New Indications: 2003

New Indications:2003

Tina H. Ayers, PharmD

While

FDA officials were busy in 2003 approving

new drugs, they also found time toevaluate several

existing drugs and approved many newindications.

Some of the highlights of the yearwith respect to

new indications are discussed here.

Oxcarbazepine (Novartis)

Two anticonvulsants receivedapproval for new indications

in 2003. Oxcarbazepine was approvedas monotherapy

for the treatment of partialseizures in children and adolescents

4 to 16 years of age. The approvalwas based on 4

randomized, double-blind, multi-center studies. Two studies

showed statistically significantresults with oxcarbazepine,

compared with placebo, and 2withdrawal-design studies

showed significant findings in favorof high-dose (2400

mg/day) oxcarbazepine.

Patients who are currently takingother antiepileptic drugs

should be started on 8 to 10 mg/kgof oxcarbazepine twice

daily, while simultaneously reducingthe concomitant drugs.

Withdrawal should occur over 3 to 6weeks, while increasing

oxcarbazepine by maximum incrementsof 10 mg/kg/day at

weekly intervals. In patients nottaking other antiepileptics,

oxcarbazepine should be initiated at8 to 10 mg/kg twice

daily, with the dose increased by 5mg/kg/day every third day

until a predefined weight-determineddose is reached. It is

important to note that only 25% to30% of patients who

experienced hypersensitivityreactions with carbamazepine

are expected to experience reactionswith oxcarbazepine.

Lamotrigine (GlaxoSmithKline)

Lamotrigine, another antiepileptic,was approved for the

maintenance treatment of adults withbipolar I disorder. This

drug is indicated to delay the timeto occurrence of mood

episodes such as depression, mania,hypomania, and mixed

episodes in patients who have beentreated for acute mood

episodes with standard therapy. TheFDA approval was based

on 2 multi-center, double-blind,placebo-controlled trials that

showed a delay in intervention formood episodes in patients

treated with lamotrigine, comparedwith placebo. The median

days to intervention were 200 and141, respectively, for

the lamotrigine-treated patients inthe 2 studies, compared

with 93 and 85 days for theplacebo-treated patients.

Dosing of lamotrigine should startat 25 mg/day, with a

doubling of the dose after weeks 2,4, and 5 to a target dose

of 200 mg at 6 weeks. The targetdose should be lower (100

mg/day) when this drug is used incombination with valproate

and higher (400 mg/day) when it isused in combination

with enzyme-inducing drugs such ascarbamazepine.

Lamotrigine also received approvalas add-on therapy for

partial seizures in children 2 yearsof age and older. The drug

already had been approved foradjunctive use in adults with

partial seizures as well as forgeneralized seizures associated

with Lennox-Gastaut syndrome inchildren 2 years of age

and older.

Olanzapine (Lilly)

The approved indications forolanzapine were expanded to

include the treatment of acute manicepisodes associated with

bipolar I disorder in combinationwith lithium or valproate.

Olanzapine previously had approvalfor monotherapy for bipolar

mania and schizophrenia. In studieswith combination

treatment, the effect of olanzapinecombined with lithium or

valproate was superior to that wheneither drug was taken

alone. When used concomitantly witheither of these drugs,

the recommended starting dose ofolanzapine is 10 mg once

daily. The safety of doses >20mg/day has not been evaluated.

Venlafaxine (Wyeth)andSertraline (Pfizer)

Two antidepressants, venlafaxineextended-

release (ER) and sertraline, were

approved for the treatment of social

anxiety disorder (SAD). Theapprovals

were based on double-blind, placebo-controlled

trials that showed a significant

improvement in SAD symptoms

in the active-treatment groups,compared

with the placebo group. In trials

with venlafaxine ER, significantimprovement

was seen at 4 to 6 weeks,

with greater reductions in symptoms

by week 12. In 1 trial withsertraline,

53% of patients responded tosertraline,

whereas only 29% of patients treated

with placebo demonstrated aresponse.

The recommended starting dose of

venlafaxine ER is 75 mg/day. It maybe

desirable for some patients to startat

37.5 mg/day for 4 to 7 days. Themaximum

recommended dose is 225

mg/day. Sertraline should beinitiated at

25 mg once daily for 1 week, after

which the dose can be increased to50

mg once daily. The maximum dose is

200 mg daily.

