News 04/03/2544

News 04/03/2544

DRUG USE CONTRAINDICATIONS AND PRECAUTIONS IN CONGESTIVE HEART FAILURE
What impact do the FDA-approved contraindications and precautions included in prescription drug labeling have on actual drug use and hospitalization risks in congestive heart failure? Medscape Pharmacists, 2001.

NOVARTIS CLAIMS LEAD IN RACE TO FIND NOVEL COPD THERAPIES
The Swiss group Novartis today claimed to be leading the race in the development of novel compounds that attack the underlying inflammatory process responsible for asthma and chronic obstructive pulmonary disease (COPD).

ROSIGLITAZONE TWICE DAILY IMPROVES GLYCEMIC CONTROL MORE THAN ONCE-A-DAY DOSING
Rosiglitazone significantly improves glycemic control in patients with type 2 diabetes mellitus, according to the results of a multicenter trial.

CONSUMER GROUP URGES FDA PROBE INTO SCHERING-PLOUGH MANUFACTURING PRACTICES
A consumer advocacy group is asking the US Food and Drug Administration to consider whether criminal charges should be brought against Schering-Plough, claiming that the company distributed defective asthma inhalers, later found to contain no active ingredient, despite known quality control problems at its New Jersey plant.

From
Medscape Pharmacists

Drug Use Contraindications and Precautions in Congestive Heart Failure

Robert A. Hamilton, PharmD

Abstract:

Objective: This study investigated the impact of FDA-approved labeling -- ie, precautions and contraindications specified for a drug's use -- on the prescribing of such drug and whether these precautions and contraindications are associated with an increased risk of hospitalization.
Methods: Medications with precautions or contraindications for use in patients with congestive heart failure (CHF) were identified. Medicaid billing records were examined to determine the frequency of use of these medications in patients with CHF and in the population as a whole. A matched-pair, case-control study of Medicaid recipients was also conducted to determine the odds ratio for hospitalization in these patients.

Results: These medications were used in patients with CHF at a rate similar to that observed in the general Medicaid population. The use of amlodipine, beta blockers, diltiazem, glucocorticoids, sympatholytics, and warfarin was associated with an increased risk of hospitalization. Calcium channel blockers other than amlodipine and diltiazem, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory drugs, and theophylline were not associated with an increased risk of hospitalization.

Conclusion: These results indicate that the precautions and contraindications appear to have little effect on the frequency of use of these medications in patients with CHF. Such use is associated with an increased risk of hospitalization in some cases, but in other cases, use of these medications in CHF patients does not increase their risk of hospitalization, suggesting that the precautions may be effective. [Medscape Pharmacists, 2001. ©2001 Medscape, Inc.]

Introduction

Prescription drugs are known to carry significant risks with their use,[1-3] prompting strategies to be in place to minimize these risks. A medication error reporting system is one strategy that helps to identify how the medication delivery system may contribute to such errors.[4,5] Identification of system errors may lead to changes in the medication delivery system capable of decreasing the likelihood of errors.[5] Lesar and colleagues[4] have reported that deficiencies related to inadequate knowledge of drug therapy and failure to account for patient disorders (eg, renal insufficiency, congestive heart failure [CHF]) when making drug therapy decisions each accounts for approximately 30% of errors detected at their institution.
The use of detailed product labeling is an effort to address this "inadequate knowledge of drug therapy" and to minimize the associated risks. The United States Food and Drug Administration (FDA) requires that product labeling carry warnings in the form of contraindications and precautions. Contraindications are defined as "Descriptions of situations in which the drug should not be used because the risk of use clearly outweighs any possible benefit."[6] Precautions contain "Information regarding any special care to be exercised for the safe and effective use of the drug."[6] Manufacturers negotiate these warnings with the FDA based on experience during clinical trials, postmarketing surveillance, and adverse reactions to the drugs as reported in the literature.

Despite these warnings, it is possible that patients with conditions that either contraindicate the use of specific drugs or require that the drugs be used with caution are still receiving these medications. The administration of a contraindicated medication may result in a serious adverse event, which obviously should be avoided. What is uncertain is, how frequently does this occur and how adverse are the outcomes?

