New Introductions - Internationally

The United States Food and Drug Administration (FDA) has approved quetiapine fumarate (Seroquel) for the maintenance treatment of patients with bipolar I disorder, as adjunct to lithium or divalproex. Quetiapine is also approved for the treatment of schizophrenia, and is the only single agent approved by the FDA for the treatment of both depressive and acute manic episodes associated with bipolar disorder.

The FDA approval was based on 2 multicentre, randomised, double-blind, placebo-controlled clinical trials which are part of the clinical trial program known as BOLDER (Bipolar Depression). These 2 studies evaluated quetiapine when used as an adjunct therapy to lithium or divalproex in the maintenance treatment of adults with bipolar I disorder. Pooled study results indicated that patients treated with quetiapine plus lithium or divalproex had a risk reduction of 70% relative to those in the placebo arm for time to recurrence of a mood event. This reduction in risk was significant for both recurrence of manic episodes and recurrence of depressive episodes. The proportion of patients who relapsed when treated with quetiapine was 19.3% versus 50.4% of patients on placebo.

The US Food and Drug Administration (FDA) has approved atomoxetine for maintenance treatment of ADHD in children and adolescents. Atomoxetine is the first FDA-approved nonstimulant to treat ADHD in children, adolescents, and adults.

The long-term, international, multicentre study, which was reviewed by the FDA as part of its decision to grant this approval, employed a treatment discontinuation design. In the study, 604 patients initially received acute open-label treatment with atomoxetine. After 10 weeks, 69% of patients qualified as responders were re-randomised to double-blind treatment with either atomoxetine or placebo for 9 months. A second 6-month randomisation occurred after approximately 1 year of treatment, with 81 patients taking atomoxetine and 82 patients in the placebo group.

Results of both randomisation phases showed that patients treated with atomoxetine had significantly greater continuous response rates versus patients taking placebo. Additionally, relapse rates for those discontinuing treatment after 1 year were lower than the relapse rates for patients who discontinued treatment during the 6 months following the open-label treatment phase.

Atomoxetine was generally well tolerated. The most common side effects reported in the study were headache and nasopharyngitis.

The US Food and Drug Administration (FDA) has approved aripiprazole as an adjunctive therapy to either lithium or valproate for the acute treatment of manic and mixed episodes associated with bipolar 1 disorder with or without psychotic features in adults.

This approval of aripiprazole is based on results from a 6-week, randomised, double-blind, placebo-controlled study in adults with manic or mixed episodes of bipolar 1 disorder who had an inadequate response to a 2-week, lead-in phase of mood stabiliser monotherapy (lithium or valproate). At study endpoint, add-on aripiprazole was superior to lithium or valproate with adjunctive placebo in the reduction of the Young-Mania Rating Scale (Y-MRS) Total Score and the Clinical Global Impressions Scale for Bipolar Disorder (CGI-BP) Severity of Illness Score for Mania.

The most commonly observed adverse reactions with adjunctive aripiprazole akathisia, insomnia and extrapyramidal disorder. The most common adverse reactions associated with discontinuation in adjunctive aripiprazole-treated patients were akathisia and tremor. Mean weight gain was low (0.6 kg for adjunctive aripiprazole vs. 0.2 kg for adjunctive placebo)

The US Food and Drug Administration (FDA) has approved approved a new recommended starting and target dose of 15 mg daily for aripiprazole monotherapy in the treatment of bipolar 1 disorder in adults.

The approval of the starting dose of 15 mg daily for aripiprazole is based on results from two 3-week, randomised, double-blind, placebo-controlled studies in adults with manic or mixed episodes of bipolar 1 disorder. At the 3-week study endpoint, aripiprazole was superior to placebo in the reduction of the Y-MRS Total Score and CGI-BP Severity of Illness Score for Mania.

The US Food and Drug Administration (FDA) has approved lisdexamfetamine dimesylate for the treatment of attention-deficit/hyperactivity disorder (ADHD) in adults. Lisdexamfetamine is the first and only once-daily prodrug stimulant approved to treat adults with ADHD.

The trial that led to the FDA approval was a double-blind, placebo-controlled, 4-week study with dose escalations in 414 adults aged 18 to 55 years. In this study, adults with ADHD experienced significant improvements in ADHD symptom control within 1 week of treatment with once-daily lisdexamfetamine. Treatment with lisdexamfetamine at all doses studied (30, 50, and 70 mg) was significantly more effective than placebo, providing a reduction in ADHD Rating Scale (ADHD-RS-IV) scores ranging from 16.2 to 18.6 points. Investigators also measured the efficacy of lisdexamfetamine with the Clinical Global Impressions-Improvement (CGI-I) scale and found that the percentage of subjects taking lisdexamfetamine who rated "improved" ranged from 57% to 61% across all doses and was significantly greater than placebo.The most commonly reported adverse events in this study were decreased appetite, difficulty falling asleep, and dry mouth.

The US Food and Drug Administration (FDA) has approved a rivastigmine transdermal system for the treatment of mild to moderate Alzheimer's dementia and mild to moderate dementia associated with Parkinson's disease.

