April 2001 Therapeutics Letter

April 2001                                        Bruce H. Woolley, Pharm.D., Editor                                     Vol. 8, No. 4
Kenneth J. Hunt, Associate Editor

Crohn's disease (CD) is characterized by chronic inflammation at various sites in the gastrointestinal tract, most commonly the distal ileum and colon. The major symptoms are diarrhea, abdominal pain, enterocutaneous and perianal fistulas, and weight loss. Annual incidence of CD in the United States has been estimated to be 5 cases per 100,000 people. Though any age group can be affected, the peak age of onset is 15-25 years. The average total direct medical cost associated with CD is nearly $7000 per patient per year. Patients with CD may also bear substantial indirect costs due to loss of work or forced early retirement.

Management of CD includes alleviating symptoms, maintaining remission, healing damaged mucosae or fistulas and modifying the underlying disease process. Drugs traditionally used to manage CD are aminosalicylates, antimicrobials, and corticosteroids. Infliximab is a monoclonal antibody targeted at human tumor necrosis factor (TNF), an inflammatory cytokine important in the pathogenesis of CD. Infliximab antagonizes the biological activity of TNF by binding to it on macrophage and T cell surfaces.

Recent clinical trials have shown infliximab to be effective in producing and maintaining a clinical response in patients with refractory, moderate to severe CD. Use of Infliximab promotes healing of intestinal mucosa and closure of fistulas. Infliximab may act more rapidly than most traditional agents and produces fewer severe adverse effects. (The most frequent adverse effects are headache, nausea, and upper-respiratory infections) Infliximab is generally given at eight-week intervals for maintenance or management of flare-ups. The use of this drug appears useful in the treatment of CD and may improve patients' quality of life.

Garnett WR and Yunker N; Am J Health-Syst Pharm 58(04):307-319, 2001.

Tibolone in the Prevention of Osteoporotic Fractures

Osteoporosis is one of the world's leading causes of morbidity and mortality in the elderly. In the United States, as many as 15% of women around the age of 50 years and up to 70% of women over the age of 80 years are thought to be osteoporotic. The most commonly targeted age group is postmenopausal women. Hormone replacement therapy (HRT) has been shown in various clinical trials in the United States and Europe to protect against fractures, as well as to alleviate critical symptoms related to menopause. Unfortunately, HRT has a number of adverse effects and many patients are noncompliant.

The primary risk posed by osteoporosis is the high likelihood of bone fractures, the most debilitating and costly of which occur in the hip. Internationally, it has been estimated that approximately 40% of women, and even 14% of men, will experience one or more osteoporotic fractures after the age of 50 years, and more than one-third of these will be hip fractures. With the unprecedented longevity in the developed world, new treatments for osteoporosis are an important area of pharmaceutical and therapeutic research.

Tibolone (Livial7/Organon) is a synthetic steroid with tissue-specific estrogenic, progestogenic and androgenic effects. In a recent clinical trial conducted in Sweden, tibolone was shown to prevent the loss of bone mass as well as to relieve critical symptoms in postmenopausal women, with fewer accompanying adverse effects. The investigators reported that 22% of hip fractures and 13% of combined hip, vertebral and forearm fractures can be avoided over a 25-year time-period by administering tibolone to osteoporotic women.

Depending on the severity of loss in bone mass and the values assumed for key parameters, estimates of the cost effectiveness of treatment range from cost saving to incremental costs per quality-adjusted life-year gained of around $20,000 USD (200,000 Swedish Kronas). Delaying treatment to late menopause tends to decrease cost effectiveness.

This study suggests that the administration of tibolone in women with osteopenia and osteoporosis for the prevention of bone fractures is cost effective relative to a policy of no treatment, especially when treatment is initiated around the onset of menopause (around 53 years of age) and treatment is administered for a duration of 5 years.

Wills M, et al. Clin Drug Invest 21(2):115-127, 2001.

A Summary of Hair Loss Treatment

Non-scarring alopecia refers to hair loss without permanent destruction of the hair follicle. This is the most common pathogenesis of baldness in men and women and includes androgenetic and chemical alopecia, as well as mild folliculitis and certain inherited disorders of the hair shaft. The approach to diagnosing and treating patients with hair loss involves broad methods of treatments, including psychological support

The diagnosis of androgenetic alopecia, the most common form of hair loss, is usually straightforward in men. Diffuse frontal to vertex thinning in women may provide a greater diagnostic challenge. It is important to rule out other causes of diffuse hair loss, such as illness (e.g., hypothyroidism), medications, or trauma. A family history of similar hair loss is suggestive of androgenetic alopecia.

Treatment of hair loss includes oral and topical drugs, as well as patient education. Oral finasteride (Propecia) and topical solutions of minoxidil (Rogaine) are the only drugs approved by the FDA for treatment of androgenetic alopecia in men. Only minoxidil is approved in women. Taking photographs prior to the initiation of therapy and four months afterward may be helpful to document any change in appearance.

