While FDA officials were busy in 2003 approving new drugs, they also found time to evaluate several existing drugs and approved many new indications. Some of the highlights of the year with respect to new indications are discussed here.
Two anticonvulsants received approval for new indications in 2003. Oxcarbazepine was approved as monotherapy for the treatment of partial seizures in children and adolescents 4 to 16 years of age. The approval was based on 4 randomized, double-blind, multi-center studies. Two studies showed statistically significant results with oxcarbazepine, compared with placebo, and 2 withdrawal-design studies showed significant findings in favor of high-dose (2400 mg/day) oxcarbazepine. Patients who are currently taking other antiepileptic drugs should be started on 8 to 10 mg/kg of oxcarbazepine twice daily, while simultaneously reducing the concomitant drugs. Withdrawal should occur over 3 to 6 weeks, while increasing oxcarbazepine by maximum increments of 10 mg/kg/day at weekly intervals. In patients not taking other antiepileptics, oxcarbazepine should be initiated at 8 to 10 mg/kg twice daily, with the dose increased by 5 mg/kg/day every third day until a predefined weight-determined dose is reached. It is important to note that only 25% to 30% of patients who experienced hypersensitivity reactions with carbamazepine are expected to experience reactions with oxcarbazepine.
Lamotrigine, another antiepileptic, was approved for the maintenance treatment of adults with bipolar I disorder. This drug is indicated to delay the time to occurrence of mood episodes such as depression, mania, hypomania, and mixed episodes in patients who have been treated for acute mood episodes with standard therapy. The FDA approval was based on 2 multi-center, double-blind, placebo-controlled trials that showed a delay in intervention for mood episodes in patients treated with lamotrigine, compared with placebo. The median days to intervention were 200 and 141, respectively, for the lamotrigine-treated patients in the 2 studies, compared with 93 and 85 days for the placebo-treated patients. Dosing of lamotrigine should start at 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 target dose should be lower (100 mg/day) when this drug is used in combination with valproate and higher (400 mg/day) when it is used in combination with enzyme-inducing drugs such as carbamazepine. Lamotrigine also received approval as add-on therapy for partial seizures in children 2 years of age and older. The drug already had been approved for adjunctive use in adults with partial seizures as well as for generalized seizures associated with Lennox-Gastaut syndrome in children 2 years of age and older.
The approved indications for olanzapine were expanded to include the treatment of acute manic episodes associated with bipolar I disorder in combination with lithium or valproate. Olanzapine previously had approval for monotherapy for bipolar mania and schizophrenia. In studies with combination treatment, the effect of olanzapine combined with lithium or valproate was superior to that when either drug was taken alone. When used concomitantly with either of these drugs, the recommended starting dose of olanzapine is 10 mg once daily. The safety of doses >20 mg/day has not been evaluated.
Venlafaxine (Wyeth) and Sertraline (Pfizer)
Two antidepressants, venlafaxine extended- release (ER) and sertraline, were approved for the treatment of social anxiety disorder (SAD). The approvals 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, significant improvement was seen at 4 to 6 weeks, with greater reductions in symptoms by week 12. In 1 trial with sertraline, 53% of patients responded to sertraline, whereas only 29% of patients treated with placebo demonstrated a response. The recommended starting dose of venlafaxine ER is 75 mg/day. It may be desirable for some patients to start at 37.5 mg/day for 4 to 7 days. The maximum recommended dose is 225 mg/day. Sertraline should be initiated at 25 mg once daily for 1 week, after which the dose can be increased to 50 mg once daily. The maximum dose is 200 mg daily.
Latanoprost became the first prostaglandin 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 treated with latanoprost exhibited reductions in IOP of 6 to 8 mm Hg. One drop of the ophthalmic solution should be administered 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 or intravenously once every 24 hours for 7 to 14 days. Gemifloxacin also received approval for treatment of community-acquired pneumonia, as well as for acute bacterial exacerbation of chronic bronchitis. Levofloxacin was approved for the treatment of chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, or Staphylococcus epidermidis.
The indications for rosiglitazone were expanded to include combination therapy with insulin for type 2 diabetes. Previously, this drug was approved for monotherapy and for use in combination with metformin or sulfonylureas. In one trial of patients whose disease was inadequately controlled on insulin alone, patients who were randomized to rosiglitazone plus insulin showed significant reductions in HbA1c, compared with patients receiving placebo plus insulin. Approximately 40% of patients treated with insulin and rosiglitazone were able to reduce their dose of insulin. In patients who are on a stable dose of insulin, rosiglitazone can be initiated at 4 mg daily. Doses >4 mg in combination with insulin are not currently recommended. If the patient reports fasting plasma glucose concentrations of less than 100 mg/dL or hypoglycemia, the insulin dose should be decreased by 10% to 25%.
In addition to its indication for asthma, montelukast was recently approved for the treatment of seasonal allergic rhinitis in adults and in children 2 years of age and older. The approval was based on 5 randomized, double-blind, placebo- and active-controlled clinical trials in more than 5000 patients. In these trials, a significant improvement was seen in favor of montelukast over placebo. The dose for adults and adolescents 15 years of age and older is 10 mg once daily. Chewable tablets in doses of 4 or 5 mg are available for children 2 to 5 years of age or 6 to 14 years of age, respectively.
Based on the results of the Carvedilol Post Infarction Survival Control in Left Ventricular Dysfunction (CAPRICORN) study, the FDA expanded the indications for carvedilol to include reduction in the risk of death among patients with left ventricular dysfunction following 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 reduced the risk of death for any reason by 23% and was associated with a 41% reduction in the risk of recurrent nonfatal MI. Treatment with carvedilol can be initiated in an inpatient or outpatient setting as long as the patient is hemodynamically stable and fluid retention has been minimized. Dosing should start at 6.25 mg twice daily, with a subsequent increase after 3 to 10 days if tolerated to 12.5 mg twice daily, then again to the target dose of 25 mg twice daily. Dosing of this drug should be individualized, with close monitoring during up-titration.
It was a busy year for the FDA with respect to new indications. For information regarding additional drug approvals, visit the FDA?s Web site at www.fda.gov .
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