TEST MONITORING GUIDELINES: Patients with moderately elevated ALT levels at the start of therapy (greater than 1.5 times the upper limit of normal) should not be initiated on troglitazone therapy. ALT levels should be measured at the start of troglitazone therapy and monthly for eight months, then every two months for the remainder of the first year and periodically thereafter. Patients whose ALT levels are found to be moderately elevated (greater than 1.5 to 2 times the upper limit of normal) during troglitazone therapy should have ALT levels retested within a week and then weekly until the levels either return to normal or rise above 3 times the upper limit of normal, at which point troglitazone should be discontinued. Note: No dosage adjustment is needed for renal impairment, but caution should be used when administering to a patient with hepatic insufficiency, since the drug is extensively metabolized and LFT elevations may occur. Troglitazone should not be administered if the patient has active liver disease (see section on Adverse Effects).

Conclusion
Troglitazone is an oral antidiabetic agent that primarily increases insulin sensitivity by increasing peripheral glucose disposal in the skeletal muscles. It has been shown to lower fasting blood sugar and HbAlc as monotherapy. However, the high cost of troglitazone, as well as the cost of the required LFT monitoring and the risk of serious hepatic toxicity, precludes its use as first line monotherapy in the treatment of Type 2 diabetes. Patients with liver dysfunction at baseline should not be started on troglitazone. Since it has been shown to lower blood glucose in combination therapy, it has a role in improving glycemic control in patients on sulfonylureas and/or metformin with borderline control, where the addition of troglitazone may delay or prevent the addition of insulin to the patient regimen. Troglitazone may allow for a reduction in insulin dose in diabetic patients on insulin. It is also an option in patients on high doses of insulin who can not establish satisfactory glucose control. Use as first line drug therapy should be considered only in patients who have failed diet and exercise and are unable to take sulfonylureas and/or metformin because of intolerance or other concomitant disease states.

Table 5. Cost Comparisons of Antidiabetic Agents
Drug	Dosing Range	Cost ($)*
Acarbose (Precose[R])	25 to 100 mg tid	41 to 53
Glipizide (generic, Glucotrol [R])	5 mg qd to 20 mg bid	9 to 61
Glyburide (generic, Diabeta[R])	1.25 mg qd to 10 mg bid	6 to 54
Glimepirid (Amaryl[R])	1 mg qd to 8 mg qd	7 to 41
Insulin, human (Humulie[R])**	100 units/ml (one 10 ml bottle)	21
Metformin (Glucophage[R])	500 mg bid to 850 mg tid	32 to 82
Tolbutamide	500 mg qd to 1 g bid	4 to 8
Troglitazone (Rezulin [R])	200 mg qd to 400 mg qd 600 mg qd***	89 to 142 284
*Average cost to the pharmacist for 30 days of therapy based on average wholesale price (AWP) listings in Drug Topics Red Book 1998 for a generic product when available. **This cost does not reflect the cost of insulin syringes or other supplies needed to administer the drug. ***600 mg tablet not available-price is for two 300 mg tablets daily.

References
1. Parke-Davis. Rezulin Package Insert. Morris Plains, NJ. 1998 July.
2. N Engl J Med 1998;338:867-72.
3. Ann Intern Med 1998; 128:176-85.
4. Diabetes 1997;46:433-9.
5. N Engl J Med 1998;338:861-6.
6. Diabetic Med 1996; 13:365-70.
7. N Engl J Med 1998;338:916-7.
8. Food and Drug Administration. FDA Talk Paper T9761: Patient testing and labeling strengthened for Rezulin. December 1, 1997. Available from http://www.fab.gov/ bbs/topics/ANSWERS/ANS00837.html.
9. Ann Pharmacother 1998;32:337-48.
10. Diabetologica 1995; 38 (suppl 1): A200. Abstract.
11. Diabetes 1995; 44(Sl): 109A. Abstract
12. Diabetes Res Clin Pract 1991; 11: 146-54.
13. Ann Intern Med 1998; 129: 36-8.
14. Ann Intern Med 1998; 129: 38-41.
15. Parke-Davis. Dear Pharmacist Letter. Morris Plain, NJ. 1998, July.
16. Diabetes Care 1998; 21: 1462-9.
17. Diabetes Care 1998; 21: 1455-61.

ACETAMINOPHEN WITH HYDROCODONE Elixir: 167 mg acetaminophen with hydrocodone 2.5 mg per 5 ml This combination product (Lortabo - Whitby) is indicated for the relief of moderate to moderately severe pain.

CLONIDINE Epidural Injection: 100 mcg per ml Clonidine epidural (Duraclon[R] - Roxane) is indicated for use in combination with opiates for the treatment of severe pain in cancer patients. NOTE: For epidural use only; not indicatedfor the management of hypertension.

CLOPIDOGREL Tablets: 75 mg Clopidogrel (Plavix[R] - Pharmacia & Upjohn) is an inhibitor of platelet aggregation indicated for the reduction of atherosclerotic events in patients with atherosclerosis documented by recent stroke or myocardial infarction, or established peripheral arterial disease.