These questions prompted investigators to come up with a single disease or condition that could be studied as an example. They determined that the ideal condition should have a prevalence that permits reasonable estimates of drug exposures to be calculated and must be one for which commonly used medications are either contraindicated or for which precautions regarding the use of the medication exist. The result of such use should be expected to result in a measurable outcome. CHF meets these conditions: it is prevalent; there are a number of medications that can adversely affect its course; and use of these medications can be expected to result in hospitalization.

The objective of this report is to document the frequency of use of contraindicated agents or agents to be used with precaution in patients with CHF and describe the risk of hospitalization associated with such use.

Methods

The New York State (NYS) Drug Utilization Review (DUR) Board was created under federal legislation, the Omnibus Budget Reconciliation Act of 1990 (OBRA 90). This legislation mandated the DUR Board to provide prospective and retrospective drug utilization review to NYS Medicaid recipients and education to NYS Medicaid providers. Data used for the retrospective function were used for this study.
To accomplish the retrospective function, the DUR Board performed a matched-pair, case-control study of Medicaid recipients using billing records. (The data set did not provide clinical information such as New York Heart Association Class.) Each year, an 8-month period was selected to define the population and conduct the study. Study data were collected from the billing records of selected eligible patients. Eligible patients were Medicaid recipients who received services during the first and last 2-month periods of the 8-month study period. It was assumed that receiving services during these periods made the recipients highly likely to have been eligible for Medicaid during the intervening 4 months. Cases were all Medicaid recipients who were hospitalized for nonobstetric indications during that 4-month period. Each case patient was then randomly matched with a control patient who was not hospitalized during that same 4-month period. Thus, the control population represented a random sample of NYS Medicaid recipients during the study period. Matching was based solely on concurrent Medicaid eligibility.

For each case and control patient, Medicaid claims were reviewed to identify the presence of specific medications and diseases. Using matched-pair methodology, odds ratios and 90% confidence intervals for hospitalization were calculated for various disease-drug and drug-drug combinations.[7] The results of the drug-drug interactions have been previously reported.[8] Patients for whom claims were made with the diagnosis of CHF were considered to have CHF.

Potentially hazardous medications (PHMs), ie, medications that are contraindicated or are to be used with caution in CHF (as per FDA labeling) were identified from the reference Clinical Pharmacology (Gold Standard Media, April 2000, Tampa, Florida). These medications were grouped into medication classes as identified in Table 1. An exception to this process was made for the calcium channel blockers. Because of the unique characteristics of the calcium channel blockers, the database was constructed to identify patients having received any calcium channel blocker, as well as those having received diltiazem, amlodipine, or verapamil individually. In order to provide the most accurate estimates of exposure and risk, the number of patients receiving the 3 individually identified calcium channel blockers was subtracted from the total number of patients receiving calcium channel blockers. The frequency of use of these medications in the control population with CHF claims was used as an estimate of the prevalence of use of PHMs in the CHF patients. This analysis was repeated annually and new medications were periodically added to the database. For this report, the exposure data were combined for all available years (a total of 5 analyses, representing 5 years). For comparison purposes, the prevalence of use of each PHM in the entire control population was also determined.

To determine the risk that PHMs represent in CHF patients, the odds ratios between the case and control groups for both exposure to PHMs and presence of CHF were compared with the odds ratios for exposure to PHMs and presence of CHF alone. Nonoverlapping confidence intervals were interpreted as being statistically significant changes in risk.

Results

CHF was present in 2994 patients of the 336,749 patients in the control population (0.9%). The frequency of use of PHMs in nonhospitalized (control) CHF patients is given in Table 2. (Because new medications were added to the Medicaid data set each year, the number of CHF patients for the denominator is different for some medications.) This frequency ranged from 0.2% for monoamine oxidase inhibitors (MAOIs) to 14.1% for other calcium channel blockers (dihydropyridine-based calcium channel blockers other than amlodipine). This prevalence is similar to that of the entire control population, in whom the frequency ranged from 0.1% for MAOIs to 11.9% for nonsteroidal anti-inflammatory drugs (NSAIDs) (Table 2).
The odds ratios for hospitalization of CHF patients exposed to each drug, alone and in combination, are given in Table 3 and presented graphically in Figure 1. A number of potentially hazardous medications were associated with an increased risk of hospitalization when used in patients with CHF, including amlodipine, beta blockers, diltiazem, glucocorticoids, sympatholytics, and warfarin. Medications not associated with an increased risk included other calcium channel blockers, MAOIs, NSAIDs, theophylline, and verapamil.

