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
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
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
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
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
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
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
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
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
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.