News Briefs
News Briefs
FDA compounding list nears completion
The Food and Drug Administration is moving forward with efforts to complete its list of bulk substances acceptable for pharmacy compounding. Earlier this year, the FDA’s Pharmacy Compounding Advisory Committee met to review findings on 10 substances nominated for inclusion. As a result, four substances: betahistine dihydrochloride, cyclandelate, monosodium aspartate, and squaric acid, made the cut.
The FDA Modernization Act of 1997 says compounders may use substances that have a U.S. Pharmacopeia or National Formulary monograph, are components of FDA approved drugs, or appear on the list that is now being compiled.
Once the list is finalized, it will be illegal to use unspecified substances, along with substances that are expressly forbidden by their inclusion on the "negative list." The FDA expects to issue proposed general regulations in January.
Drug distribution limited after liver failure reports
The Food and Drug Administration and Pfizer are now recommending curtailed use of the drug trovafloxacin and its prodrug derivative alatrofloxacin. Published reports say distribution of the drugs will be limited to hospitals and long-term nursing facilities.
The move reportedly follows 140 reports of hepatic events associated with the two products, including 14 cases of acute liver failure. At least six patients died.
The new recommendations are that the drugs be used only under the following circumstances: the infection is serious and threatens life or limb, therapy is begun in a hospital or long-term care nursing facility, and the physician believes the benefits outweigh the potential risks. European regulators also are reviewing the use of the two drugs.
Lisinopril: FDA considers approving higher doses
AstraZeneca Pharmaceuticals in Wilmington, DE, filed a supplemental new drug application a few months ago to request approval for the use of its long-acting ACE inhibitor Zestril (lisinopril) at doses of up to 35 mg once daily in managing heart failure.
Lisinopril already is indicated as adjunctive therapy in the management of heart failure for patients not responding adequately to diuretics and digitalis. The drug also is indicated for treating hypertension and improving survival of hemodynamically stable patients within 24 hours of heart attack. Its usual effective dosage range for congestive heart failure (CHF) patients is 5 mg to 20 mg, once daily.
But cardiologists have been prescribing larger doses all along, says David S. Roffman, PharmD, BCPS, associate professor of pharmacy practice and science at the University of Maryland’s school of pharmacy in Baltimore and therapeutic consultant for the medical system’s cardiac care unit.
"Cardiologists typically give high doses of ACE inhibitors anyway," he says, "based on the premise that higher doses — if they are tolerated, and they usually are — do more for symptomatic improvement than lower doses." He says physicians have the prerogative to use meds in a way they think is appropriate for patients, irrespective of FDA-approved labeling. "The majority of physicians will, on occasion, use a drug for a non-FDA-approved indication in a dose that is not necessarily FDA-approved because they see evidence for its benefit in the literature."
"There is symptomatic improvement when lisinopril dosage is increased to the 40 mg level," Roffman explains. "Whether that improvement could be translated to mortality in a larger study is unknown at this point, but early indications from ATLAS imply that patients who don’t get systematic improvement on 20 mg of lisinopril, for example, may experience improved symptoms when the dosage is increased to 40. That is the impetus for AstraZeneca’s application to the FDA for increasing the dose."
He says that while many CHF cardiologists have been prescribing 40 mg doses of Prinivil or Zestril for a long time despite FDA approvals, "unfortunately, in the community population, people are put on small doses of ACE inhibitors and left on them." Overall, he says, ACE inhibitors are underused. Only 30% to 50% of CHF patients are on them.
AstraZeneca’s rationale for the label change is based on the results of a five-year clinical trial, ATLAS (Assessment of Treatment with Lisinopril and Survival), which evaluated the effect of low (2.5 mg to 5 mg) vs. high (32.5 mg to 35 mg) doses of lisinopril on mortality and morbidity in more than 3,000 CHF patients. ATLAS results were first presented last year at the 47th annual American College of Cardiology scientific session in Atlanta, and they indicated a 12% risk reduction in all-cause mortality and all-cause hospitalizations when patients were treated with higher doses.
Raymond Urbanski, MD, associate medical director at AstraZeneca, explained the complexity of determining ideal dosages for CHF: "For a condition like hypertension, you can monitor a pa tient’s blood pressure and adjust the dose that way. But in patients with heart failure, you’re not sure what dosages are more or less effective because you don’t have such a simple marker as you do with hypertension. Instead, you have to look at different specific dosage levels and then look at outcomes data — morbidity and mortality statistics — to ascertain what doses are more efficacious."
That was the rationale for the ATLAS study. "Based on that data," he says, "it appears that higher doses [of lisinopril] produce a better outcome with regard to morbidity and mortality than lower doses." The dose-response relationship between lisinopril and its mechanism of action in CHF — its effect on the left ventricular remodeling process — is not known. It appears that lisinopril acts at the cardiac level by altering some of the neurohumeral factors that are involved in worsening heart failure. "We don’t know the dose-response relationship to that," he says, "but based on the ATLAS data, it appears that higher doses are efficacious in counteracting that pathologic process, and that low doses, while effective, are not as effective as the higher doses."
[For more on Zestril, call (800) 456-3669, ext. 2231; www.usa.zeneca.com/pharm/pibs/pib_zestril.htm. For more on Prinivil, call (215) 652-5000; www.merck. com.]
Reference
1. Packer M. Do angiotensin-converting enzyme inhibitors prolong life in patients with heart failure treated in clinical practice? J AM Coll Cardiol 1996; 28:1,323-1,327.
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