Figure 1. Odds ratios for hospitalization and 90% confidence intervals for potentially hazardous medications (represented by a vertical line), congestive heart failure (represented by a diamond), and the combination (represented by a box). Nonoverlapping confidence intervals indicate statistically significant differences. (CCB = calcium channel blockers; MAO = monoamine oxidase; NSAIDs = nonsteroidal anti-inflammatory drugs)

Discussion

This study demonstrated that medications that carry contraindications to use or precautions in patients with CHF are used in up to 15% of patients, depending on the medication. Furthermore, the frequency of use of PHMs in the CHF population was similar to or greater than that observed in the general population. On closer inspection, the PHMs that are used more commonly in the CHF population than in the general population are those with cardiovascular indications, such as calcium channel blockers and warfarin. This is not surprising, given that many patients with CHF have other cardiovascular diseases as well and would be expected to have more indications for use of the PHM that has cardiovascular indications. Some of the PHMs do not have cardiovascular indications, eg, glucocorticoids and NSAIDs. These 2 groups of medications were, in fact, used less frequently in the CHF population than in the general population. However, these differences were slight and did not achieve statistical significance.
Since the PHMs with cardiovascular indications are used more frequently in the CHF population than in the general population, and the PHMs without cardiovascular indications are used at approximately the same frequency in the CHF population as in the control population, it would appear that the precautions and contraindications required in the FDA-approved labeling do not have a major effect on the clinical use or prescribing of these medications. This observation might cause one to question whether the precautions and contraindications in FDA-approved labeling are meaningful. Further, the data in Figure 1 and Table 3 show that many of the PHMs are associated with an increased risk of hospitalization when used in CHF patients. However, no clear pattern is observed with regard to the risk -- ie, the PHMs that are associated with increased risk of hospitalization include both those with and those without cardiovascular indications.

Since precautions rather than contraindications appear on the labeling of most of the PHMs, it may be that in some cases the PHMs are being used with caution. Some of the data reported here are consistent with that view. For example, the adverse effect of NSAIDs on CHF patients is known[9,10] and the odds ratio for hospitalization is not statistically different from the risk for CHF alone. Similarly, the dihydropyridine calcium channel blockers and verapamil are labeled to be used with caution in CHF patients, and the risk of hospitalization associated with these medications is also not statistically significant. The fact that use of these medications did not lead to an increased risk of hospitalization in patients with CHF may indicate that appropriate caution was used in these patients.

The significant risk observed with some medications may be a reflection of changing patterns of use. Amlodipine has been shown to be safe in patients with depressed left ventricular function[11] but has not been shown to affect outcomes in CHF.[12] The perception that it is safe may result in its more frequent use in the CHF population, perhaps in the patients at greatest risk for hospitalization. Such preferential use was not observed in this study. Table 2 demonstrates that, while amlodipine is used approximately 2.7 times more in the CHF population than in the control population, the other calcium channel blockers are used 2.3 times more frequently in the CHF population than in controls. These relative differences are not suggestive of a major difference in attitudes toward use. Both of these relative changes are greater in magnitude than those observed with diltiazem or verapamil use (1.3- and 1.2-fold increases, respectively).

There is increasing recognition of the role of beta blockers in the management of CHF.[13, 14] Indeed, the product labeling for carvedilol recognizes this by including heart failure as an indication while still advising caution during the initiation of therapy and in patient selection.[15] It is possible that beta blockers are being used more frequently in patients with more severe CHF, and that it is the severity of the disease rather than the use of the medication that is responsible for the increased risk of hospitalization. Analysis of the data prior to aggregation reveals that the frequency of beta blocker use increased in both the controls and the case cohorts with CHF (almost 3-fold in the case cohort vs 2-fold in the control population [data not shown]).

In conclusion, these data reflect that PHMs labeled with precautions or contraindications regarding their use in CHF are prescribed at approximately the same frequency in CHF patients as in patients without CHF. For a number of these PHMs, the precautions seem to be warranted, as there is an increased risk of hospitalization associated with their use in patients with CHF. For those medications not associated with an increased risk of hospitalization, it is possible that the precautions have had their intended effect, with the result that patients receiving such medications are not hospitalized.

