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June 2000 Bruce H. Woolley, Pharm.D., Editor Vol. 7, No. 6
Kenneth J. Hunt, Associate Editor

Zyvox Approved by the FDA

Infections due to enterococci and methycillin-resistant staph aureus (MRSA) have become an important problem in hospitalized and immune compromised patients. For the past decade, there has been a rapid increase in enterococci and MRSA that are resistant to vancomycin, our last resort medication for such infections. The limited availability of therapeutic options for infections with vanocmycin-resistant enterococcal (VRE) has created a haste among drug developers to solve the problem.

The FDA recently approved Zyvox (linezolid), the first antibacterial drug in the oxazolidinone class to treat infections associated with VRE. The drug acts as an inhibtor of bacterial protein synthesis and has bactericidal activity primarily against gram positive pathogens. Zyvox was also approved for treatment of hospital-acquired pneumonia and complicated skin due to MRSA. Approval was granted for treatment of community-acquired pneumonia and uncomplicated skin infections. It is the first drug in over 40 years to be introduced into the US market for treatment of MRSA infections.

Clinical trials demonstrated linezolid to be effective against VRE and MRSA strains. The drug’s efficacy was supported by controlled clinical trials involving more than 4000 patients. Types of VRE infections investigated included complicated intra-abdominal infections, skin and skin structure infections, urinary tract infections, and bacteremia of unknown origin. The cure rate for Zyvox was 67 percent at higher doses and 52 percent in lower doses.

Zyvox is as effective as vancomycin for treatment of hospital-acquired pneumonia, including cases due to MRSA. The approval for complicated skin and soft tissue infections was based on a trial comparing linezolid with oxacillin/ dicloxacillin. The most frequently reported side effects attributed to Zyvox in clinical studies were headache, nausea, diarrhea, and vomiting. The most important laboratory test change was a decrease in platelet counts.

Zyvox may interact with certain drugs, including over-the-counter cold remedies that contain pseudoephedrine or phenylpropanolamine, and may moderately increase blood pressure. Physicians should ensure that patients do not take these contraindicated medications.

Zyvox is expected to be implemented in hospital or institutional care settings. The drug’s manufacturers, Pharmacia and Upjohn will initially market it in the United States. Due to concerns about inappropriate use of antibiotics leading to an increase in resistant organisms, physicians should carefully consider alternatives before initiating treatment with Zyvox in the outpatient setting. Resistance to anti-microbial medications remains a dilemma that is progressing faster than our solutions to it.

From Medscape Infectious Diseases, May 4, 2000 Linezolid: A Newly Approved Antibiotic

COX-2 and Kidney Failure

 The use of cyclooxygenase-2 (COX-2) inhibitors for pain management has been demonstrated to result in acute renal failure in patients with chronic renal insufficiency. Physicians from Yale University recently presented several case reports of renal failure in COX-2 patients in the May issue of the American Journal of Kidney Diseases. The three cases presented were chronically ill and treated with the celecoxib or rofecoxib for pain amelioration.

All three patients had some form of renal insufficiency and presented with acute renal failure within two weeks of beginning COX-2 therapy. Once the medications were discontinued, diuretic therapy or dialysis returned renal function to near baseline. The researchers attributed each case of acute renal failure to celecoxib or rofecoxib therapy.

There is an increasingly strong preference among physicians to use COX-2 inhibitors for relieving pain and inflammation in high-risk patients, especially among those who wish to avoid the complications of narcotic analgesics. Case reports such as these indicate the need to monitor renal function prior to and during treatment with COX-2 inhibitors. The trend of use of these drugs should continue safely and additional drugs with enhanced safety and efficacy are on the horizon.

Thanks to Am J Kidney Dis 2000;35:937-940,976-977.


Combination Therapy for Type II Diabetes



The recent annual meeting of the American Association of Clinical Endocrinologists included discussion on the use of metformin and glyburide as first line therapy for patients with type II diabetes. According to the reporting physicians, therapy with these two drugs in combination provides the best and most persistent control of blood glucose.