DOLASETRON Injection: 12.5 mg per 0.625 ml ampul Dolasetron (Anzemet[R] - Hoechst Marion Roussel) injection is indicated for the prevention and treatment of nausea and vomiting. NOTE: The use of dolasetron is restricted to prescribing by Anesthesia in the OR and PA CU. HYALURONATE SODIUM Injection: 10 mg per ml, 2 ml syringe Sodium hyaluronate (Hyalgan[R] - Sanofi) injection is indicated for the pain of osteoarthritis of the knee in patients who have failed to respond to analgesics and non-pharmacologic therapy.

INTERFERON ALFACON-1 Injection: 9 mcg, 15 mcg Interferon alfacon-1 (concensus interferon, Infergen[R] - Amgen) is indicated for the treatment of chronic hepatitis C virus infection. NOTE: The prescribing of interferon a~facon-] is restricted to treatment of chronic hepatitis patients who have relapsed after treatment with interferon alpha-2afinterferon alpha-2b or who have high viral titers andlor infection with HCV genotype I with compensated liver disease.

MOMETASONE Nasal spray: 50 mcg per spray Mometasone (Nasonex[R] - Schering) nasal spray is a corticosteroid indicated for the prophylaxis and treatment of the nasal symptom of seasonal allergic and perennial rhinitis.

NALTREXONE Tablets: 50 ing Naltrexone (ReVia[R] - Dupont) is an opioid antagonist indicated for the treatment of alcohol dependence and the blockade of the effects of exogenously administered opioids.

OPRELVEKIN Injection: 5 ing per vial Oprelvekin (IL- 11, interleukin- 11, Neumega[R] - Genetics Institute) is a hematopoietic growth factor indicated for the prevention of chemotherapy-induced thrombocytopenia. NOTE: 77te Prescribing of oprelvekin is restricted to patients with nonmyeloid malignancies who have required platelet transfusions during prior chemotherapy cycles.

PROGESTERONE, MICRONIZED Capsules: 100 ing Micronized progesterone (Prometrium[R] - Solvay) capsules are used for hormone replacement therapy and the management of secondary amenorrhea.

RIBAVIRIN WITH INTERFERON ALFA-2b Capsules: 200 mg ribavirin Injection: 3 million IU per 0.5 ml interferon alfa-2b The combination of these two drugs (Rebetron[R]- Schering) is indicated for the treatment of chronic hepatitis C in patients with compensated liver disease who have relapsed following alpha interferon therapy alone. Cost: Available as 3 different kits (2-week supply each) in the following quantities:

• Ribavirin 200 mg (x 42 capsules) plus interferon alfa-2b 3 mu (x 6 vials) to provide ribavirin 600 mg/day and interferon alfa-2b 3 mu. three times weekly;
• Ribavirin 200 mg (x 70 capsules) plus interferon alfa-2b 3 mu (x 6 vials) to provide ribavirin 1000 mg/day and interferon alfa-2b 3 mu three times weekly;
• Ribavirin 200 mg (x 84 capsules) plus interferon alfa-2b 3 mu (x 6 vials) to provide ribavirin 1200 mg/day and interferon alfa-2b 3 mu three times weekly;

NOTE: The entire kit must be dispensed. Oral ribavirin (Rebetol") is not indicated as monotherapy.

SILDENAFIL Tablets: 25 mg, 50 mg, 100 mg Sildenafil (Viagra[R]) - Pfizer) is indicated for the treatment of erectile dysfunction. NOTE: Concomitant use of sildenafil with nitrates is contraindicated due to the potentiation of hypotensive effects; fatalities have been reported.

SODIUM BENZOATE Capsules: 500 mg, 1 g Sodium benzoate capsules are used for the treatment of refractory hepatic encephalopathy.

TROVAFLOXACIN Tablets/ALATROFLOXACIN Injection Tablets: 100 mg, 200 mg Injection: 200 mg per 40 ml vial; 300 mg per 60 ml vial Trovafloxacin/alatrofloxacin (Trovan[R] - Pfizer) is a quinolone antibiotic. NOTE: The prescribing of trovafloxacinlalatrofloxacin is restricted to treatment of diabetic patients with soft tissue infections orformal Infectious Diseases recommendation. ADDITIONAL ACTIONS

CALCIUM CARBONATE 1250 ing TABLETS This strength was added to stock.

DIDANOSINE POWDER FOR ORAL SOLUTION The powder is reconstituted to a concentration of 10 mg per ml.

MAFENIDE ACETATE POWDER A sterile powder (Sulfamylon[R]) for the preparation of a topical solution is now commercially available.

SALICYLIC 6% TOPICAL GEL This product (Keralyt[R]) is again commercially available.

VITAMIN E 1,000 IU CAPSULES This additional strength was added to stock

WARFARIN 3 mg, 4 ing and 6 ing TABLETS These tablet strengths were added to stock Note: The cost following each brief monograph is the UIHC acquisition cost. DRUGS DELETED FROM STOCK

ETRETINATE (TEGISON) CAPSULES Discontinued by the manufacturer. Acetretin (Soriatane[R]) capsules are available. Next Page | Previous Page | Title Page