New indications sustain and can invigorate drugs as they mature. For drug manufacturers seeking new indication approval from the FDA, 2004 was a busy year. For specific populationsespecially the mentally ill and people with "unmentionable" problems2004's new indications offer hope.
The shortest 1.2% of children (having idiopathic short stature) may now be given the growth hormone somatropin, rDNA origin, for injection (Humatrope; Lilly) for longterm treatment. Somatropin-treated children grew an extra 1.5 to 2.8 inches in clinical trials. This is the first growth hormone therapy to specify a height restriction in children: it is indicated for those who are >2.25 SDs below the mean for their age and sex. The manufacturer is marketing somatropin solely to pediatric endocrinologists for this indication and is controlling distribution; it will not use direct-to-consumer advertising.
The FDA also has approved etanercept (Enbrel; Immunex), a fully human tumor necrosis factor antagonist, for active ankylosing spondylitis (AS). This chronic inflammatory disease primarily affects the lower back and joints, often leading to stiffening and fusion of the spine and hunched stature. (At press time, Centocor Inc had approached the FDA for a new indication for infliximab [Remicade] for the treatment of AS as well.)
Mind and Brain
Among the drugs employed for mind and brain disorders, significant changes have occurred:
Three antiepileptic drugs are breeching the borders of "broad spectrum," too:
Traditionally, superficial basal cell carcinoma (BCC) has been surgically excised or frozen. The FDA has approved the immune-response modifier imiquimod (Aldara; 3M) for "topical treatment of biopsy-confirmed, primary superficial BCCs in immunocompetent adults" that are 2 cm in diameter or less, and located only on the trunk, neck, or extremities (excluding hands and feet). This indication supplements the drug's previous indications: external genital warts and actinic keratoses on the face or scalp. Safety and efficacy data are lacking for superficial BCCs on the head, face, and anogenital areas. Imiquimod treatment, however, is cosmetically superior to freezing because it avoids hypopigmentation.
The FDA has approved oxaliplatin (Eloxatin; Sanofi-Synthelabo) with 5- fluorouracil/leucovorin for first-line treatment of advanced colorectal cancer. Since August 2002, oxaliplatin has been second-line treatment for metastatic colon or rectum cancer.
In addition, docetaxel injection (Taxotere; Aventis) is now approved with prednisone for patients with advanced metastatic prostate cancer. This is the first drug showing a survival benefit in hormone refractory prostate cancer.
The promotility agent tegaserod maleate (Zelnorm; Novartis) now has a supplemental indication: chronic idiopathic constipation in patients less than 65 years old. In 2 randomized, double-blind, placebo-controlled, multinational phase 3 clinical trials enrolling 2600 men and women, tegaserod significantly increased the frequency of complete spontaneous bowel movements.
Men who suffer from benign prostatic hyperplasia (BPH) will find relief: finasteride (Proscar; Merck) in combination with doxazosin is indicated to reduce BPH symptoms from progressing over time. The new indication is based on the 3047-patient Medical Therapy of Prostatic Symptoms study.
Botulinum toxin (Botox; Allergan) has added "primary axillary hyperhidrosis" to its approved indications. The procedure will interest Americans who sweat 5 times more than normal, with stained clothing, embarrassment, and sometimes career issues as results. Botox deactivates nerves leading to sweat glands for up to 8 months. In a clinical trial of 600 adults, 91% reported a sweating reduction of 50%.
In addition, valacyclovir (Valtrex; GlaxoSmithKline), first approved in 1995, is now approved to reduce heterosexual transmission risk of genital herpes when used with safe sex practices in susceptible partners with healthy immune systems.
Nateglinide (Starlix; Novartis) has been approved for use in combination with a thiazolidinedione (TZD) in patients with type 2 diabetes who are inadequately controlled after a therapeutic response to a TZD. The drug previously was approved as monotherapy for drug-naive patients with type 2 diabetes and with metformin.
Fondaparinux sodium (Arixtra; Organon and Sanofi-Synthelabo) has been approved for acute or extended prophylaxis of deep venous thrombosis (DVT) in patients undergoing hip fracture surgery. It is the only antithrombotic agent currently approved for extended DVT prophylaxis in hip fracture surgery patients.
Voriconazole (Vfend; Roerig), a broad-spectrum antifungal available in tablets and for intravenous infusion, is now indicated for the treatment of esophageal candidiasis.
Levofloxacin (Levaquin; Ortho-McNeil) is now indicated for chronic bacterial prostatitis. This drug is available in tablet and injection form.
More Heart and Lung Protection
Losartan (Cozaar; Merck) can now be prescribed to manage hypertensive patients with left ventricular hypertrophy to reduce the risk of stroke. The new indication excludes Afro- Caribbean patients with hypertension, however; evidence of efficacy is lacking in this group.
Eplerenone (Inspra; Pfizer), an alsdosterone receptor blocker (first approved in 2002 for hypertension), has an added indication for improving survival of heart failure patients following acute myocardial infarction. The use of eplerenone with other appropriate therapy in the placebo controlled pivotal clinical trial resulted in a significant (15%) reduction in death risk.
Fluticasone propionate 250 mcg and salmeterol 50 mcg inhalation powder (Advair Diskus 250/50; Glaxo- SmithKline) is now indicated for chronic obstructive pulmonary disease patients with chronic bronchitis. Used twice daily for airflow obstruction, it must not replace the fast-acting inhalers used for acute shortness of breath.
Importance of New Indications
New indications offer clues about the directions in which medicine is going and a better understanding of cellular functions, neurohormonal transmission, and biology. They also improve one's understanding of why and how other drugs from the same or similar classes are being used off label. Best of all, new indications offer hope for patients whose previous responses to medication have been incomplete.
Ms. Yeznach Wick is a senior clinical research pharmacist at the National Cancer Institute, National Institutes of Health. Dr. Zanni is a health systems consultant and a former mental health commissioner for Washington, DC. The views expressed are those of the authors and not those of any governmental agency.
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