Epilepsy drug exposure does not increase newborn orofacial cleft risk

In continuation of my update on  lamotrigine

Pregnant women with epilepsy should not rule out continuing lamotrigine therapy due to concerns that exposure could increase the risk of orofacial clefts (OCs) in their babies, say investigators.

Their findings indicate that the excess risk of OC is less than one in every 550 babies exposed to lamotrigine and therefore they do not support the sixfold increased risk suggested by the North American antiepileptic drug registry in 2006, a signal that led to warnings of the risk being added to patient information.

Helen Dolk (Ulster University, UK) and team looked at data from 21 EUROCAT congenital anomaly registries on more than 10 million births spanning 16 years, including from 2006 onwards when lamotrigine exposure was nearly three times more prevalent.

Congenital anomalies were identified in 226,806 babies and within this group 147 with nonchromosomal anomalies had been exposed to lamotrigine within the first trimester of pregnancy.

Exposure to lamotrigine monotherapy was not associated with a significant increase in the incidence of any OC, isolated OCor cleft palate specifically, with odds ratios of 1.31, 1.45 and 1.69.

"Our estimate of the risk of OC relative to other anomalies is nonsignificant with an upper confidence limit of 2.3", reports the team in Neurology.

They add: "Our results concur with other studies published since the original signal, which do not find a large excess of OC or cleft palate."

They suggest that the difference compared with the North American findings may be due to use of a larger baseline population risk of OC of 1.4 per 1000, compared with 1.1 per 1000.

"The size of the original OC signal may also have been a chance finding, or exacerbated by coexposures", the researchers suggest.

Dolk and colleagues also studied the risk of club foot among the sample, having found a significant excess in a previous study. While the current data gave a significant 83% increased risk with lamotrigine exposure, data from an independent study population of 6.3 million births mainly from 2006 on wards found no increased risk.

Epilepsy drug exposure does not increase newborn orofacial cleft risk: Pregnant women with epilepsy should not rule out continuing lamotrigine therapy due to concerns that exposure could increase the risk of orofacial clefts in their babies, say investigators.

Add-on lamotrigine enhances bipolar depression treatment

Combining lamotrigine with quetiapine improves the treatment of depressive symptoms in patients with bipolar disorder, with the benefits maintained for at least a year, show findings from the CEQUEL trial.

Scores on the Quick Inventory of Depressive Symptomatology–self report version 16 (QIDS-SR16) at 12 weeks were, on average, 1.73 points lower among 101 moderately depressed bipolar patients randomly assigned to receive lamotrigine (25 mg/day titrated to 200 mg/day) in addition to quetiapine, compared with 101 assigned to receive add-on placebo.

By 52 weeks, the difference was significant at an average of 2.69 points lower for those taking add-on lamotrigine, after taking into account age, bipolar disorder type and dose of quetiapine (< or ≥300 mg/day), the researchers led by John Geddes (University of Oxford, UK) report in The Lancet Psychiatry.

They also found that significantly more patients taking lamotrigine plus quetiapine were in remission at 12 weeks (31 vs 16%) and 52 weeks (36 vs 13%), with relative risks of 2.11 and 3.73, respectively.

Discussing the findings in a related comment, Gin Malhi (University of Sydney, New South Wales, Australia) says: “[T]he investigators skillfully take advantage of the synergy between quetiapine and lamotrigine that arises from their differing, but complementary, mechanisms of action and the separate timescales over which they exert their effects.”

He explains that quetiapine is often given in the short term to ameliorate acute symptoms, whereas lamotrigine is more effective over the longer term. The drug is therefore able to “achieve a therapeutic level and exert its actions under the initial cover of the antipsychotic, which can then be gradually tapered and withdrawn”, he writes.

Add-on lamotrigine enhances bipolar depression treatment

Eton Pharmaceuticals Announces FDA Acceptance of New Drug Application for ET-105

In continuation of my update on  lamotrigine

Eton Pharmaceuticals, Inc (Nasdaq: ETON), a specialty pharmaceutical company focused on developing and commercializing innovative drug products, today announced that Aucta Pharmaceuticals' New Drug Application for ET-105, an innovative formulation of lamotrigine which Eton acquired the U.S. marketing rights to in June 2019, has been accepted for review by the U.S. Food and Drug Administration (FDA). The FDA has assigned the application a Prescription Drug User Fee Act (PDUFA) target action date of March 17, 2020.

“The NDA acceptance of ET-105 marks an important milestone for Eton as this strengthens our growing pipeline of near-launch products. We are very excited about the potential for ET-105 to address a significant unmet need in this large and growing market,” said Sean Brynjelsen, Chief Executive Officer of Eton Pharmaceuticals. “Our team looks forward to working with Aucta and the FDA over the coming months as we prepare for a potential commercial launch in the first half of 2020.”

ET-105 is a patent-pending formulation of lamotrigine, for which Aucta is seeking approval as an adjunct therapy for partial seizures, primary generalized tonic-clonic seizures, and generalized seizures of Lennox-Gastaut syndrome in patients two years of age and older. Lamotrigine is one of the most widely used anti-epilepsy medications in the U.S. with sales exceeding $700 million and 1 billion tablets annually but is only FDA-approved in tablet formulations. ET-105’s innovative formula will be delivered to patients as an oral liquid and has been developed specifically to address the significant unmet need in patients with dysphagia and pediatric patients requiring precision dosing at levels below the currently available tablet strengths.

Oldest epilepsy drug (Ethosuximide) best for Children with "Petit Mal"....

Ethosuximide ( see structure)  is a succinimide anticonvulsant, used mainly in absence seizures. Ethosuximide is considered the first choice drug for treating absence seizures in part because it lacks the idiosyncratic hepatotoxicity of the alternative anti-absence drug Valproic acid. There is some controversy over the exact mechanism by which ethosuximide prevents absence seizures. While the view that ethosuximide is a T-type calcium channel blocker gained widespread support following its proposal, attempts to replicate the initial finding were inconsistent.

Now researchers, lead by Dr. Tracy A. Glauser, Director of Comprehensive Epilepsy Center at Cincinnati Children's Hospital Medical Center, have come up with an interesting finding, i.e., ethosuximide (Zarontin), one of the oldest anti-seizure medications  is most effective at controlling what is called absence or "petit mal" epilepsy, with the fewest side effects. Valproic acid (Valproate, Depakote) came second, and the newest drug, lamotrigine (Lamictal), was third.

The study included children aged 2.5 to 13 years, newly diagnosed with epilepsy and free of other problems, such as autism. They were randomly assigned to one of the three drugs. The study measured primarily whether they were free of seizures without intolerable side effects after 16 weeks, with a few children continuing for as long as 20 weeks. The study also measured how the drugs affected the children's ability to pay attention.

Ethosuximide prevented seizures in 53 percent of the children, slightly less than the 58 percent freedom-from-failure rate of valproic acid but significantly better than the 29 percent for lamotrigine. But only 33 percent of those taking the older drug had significant attention problems, compared to 49 percent of those taking valproic acid, the researchers found. 

Researchers conclude that, it was somewhat unexpected that the oldest of the drugs had as good an effect as the other and better side effects &  the study highlights the importance of looking not only at seizure control but also how the child does otherwise.......

Ref : http://www.cincinnatichildrens.org/about/news/release/2010/epilepsy-trial-3-4-2010.htm