References

Lazarou J, Pomeranz BH, Corey PN, et al. Incidence of adverse drug reactions in hospitalized patients: a meta analysis of prospective studies. JAMA.1998; 279:1200-1206.
Bates DW, Cullen DJ, Laird N, et al. Incidence of adverse drug events and potential adverse drug events: implications for prevention. JAMA. 1995;274:29-34.
Kohn LT, Corrigan JM, Donaldson MS, eds. To err is human. Building a safer health system. Committee on Quality of Health Care in America. Institute of Medicine. Washington, DC: Academy Press; 1999.
Lesar TS, Briceland L, Stein D. Factors related to medication prescribing errors. JAMA. 1997;277:312-317.
Lesar TS. Medication prescribing error reporting and prevention program: a 14-year experience. Medscape Pharmacists. 2000. Available at http://www.medscape.com/Medscape/pharmacists/journal/ 2000/v01.n04/mph7176.lesa/mph7176.lesa-01.html.
United States Food and Drug Administration. Labeling review acceptable? Available at http://www.fda.gov/cder/handbook/labelrev.htm
Hennekens CH, Buring JE. Epidemiology in Medicine. Boston, Mass: Little, Brown and Co; 1987: 302-303.
Hamilton RA, Briceland LL, Andritz MH. Frequency of hospitalization following exposure to drugs known to interact in a Medicaid population. Pharmacotherapy. 1998;18:1112-1120.
Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients. Arch Intern Med. 2000;160:777-784.
Heerdink ER, Leufkens HG, Herings RM, et al. NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med. 1998;158:1108-1112.
Packer M, O'Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med.1996;335:1107-1114.
Packer M. PRAISE-2. Presented at the 49th Annual Scientific Session of the American College of Cardiology; March 15, 2000; Anaheim, Calif.
Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996;334:1349-1355.
Hjalmarson A, Goldstein S, Fagerberg B, et al. Effcts of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure. JAMA. 2000;283:1295-1302.
Anonymous. Coreg Product Label. Physician's Desk Reference. Montvale, NJ: Medical Economics Company, Inc.; 2001:3081-3083.

Robert A. Hamilton, PharmD, is Professor, Department of Pharmacy Practice, Albany College of Pharmacy, and Member, New York State Drug Utilization Review Board, Albany, New York.

Novartis Claims Lead in Race to Find Novel COPD Therapies

LONDON (Reuters Health) Feb 27 - The Swiss group Novartis today claimed to be leading the race in the development of novel compounds that attack the underlying inflammatory process responsible for asthma and chronic obstructive pulmonary disease (COPD).

"What we have decided to do is to really attack the underlying disease and aim to come up with a cure rather than symptomatic treatment," the head of respiratory research, Dr John Westwick, told Reuters Health.

"Within phase l, we have novel treatment for both COPD and asthma. As far as we are aware, other companies do not have these," he added.

Westwick, a former professor of pharmacology, declined to disclose the mechanism of action of the new compounds, but said the targets were moderate to severe asthma and severe COPD.

New therapies are badly needed, he said, because existing drugs only worked in mild to moderate disease. "In the UK alone, about 25 000 people will die this year from COPD, many more than from asthma. There is no really effective treatment. COPD is crying out for a product that works."

"For COPD we are not yet at the stage to announce where we are," he continued. However, the strategy is "to inhibit the neutrophils, the macrophages and the T cells that are driving the breakdown of the pulmonary tissue that occurs within COPD."

Westwick said that Novartis, like most other companies, has been exploiting commercial human genome databases to carry out its research.

"We have been acquiring positional cloning techniques to try to find a polymorphism in the particular gene which was responsible for a particular clinical phenotype. And we have been doing things like expression profiling between normal and diseased tissue to see whether different proteins are being regulated."

Novartis already has several new asthma compounds, including the recently launched beta-2 agonist Foradil and Xolair, which is being developed for acute asthma and rhinitis

Rosiglitazone Twice Daily Improves Glycemic Control More Than Once-a-Day Dosing

WESTPORT, CT (Reuters Health) Feb 27 - Rosiglitazone significantly improves glycemic control in patients with type 2 diabetes mellitus, according to the results of a multicenter trial. Twice-daily dosing was more effective than an equivalent dose given once a day.

Dr. Lawrence S. Phillips, of Emory University School of Medicine in Atlanta, and colleagues randomly assigned 959 patients from 65 centers in the US to placebo or one of four dosages of rosiglitazone for 26 weeks, after a 4-week placebo run-in period. The dosages studied were 4 mg/day, 2 mg b.i.d., 8 mg/day and 4 mg b.i.d.