Researchers at Bristol-Myers Squibb are currently conducting a 52-week, open-label trial investigatin the efficacy of the drug combination in patients with NIDDM. The trial will include 826 diabetic patients assigned to therapy with metformin and glyburide at varying doses, depending on their initial hemoglobin A1c levels.

The rationale behind the use of two drugs is that medications using different mechanisms of action, control of glucose will be greatly enhanced. Metformin enhances insulin sensitivity in liver and muscle, but does not stimulate insulin secretion. Glyburide is a sulfonylurea that stimulates the release of insulin from the pancreas. This type of therapy is already established for hypertension and several other chronic conditions. Data from Bristol-Myers-Squibb and other similar trials will be presented to the Food and Drug Administration for review soon.

Popular Herbal Products: Ginger for nausea and vomiting

This month’s review of herbs covers a common alternative therapy that is one of the several culinary herbs. Ginger Root (Zingiber officinale) is often advocated as beneficial in the alternative treatment for nausea and vomiting. The true safety and efficacy of this drug, however, still a matter of debate.

Since 1995, there have been more than ten randomized controlled trials on the efficacy of ginger for nausea and vomiting. Several of these studies were published in major anesthesia journals and investigated the use of ginger root for postoperative nausea and vomiting. Two of the studies suggested that ginger was superior to placebo and equally effective as metoclopramide, a strong anti-emetic commonly used after surgery and chemotherapy.

There are also several trials that investigate ginger’s effectiveness against nausea and vomiting associated with seasickness, morning sickness and chemotherapy-induced nausea. As a whole, these studies collectively favor ginger over placebo, but do not make comparisons to commonly used anti-emetic medications.

There are no frequently reported side effects or drug interactions listed for use of ginger root. Patients with gallstones should use caution in taking ginger and the herb should not be used by pregnant women for the treatment of morning sickness. Ginger root is an example of an herb that is not harmful and has some clinically proven therapeutic activity. As always, health professionals should keep patients informed as to the proven benefits and safety issues of herbs they may be taking.

Br J Anaesth 2000 Mar;84(3):367-71

Caffeine and Bone Loss

 As osteoporosis becomes increasingly prevalent in the United States, a number of studies are attempting to demonstrate appropriate dietary and pharmacologic approaches to maintaining bone density. Calcium has been the most widely studied factor, but the impact of other factors such as caffeine and certain divalent minerals and fiber have also been investigated.

Researchers from the Milton S. Hershey Medical Center in Pennsylvania recently conducted a longitudinal trial on caffeine’s impact on bone density. Published in the Journal of the American College of Nutrition, the study found no significant correlations between dietary caffeine and bone density changes in 92 postmenopausal women over a 2-year time span.

The authors concluded that the study does not support the currently accepted view that caffeine is a risk factor for bone loss. Subjects in the group were a homogenous group of Caucasian females, none of whom had any other risk factors for osteoporosis. The study also did not address the impact caffeine might have on absorption of dietary calcium.

J Am Coll Nutr 2000;19:256-261.

Warning Issued on Anti-Cancer Drug 

Numerous medications are in development to aid in the fight against various cancers. Makers of herceptin (trastuzumab), a drug recently approved for the treatment of certain metastatic breast cancers, recently issued an alert to physicians about 62 postmarketing reports of serious adverse events related to the use of the drug. Several of these events included fatal outcomes. Serious adverse events included hypersensitivity, infusion, and pulmonary reactions.

Due to this new information, Genentech, Inc will modify product labeling to include additional adverse reactions: Hypersensitivity reactions including fatal anaphylaxis; infusion reactions, including some with a fatal outcome; and pulmonary events, including adult respiratory distress syndrome and death.