Minoxidil (Rogaine®/Pharmacia) promotes hair growth by increasing the duration of the hair growth cycle and enlarging miniaturized and suboptimal follicles. Topical minoxidil is available over the counter in both 2% and 5% solutions. Studies have shown that patients applying minoxidil to the scalp twice daily results in up to 45% higher hair counts, more than five times higher than placebo. A normal, healthy scalp is required for this medication to be effective and cosmetically significant hair growth occurs in only 30% to 40% of patients. Treatment must be continued indefinitely; once discontinued, any hair maintained or regrown as a result of the medication will be lost.

Finasteride (Propecia®/Merck) is an inhibitor of 5alpha-reductase, the enzyme that normally converts testosterone to dihydrotestosterone. An oral dose of 1 mg/day rapidly lowers serum and scalp dihydrotestosterone levels by more than 60 percent. It does not, however, have any effect on testosterone action or any steroidal effects of its own. The 1 mg dose of finasteride used to treat hair loss is much lower than the typical 5 mg dose used to treat benign prostatic hypertrophy (BPH), eliminating many of the side effects seen in BPH treatment.

There are as yet no head-to-head comparisons between finasteride and minoxidil, but clinical observations suggest that finasteride is easier for patients to use and thus may increase compliance with therapy resulting in better outcomes. Patients should be educated regarding day-to-day treatment of their hair and scalp as well. The use of hair treatments and tonics should be discouraged as they are unproven and may be damaging. Minoxidil solution should be used for an indefinite time and it is not usually covered by insurance. Once stopped, any hair regrowth will be lost and a response will not be seen for at least four months before evaluating response to therapy.

Price, VH. Treatment of hair loss. N Engl J Med 1999; 341:964.
Goldstein BG; Hair Loss. Up To Date 2001, http://www.medscape.com/

Aspirin Use in Diabetics: Implications for CVD prevention

According to a recent article in Diabetes Care, aspirin therapy for the prevention of cardiovascular disease (CVD) may be particularly beneficial for people with diabetes. People with diabetes are two to four times as likely to develop CVD as people without the disease and patients with diabetes have been observed to have altered platelet function with increased production of thromboxane, the important target of aspirin therapy in the context of CVD.

The investigators implemented data from the Third National Health and Nutrition Examination Survey (NHANES, 1988-1994), using a probability sample of the U.S. population that included an interview, physical examination, and laboratory studies. The survey participants included 1,500 adults with self-reported diabetes. The investigators defined regular aspirin use as reported having taken aspirin more than 15 times in the previous month.

An estimated 27% of adults with diabetes had CVD, and an additional 71% had one or more CVD risk factors. Aspirin was used regularly by 37% of those with CVD and by 13% of those with risk factors only. Adjusted odds of regular aspirin use were significantly greater for individuals with CVD than for those with one CVD risk factor

Nearly every adult in the U.S. with diabetes has at least one risk factor for CVD and thus may be considered a potential candidate for aspirin therapy. During 1988-1994, only 20% of patients in this demographic took aspirin regularly. The investigators argue that more concentrated efforts are needed to increase aspirin use for the prevention of CVD.

Rolka DB, et al. Diabetes Care 24(2):197-201, 2001

Safety Information for Miconazole

The FDA recently released an advisory to women who take the prescription blood-thinner warfarin, recommending that they consult their doctor or pharmacist prior to using an OTC vaginal miconazole product. Manufacturers of vaginal creams and suppositories containing miconazole have been advised to add a new warning to the Drugs Facts box on product labels. The warning states: Ask a doctor or pharmacist before use if you are taking the prescription blood thinning medicine warfarin, because bleeding or bruising may occur.

The FDA has received several adverse event reports indicating abnormal blood clotting tests with women who took anticoagulant therapy and used vaginal miconazole. Adverse events included abnormal tests, bruises, bleeding gums and a nosebleed. Additionally, two articles from medical journals reported cases of probable warfarin interaction with vaginal miconazole. The FDA aims to educate consumers about a drug's potential risks before deciding to use it.

Miconazole is an antifungal drug that is available by prescription and over-the-counter in different forms such as creams and suppositories used to treat vaginal yeast infections. The interaction of systemically administered miconazole with warfarin is well established, and is included in the warfarin labeling. Physicians and patients should be aware that patients who need to use both products simultaneously should be appropriately monitored. The new warning label will be included in consumer brochures.

FDA Talk Paper http://www.fda.gov/cder/

Warning Issued on Zyvox (linezolid)

There have been several reports of myelosuppression (anemia, leukopenia, pancytopenia and thrombocytopenia) in patients receiving linezolid (Zyvox®/Pharmacia), a synthetic antibiotic used in adults infected with multiple resistant strains of bacteria. Pharmacia, the manufacturer of the drug, issued a letter to physicians recommending that complete blood counts should be monitored weekly in patients who receive linezolid. This is especially important in patients who 1) receive linezolid for longer than two weeks, 2) patients with pre-existing myelosuppression, 3) patients receiving concomitant drugs that produce bone marrow suppression, or 4) patients with chronic infection who have received previous or concomitant antibiotic therapy.