The mean decreases in glycosylated hemoglobin (HbA1c) were -0.8%, -0.9%, -1.1%, and -1.5% in the four rosiglitazone treatment groups, respectively, from mean baseline values of 8.9% to 9.0%. These reductions occurred between week 8 and week 18. Fasting plasma glucose also decreased compared with placebo, the investigators report in the February issue of Diabetes Care.

Rosiglitazone was most effective in drug-naive patients, with 25% to 40% of patients achieving an HbA1c concentration of 7.0% or less, compared with 17% of those using placebo. Corresponding results in patients who had received prior oral monotherapy were 13% to 25% versus 6%. In those who had previously used combination oral antihyperglycemics, only the 4 mg b.i.d. dose decreased the HbA1c concentration.

Dr. Phillips and his associates conclude, "Because responses varied by patients' treatment history, it appears that once-daily rosiglitazone may be sufficient as first-line therapy for patients with recent diagnoses, whereas 4 mg b.i.d. may be needed for patients with more advanced diabetes."

Diabetes Care 2001;24:308-315.

Consumer Group Urges FDA Probe into Schering-Plough Manufacturing Practices

By Laura Gilcrest

WASHINGTON (Reuters Health) Mar 01 - A consumer advocacy group is asking the US Food and Drug Administration to consider whether criminal charges should be brought against Schering-Plough, claiming that the company distributed defective asthma inhalers, later found to contain no active ingredient, despite known quality control problems at its New Jersey plant.

In a letter sent to US Health and Human Services (HHS) Secretary Tommy Thompson, the Public Citizen Health Research Group urged the FDA to investigate what it called "sloppy manufacturing practices" in connection with the production of the company's asthma drugs and other products. The group claimed that Schering-Plough was compelled to recall 59 million of its asthma inhalers because they lacked the active ingredient.

Public Citizen alleged that inspections by FDA staff and outside auditors have uncovered an ongoing pattern of deficiencies at the Kenilworth, New Jersey-based facility, which it blamed for the product defects.

"The practices uncovered [at the New Jersey plant] are dangerously sloppy and threaten the health of consumers," said the group's director Dr. Sidney Wolfe. "This is no way to run a drug company."

In pressing its case, the advocacy organization pointed to the FDA's suspension of Schering-Plough's operations at two sites in New Jersey and a third in Puerto Rico, as well as the FDA's decision to delay approval of Clarinex (desloratadine), successor drug to Claritin (loratadine), until the manufacturing problems are addressed.

The group quoted FDA inspectors who visited the Kenilworth site in December and January as saying that there was "no assurance that the manufacturing processes, parameters, equipment or protocols ...for the production of Clarinex...are equivalent or capable of producing product of the same quality."

Public Citizen also claimed that managers at the New Jersey plant described the atmosphere at the facility as "an imbalance between quality and production, leaning considerably toward production," when auditors from the Rockville, Maryland-based AAC Consulting Group visited the site in early 2000.

While he would not comment specifically on Public Citizen's letter, Schering-Plough spokesman Robert Consalvo told Reuters Health that the company took measures to ensure that none of its asthma inhalers that could have been affected by problems at its facilities reached consumers.

"All of the recall and manufacturing issues have been reported to the FDA and we have worked with the FDA to resolve them," he said.

Consalvo said that the deficiencies at the New Jersey plant stemmed from a faulty manufacturing protocol, which the company has since revised. After discovering the problem, Schering-Plough stopped production and suspended shipment of most of its aerosol products, he said.

Consalvo could not confirm Public Citizen's estimate of 59 million inhalers recalled by Schering-Plough, but said that the number of defective products due to the original manufacturing protocol was relatively small. He explained that the company recalled 5 lots of Vanceril (beclomethasone dipropionate) in December 1999, which contained no active ingredient, followed by a much larger recall in March 2000 of all inhalers, including those containing Vanceril and Proventil (albuterol), that could have been made under the old protocol.

Public Citizen's missive comes after shareholders weighed in earlier this week on Schering-Plough's manufacturing troubles. They filed a class action suit charging that the company withheld its regulatory problems from investors and their effect on the delay of Clarinex's approval.

Schering-Plough shares dropped 2.32 points to close at 38.78 in Thursday trading on the New York Stock Exchange.