Some of these adverse events were observed in clinical trials, but were far less severe. Most patients with fatal events had significant pre-existing pulmonary conditions due to secondary pulmonary difficulties. As patients with significant pre-existing pulmonary compromise may be at greater risk, these patients should be treated with extreme caution.

Patients experiencing any of the severe infusion-associated symptoms described in the prescribing information should discontinue treatment with herceptin and suitable therapy should be administered. Patients should be closely monitored until their symptoms resolve completely. Physicians should warn patients taking herceptin about the possibility of severe delayed reactions.

It is estimated that 25,000 breast cancer patients have been treated with herceptin worldwide since marketing approval. The new package insert that includes these warnings will be available shortly. Healthcare professionals should report any serious adverse events suspected to be associated with herceptin to the FDA's MedWatch reporting system (1-800-FDA-1088). Any additional questions regarding the drug should be directed to the Genentech Medical Information Department (1-800-821-8590).

Thanks to FDA Center for Drug Evaluation and Research










The Future of the Herbal Industry

When congress passed the Dietary Supplement Health and Education Act of 1994 (DSHEA), a six year period of unprecedented growth in the herbal and nutritional supplement industry ensued. Though there is evidence that this trend is slowing, the US public is using increasing numbers of herbal and nutritional products in conjunction with or as replacements for conventional medicine. As the primary providers of health information, physicians and pharmacists face scores of questions about the safety and efficacy of these substances.

The principal concern among patients and health professionals is the quality and reliability of the products available. Plant products present challenges from a regulatory and safety perspective due to the wide variety of potentially active constituents contained within them. There is variation in quality and content of botanicals based on the source of raw materials and the manufacturing process. Potential problems include both contamination and inconsistent concentration of active ingredients. These facets of botanical preparations are not currently regulated in the United States.

Each month, new trials and data are released on safety and efficacy issues for particular herbs and alternative medicines. Furthermore, alternative therapies are a dynamic industry that has a tremendous impact on health care and continues to be a source of legislative measures. In the absence of regulatory changes at the government level, health professionals must be familiar with the quality of popular botanical product in order to speak confidently about product to a patient.

This and future newsletter issues will contain information and updates on the most popular herbal supplements. Information will be based on published findings of safety, efficacy, and dosage for each herbal product. All health professionals should take time to learn about the major issues involved and begin to learn about the quality standards of herbal products that their patients are taking. This becomes a difficult task for busy clinicians. The monthly updates will serve as a concise look at herbal products as we hope the nation progresses toward a higher standard of assuring safe use of herbal products.

Popular Herbal Products: Garlic for Hyperlipidemia

Alternative medicine continues to hit the nation like a storm. Sales of herbal medications exceed $1.5 billion a year and are still increasing. Patients and consumers are seeking alternative therapies to supplement or even replace modern conventional medicine. The safety and efficacy of these products, however, remain a troubling problem in the herbal world. While some alternative medicines have been scientifically demonstrated, many are either controversial or unproven.

Garlic is the one currently marketed herbal product whose effects are well supported by scientific and clinical evidence. Allicin, garlic’s biologically active constituent, is a product formed by enzymatic action from alliin - a crystalline amino acid occurring in garlic oil. Common indications for garlic include use as therapy for atherosclerosis and as an antibacterial, antiviral, and antifungal agent. It is also used to treat mild hypertension and hypercholesterolemia. It is most effective in reducation of blood lipids.

More than 32 human studies since 1975 have demonstrated the lipid-lowering effects of garlic. The majority of these were completed with the most common garlic powder tablet that is standardized to 1.3% alliin. Meta-analyses have indicated that doses from 600 to 900mg of garlic powder daily for 1 to 3 months reduces total serum cholesterol by 9% to 12% and lowers serum triglycerides by 8% to 27%. However, the overall design of most studies weakens the validity of their findings. Future studies should include placebos that look, taste, and smell like garlic and also incorporate dietary habits or restrictions. Look for LDL to be used as a more precise marker of cardiovascular risk than total cholesterol.

