Approved Drugs Broaden Indications Base in 2004

New indications sustain andcan invigorate drugs as theymature. For drug manufacturersseeking new indication approvalfrom the FDA, 2004 was a busy year.For specific populations—especiallythe mentally ill and people with"unmentionable" problems—2004'snew indications offer hope.

Short Stature

The shortest 1.2% of children (havingidiopathic short stature) maynow be given the growth hormonesomatropin, rDNA origin, for injection(Humatrope; Lilly) for longtermtreatment. Somatropin-treatedchildren grew an extra 1.5 to 2.8inches in clinical trials. This is thefirst growth hormone therapy tospecify a height restriction in children:it is indicated for those whoare >2.25 SDs below the mean fortheir age and sex. The manufactureris marketing somatropin solely topediatric endocrinologists for thisindication and is controlling distribution;it will not use direct-to-consumeradvertising.

The FDA also has approved etanercept(Enbrel; Immunex), a fullyhuman tumor necrosis factor antagonist,for active ankylosing spondylitis(AS). This chronic inflammatorydisease primarily affects thelower back and joints, often leadingto stiffening and fusion of the spineand hunched stature. (At press time,Centocor Inc had approached the FDAfor a new indication for infliximab[Remicade] for the treatment of ASas well.)

Mind and Brain

Among the drugs employed formind and brain disorders, significantchanges have occurred:

• Within the selective serotonin reuptake inhibitor class, escitalopramoxalate (Lexapro; Forest Pharmaceuticals) is now approvedfor 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 socialanxiety 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 schizophreniais earning them the new descriptor "broad-spectrum psychoactivedrugs." Quetiapine (Seroquel; AstraZeneca) has addedmonotherapy and adjunct therapy with lithium or divalproex forshort-term treatment of acute manic episodes associated withbipolar I disorder to its schizophrenia indication. Also, an FDAapproval "for maintenance in the treatment of bipolar disorder" indicatesthat olanzapine (Zyprexa; Lilly) can delay mania or depressionrelapse in bipolar disorder patients. In addition, aripiprazole(Abilify; Bristol-Myers Squibb), already approved for shorter-termtreatment 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 partialseizures in patients 16 years and older when convertingfrom valproate. This antiepileptic previously wasapproved as adjunctive therapy in pediatric patients with partialseizures and as maintenance treatment for bipolar disorder.
• Topiramate (Topamax; Ortho-McNeil) has received its secondindication: migraine headache prophylaxis in adults.
• A new indication for divalproex sodium extended-release tablets(Depakote ER; Abbott Laboratories) is treatment of complexpartial seizures in isolation or in association with other types ofseizures and simple and complex absence seizures in children, aged10 and over. Divalproex sodium delayed-release tablets were approvedin 2000 for migraine prevention in adults and in 2002 for epilepsy in adults.

Cancer

Traditionally, superficial basal cellcarcinoma (BCC) has been surgicallyexcised or frozen. The FDA has approvedthe immune-response modifierimiquimod (Aldara; 3M) for "topicaltreatment of biopsy-confirmed, primarysuperficial BCCs in immunocompetentadults" that are 2 cm indiameter or less, and located only onthe trunk, neck, or extremities (excludinghands and feet). This indicationsupplements the drug's previousindications: external genital warts andactinic keratoses on the face or scalp.Safety and efficacy data are lacking forsuperficial BCCs on the head, face,and anogenital areas. Imiquimodtreatment, however, is cosmeticallysuperior to freezing because it avoidshypopigmentation.

The FDA has approved oxaliplatin(Eloxatin; Sanofi-Synthelabo) with 5-fluorouracil/leucovorin for first-linetreatment of advanced colorectal cancer.Since August 2002, oxaliplatin hasbeen second-line treatment for metastaticcolon or rectum cancer.

In addition, docetaxel injection(Taxotere; Aventis) is now approvedwith prednisone for patients withadvanced metastatic prostate cancer.This is the first drug showing a survivalbenefit in hormone refractoryprostate cancer.

