Approved Drugs Broaden Indications Base in 2004

DECEMBER 01, 2004
Jeannette Yeznach Wick, RPh, MBA, and Guido R. Zanni, PhD

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 populations—especially the mentally ill and people with "unmentionable" problems—2004's new indications offer hope.

Short Stature

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:

  • Within the selective serotonin reuptake inhibitor class, escitalopram oxalate (Lexapro; Forest Pharmaceuticals) is now approved for generalized anxiety disorder at a 10-mg to 20-mg daily dosage. Also, Paroxetine controlled-release tablets (Paxil CR; GlaxoSmith-Kline) have been granted a social anxiety disorder indication.
  • The FDA has approved the antidepressant duloxetine (Cymbalta; Lilly) for the management of diabetic peripheral neuropathic pain.
  • The role of atypical antipsychotics in disorders other than schizophrenia is earning them the new descriptor "broad-spectrum psychoactive drugs." Quetiapine (Seroquel; AstraZeneca) has added monotherapy and adjunct therapy with lithium or divalproex for short-term treatment of acute manic episodes associated with bipolar I disorder to its schizophrenia indication. Also, an FDA approval "for maintenance in the treatment of bipolar disorder" indicates that olanzapine (Zyprexa; Lilly) can delay mania or depression relapse in bipolar disorder patients. In addition, aripiprazole (Abilify; Bristol-Myers Squibb), already approved for shorter-term treatment of schizophrenia, can now be used for maintaining stability for up to 26 weeks.

Three antiepileptic drugs are breeching the borders of "broad spectrum," too:

  • The FDA has approved lamotrigine's (Lamictal; GlaxoSmith-Kline) third indication— monotherapy to treat partial seizures in patients 16 years and older when converting from valproate. This antiepileptic previously was approved as adjunctive therapy in pediatric patients with partial seizures and as maintenance treatment for bipolar disorder.
  • Topiramate (Topamax; Ortho-McNeil) has received its second indication: migraine headache prophylaxis in adults.
  • A new indication for divalproex sodium extended-release tablets (Depakote ER; Abbott Laboratories) is treatment of complex partial seizures in isolation or in association with other types of seizures and simple and complex absence seizures in children, aged 10 and over. Divalproex sodium delayed-release tablets were approved in 2000 for migraine prevention in adults and in 2002 for epilepsy in adults.


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.

Blood Disorders

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.

Infective Illness

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.