Daily consumption of moderate quantities of garlic should not pose any health risk to healthy people. Larger doses of more than one clove per day can cause heartburn, and certain mild gastrointestinal problems. As garlic reduces blood-clotting time, patients taking aspirin or anticoagulant drugs should avoid consuming large amounts. There are no other known contraindications to the use of garlic.

Future newsletters will contain similar articles on herbs and alternative therapies. The purpose of these articles is to update health professionals on current research and legislation involving safety and efficacy for therapies that our patients are commonly using.

Thanks to Drug Benefit Trends 10(5):43-50, 1998

Propulsid Withdrawn From the Market

New Jersey based Janssen Pharmaceuticals recently announced that it will stop marketing cisapride (Propulsid) in the United States as of July 14, 2000. The effective date of the voluntary action is intended to provide adequate time for patients and physicians to make alternative treatment decisions. Cisapride approved only for the severe nighttime heartburn experienced by adult patients with gastroesophageal reflux disease (GERD) that does not adequately respond to other therapies.

As of January, 2000, use of cisapride has been associated with more than 340 reports of heart rhythm abnormalities including 80 reports of deaths. Most of these adverse events occurred in patients who were taking other medications or suffering from underlying conditions known to increase risk of cardiac arrhythmia. Patients who are currently taking cisapride are urged by Janssen and the FDA to promptly contact their health care providers to discuss alternative treatments.

Physicians who are treating patients with severely debilitating conditions for whom they believe the benefits of the cisapride may still outweigh its risks are encouraged to contact Janssen at 1-800-JANSSEN. The company will continue to make the drug available to patients who meet specific clinical eligibility criteria for a limited-access protocol.

Since the drug was approved 1993, Cisapride’s labeling has been revised several times to inform health care professionals and patients about the drug’s risks. Still, the company decide that continued general prescription access to the drug poses unacceptable risks.

See letter from Janssen:

Determining Longevity of Hepatitis C Infections

Hepatitis C currently affects around 3.5 million Americans, more than five times as many as are infected with HIV. Yet, research appropriations in the U.S. for hepatitis C are 255 times smaller than those for HIV. There is no funding for the treatment of chronic hepatitis, but $500 million is spent annually for AIDS treatment. It appears, however, that we are making strides toward the diagnosis and prognosis of Hepatits C infection.

According to the April 12 issue of Science, it is now possible to determine whether hepatitis C virus (HCV) infection will become chronic or resolve by examining the genetic diversity of the virus during the early stages of infection. In a prospective study of 12 patients with acute HCV infection, an Italian research group detected a dramatic increase in the genetic diversity of a region (HVR1) of the viruses genome patients with hepatitis that proved to be slowly or rapid progressive. Patients whose infection eventually resolved showed a decrease in genetic diversity of HVR1.

The researchers note that acute hepatitis progressing to chronicity correlates with the genetic evolution of HCV within the first 4 months of infection. The direct implication of HVR1 in the development of chronic HCV infection poses a major challenge for devising preventive and therapeutic strategies against the virus. The hope is to reduce mortality and morbidity associated with Hepatits C infections, an emerging global health issue.

Science 2000;288:339-344.

Interaction with Warfarin and Celecoxib

After recent reports of patients experiencing potentially dangerous changes anticoagulation activity in elderly patients, those taking both warfarin and celecoxib should have blood clotting times closely monitored.

Though the two drugs are primarily metabolized through the same pathway, it is not certain whether this causes a competitive inhibition of either or both drugs. A short-term study of healthy subjects found that co-administration of celecoxib and warfarin did not significantly affect prothrombin times. However, in response to several reports of increased prothrombin times, especially in the elderly, the FDA has recommended a product labeling change for celecoxib.

Nurses' Drug Alert 24(4):27, 2000

The information and opinions expressed in the Therapeutics Letter do not necessarily reflect the official policy of the sponsoring organizations