"Unmentionables"

The promotility agent tegaserodmaleate (Zelnorm; Novartis) now has asupplemental indication: chronic idiopathicconstipation in patients lessthan 65 years old. In 2 randomized,double-blind, placebo-controlled, multinationalphase 3 clinical trials enrolling2600 men and women,tegaserod significantly increased thefrequency of complete spontaneousbowel movements.

Men who suffer from benign prostatichyperplasia (BPH) will find relief:finasteride (Proscar; Merck) in combinationwith doxazosin is indicated toreduce BPH symptoms from progressingover time. The new indication isbased on the 3047-patient MedicalTherapy of Prostatic Symptoms study.

Botulinum toxin (Botox; Allergan)has added "primary axillary hyperhidrosis"to its approved indications.The procedure will interest Americanswho sweat 5 times more than normal,with stained clothing, embarrassment,and sometimes career issues as results.Botox deactivates nerves leading tosweat glands for up to 8 months. In aclinical trial of 600 adults, 91% reporteda sweating reduction of 50%.

In addition, valacyclovir (Valtrex;GlaxoSmithKline), first approved in1995, is now approved to reduce heterosexualtransmission risk of genitalherpes when used with safe sex practicesin susceptible partners withhealthy immune systems.

Blood Disorders

Nateglinide (Starlix; Novartis) hasbeen approved for use in combinationwith a thiazolidinedione (TZD) inpatients with type 2 diabetes who areinadequately controlled after a therapeuticresponse to a TZD. The drugpreviously was approved as monotherapyfor drug-naive patients with type 2diabetes and with metformin.

Fondaparinux sodium (Arixtra;Organon and Sanofi-Synthelabo) hasbeen approved for acute or extendedprophylaxis of deep venous thrombosis(DVT) in patients undergoing hipfracture surgery. It is the only antithromboticagent currently approvedfor extended DVT prophylaxis in hipfracture surgery patients.

Infective Illness

Voriconazole (Vfend; Roerig), abroad-spectrum antifungal availablein tablets and for intravenous infusion,is now indicated for the treatmentof esophageal candidiasis.

Levofloxacin (Levaquin; Ortho-McNeil) is now indicated for chronicbacterial prostatitis. This drug is availablein tablet and injection form.

More Heart and Lung Protection

Losartan (Cozaar; Merck) can nowbe prescribed to manage hypertensivepatients with left ventricular hypertrophyto reduce the risk of stroke. Thenew indication excludes Afro-Caribbean patients with hypertension,however; evidence of efficacy is lackingin this group.

Eplerenone (Inspra; Pfizer), an alsdosteronereceptor blocker (firstapproved in 2002 for hypertension),has an added indication for improvingsurvival of heart failure patients followingacute myocardial infarction.The use of eplerenone with otherappropriate therapy in the placebo controlledpivotal clinical trial resultedin a significant (15%) reduction indeath risk.

Fluticasone propionate 250 mcgand salmeterol 50 mcg inhalationpowder (Advair Diskus 250/50; Glaxo-SmithKline) is now indicated forchronic obstructive pulmonary diseasepatients with chronic bronchitis. Usedtwice daily for airflow obstruction, itmust not replace the fast-actinginhalers used for acute shortness ofbreath.

Importance of New Indications

New indications offer clues about thedirections in which medicine is goingand a better understanding of cellularfunctions, neurohormonal transmission,and biology. They also improveone's understanding of why and howother drugs from the same or similarclasses are being used off label. Best ofall, new indications offer hope forpatients whose previous responses tomedication have been incomplete.

Ms. Yeznach Wick is a senior clinical research pharmacist at the National CancerInstitute, National Institutes of Health. Dr. Zanni is a health systems consultant and aformer mental health commissioner for Washington, DC. The views expressed arethose of the authors and not those of any governmental agency.