The approval in Alzheimer's dementia was based on data from the Investigation of transDermal Exelon in ALzheimer's disease (IDEAL) study, which showed that use of the rivastigmine 9.5-mg/day once-daily patch and twice-daily oral administration of a 6-mg capsule both yielded similarly significant mean improvements vs. placebo in cognitive function. Approval in Parkinson's disease was based on the EXelon in PaRkinson's disEaSe dementia Study ( EXPRESS ), which showed that rivastigmine oral therapy yielded significant improvements compared with placebo in terms of cognitive function and overall functioning. These data were judged to be applicable to the patch formulation as well.

The most commonly reported adverse events in patients receiving the 9.5-mg/24-hour rivastigmine patch that occurred at a frequency of at least 5% and incidence greater than placebo were nausea, vomiting and diarrhea.

Rivastigmine patches are available in 2 sizes: 5 cm 2 (4.6-mg/24-hour dosage) and 10 cm 2 (9.5-mg/24-hour dosage). Treatment should be initiated with a 4.6-mg/day patch applied once daily to the back, chest, or upper arm. Uptitration to the dosage of 9.5-mg/day may be considered after 4 weeks of treatment and good tolerability. Higher doses of the rivastigmine patch are not recommended because they did not confer appreciable benefit in clinical trials and were linked to a significant increase in the risk for adverse events.

When switching patients from capsules to oral solution formulations, those receiving a total daily dose of less than 6 mg of the oral formulation should initially use the 4.6-mg/24-hour patch. Initial use of the 9.5-mg/24-hour patch is advised for patients taking a total daily oral dose ranging from 6 to 12 mg. The first patch should be applied on the day following the last oral dose. In addition, patches should be replaced every 24 hours, and the time of day used should be kept consistent. Exposure of the patch to external heat sources (e.g., excess sunlight, saunas, and solarium) for long periods should be avoided.

The U.S. FDA has expanded the indication of interferon beta-1b (Betaseron) to include patients with multiple sclerosis (MS) who have experienced a first clinical episode and have MRI features consistent with MS.

Interferon beta-1b is indicated for the treatment of relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations. Interferon beta-1b is the only high-dose, high-frequency interferon beta indicated for patients at the earliest stage of MS.

The new indication is based on results from the BENEFIT (BEtaseron in Newly Emerging multiple sclerosis for Initial Treatment) Study of patients with a first clinical demyelinating event and MRI features suggestive of MS. In this randomized, double-blind, placebo-controlled, multicenter trial, 468 participants were given either interferon beta-1b or placebo until they experienced a second clinical event or relapse or they had been followed for at least 24 months. Results showed that treatment with interferon beta-1b reduced the risk of progression to clinically definite MS by about 50% and to MRI-defined MS by 46% compared to placebo. Further, interferon beta-1b delayed the time to a second clinical event by one year compared to patients in the placebo arm. Interferon beta-1b appears to be a safe and well- tolerated treatment, as evidenced by the findings that 93% of patients completed the study, and only 2.7% of patients in the trial discontinued therapy because of adverse events.

The US Food and Drug Administration has approved a new use of lamotrigine for the treatment of Primary Generalized Tonic-Clonic (PGTC) seizures. With this new indication, lamotrigine can now be used as add-on therapy to treat PGTC seizures in children aged two and older as well as adults.

The approval of lamotrigine as add-on therapy in patients with PGTC seizures was based on a multicenter, placebo-controlled trial in pediatric (age 2) and adult patients (n=117). In the study, lamotrigine was given to patients whose seizures were not well controlled, even while taking one or two other anti-seizure medications.

Results showed that lamotrigine was highly effective in reducing the frequency of PGTC seizures. Over the entire treatment period, lamotrigine significantly reduced PGTC seizures by 66% compared to 34% for the placebo group. Similar effects were seen during the titration and maintenance phases of the study. Significantly more patients receiving lamotrigine as maintenance therapy experienced at least a 50% reduction compared to placebo (72 % vs. 49 %). Efficacy was similar across age groups.
Overall, lamotrigine had a favorable tolerability profile.

The most common drug-related side effects observed in this clinical trial were dizziness, drowsiness and nausea.

The US FDA has approved the use of levetiracetam as an adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy.

The clinical trial supporting this new indication for levetiracetam was a phase III, double-blind, randomized, placebo-controlled study on the safety and efficacy of levetiracetam as an add-on therapy in patients with juvenile myoclonic epilepsy experiencing myoclonic seizures. Patients in this study included those with juvenile myoclonic epilepsy, juvenile absence epilepsy or with generalized tonic-clonic seizures on awakening. The majority were patients with juvenile myoclonic epilepsy.

The responder rate defined as = 50% reduction in myoclonic seizure days during the treatment period versus baseline was significantly greater in patients treated with levetiracetam as compared with placebo (60.4% with levetiracetam vs. 23.7% with placebo). A total of 15.1% of patients in the levetiracetam group achieved freedom from myoclonic seizures during the treatment period compared with 3.4 % of placebo patients.

The most common adverse events seen with levetiracetam were somnolence, neck pain, and pharyngitis.

The US FDA has approved an intravenous formulation of levetiracetam as an alternative treatment for epileptic seizures if the oral forms of the drug are not appropriate for patients.

The new formulation must be diluted prior to use and administered as a 15-minute intravenous infusion.

Levetiracetam is approved as an add-on therapy for the treatment of partial onset seizures in adults and children 4 years of age or older with epilepsy. The drug is currently available in tablet and in oral solution.