Latanoprost (Pfizer)

Latanoprost became the firstprostaglandin

agonist approved for first-line

treatment of elevated intraocular

pressure (IOP) associated with open-angle

glaucoma or ocular hypertension.

In multi-center, randomized,

controlled trials, patients treatedwith

latanoprost exhibited reductions in

IOP of 6 to 8 mm Hg. One drop of the

ophthalmic solution should beadministered

in the affected eye(s) once

daily in the evening. More frequent

administration may decrease the IOP-lowering

effect; dosing more often

than once daily is not recommended.

Moxifloxacin(Bayer),Gemifloxacin (GlaxoSmithKline),and Levofloxacin(Ortho-McNeil)

The FDA approved new indications

for 3 fluoroquinolone antibiotics.Moxifloxacin

was approved for community-acquired

pneumonia due to penicillin-resistant

Streptococcus pneumoniae

.The

dose is 400 g orally orintravenously

once every 24 hours for 7 to 14days.

Gemifloxacin also received approvalfor

treatment of community-acquired

pneumonia, as well as for acutebacterial

exacerbation of chronic bronchitis.

Levofloxacin was approved for thetreatment

of chronic bacterial prostatitis due

to Escherichia coli, Enterococcusfaecalis, or

Staphylococcus epidermidis

.

Rosiglitazone (GlaxoSmithKline)

The indications for rosiglitazonewere

expanded to include combinationtherapy

with insulin for type 2 diabetes.Previously,

this drug was approved for

monotherapy and for use incombination

with metformin or sulfonylureas.

In one trial of patients whosedisease

was inadequately controlled oninsulin

alone, patients who were randomizedto

rosiglitazone plus insulin showedsignificant

reductions in HbA1c, compared

with patients receiving placebo plusinsulin.

Approximately 40% of patients

treated with insulin androsiglitazone

were able to reduce their dose ofinsulin.

In patients who are on a stable dose

of insulin, rosiglitazone can beinitiated

at 4 mg daily. Doses >4 mg incombination

with insulin are not currently

recommended. If the patient reports

fasting plasma glucoseconcentrations

of less than 100 mg/dL orhypoglycemia,

the insulin dose should be decreased

by 10% to 25%.

Montelukast (Merck)

In addition to its indication forasthma,

montelukast was recently approved

for the treatment of seasonalallergic

rhinitis in adults and in children 2years

of age and older. The approval was

based on 5 randomized, double-blind,

placebo- and active-controlledclinical

trials in more than 5000 patients.In

these trials, a significantimprovement

was seen in favor of montelukastover

placebo. The dose for adults andadolescents

15 years of age and older is 10 mg

once daily. Chewable tablets indoses of

4 or 5 mg are available for children2 to

5 years of age or 6 to 14 years ofage,

respectively.

Carvedilol (GlaxoSmithKline)

Based on the results of theCarvedilol

Post Infarction Survival Control inLeft

Ventricular Dysfunction (CAPRICORN)

study, the FDA expanded theindications

for carvedilol to include reduction

in the risk of death among patients

with left ventricular dysfunctionfollowing

myocardial infarction (MI).

CAPRICORN enrolled almost 2000

patients and was conducted in more

than 160 sites in 17 countries.Patients

were randomized to receive either long-term

treatment with carvedilol or

placebo following a proven acute MI.

Treatment with carvedilol reducedthe

risk of death for any reason by 23%and

was associated with a 41% reductionin

the risk of recurrent nonfatal MI.

Treatment with carvedilol can be

initiated in an inpatient oroutpatient

setting as long as the patient ishemodynamically

stable and fluid retention

has been minimized. Dosing should

start at 6.25 mg twice daily, with asubsequent

increase after 3 to 10 days if

tolerated to 12.5 mg twice daily,then

again to the target dose of 25 mgtwice

daily. Dosing of this drug should be

individualized, with closemonitoring

during up-titration.

Summary

It was a busy year for the FDA with

respect to new indications. Forinformation

regarding additional drug

approvals, visit the FDA?s Website at

www.fda.gov .