This past month we had a new drug, Toviaz™, approved for overactive bladder (urge incontinence). I am not sure if there is any particular advantage to this new drug compared to the five or six already out there. There's also a newly approved, lower-dose, extended-cycle oral contraceptive called LoSEASONIQUE®. The nasal-spray antihistamine, azelastine, has a new formulation, Astepro™, that is reported to be better tolerated than the original Astelin®. Perhaps the most interesting drug to be approved recently is Vimpat®, an antiepileptic drug with a unique and interesting dual mechanism of action. Some Dextroamphetamine Sulfate 5mg tablets have been recalled because of oversized tablets containing higher amounts of the drug. Raptiva®, the parenterally administered drug for refractory psoriasis, has been given a black box warning. Finally, I threw in an interesting study on vitamin D activation in the lungs and one about unraveling the mystery of fibromyalgia.
Toviaz (fesoterodine fumarate) is the newest addition to the class of drugs for treatment of overactive bladder (OAB) symptoms.
Remember, urge incontinence (overactive bladder) symptoms are due to increased activity of the detrusor muscles in the bladder (which are under parasympathetic nervous system control). Fesoterodine is structurally similar to tolterodine (Detrol®) and, like all others in its class, the drug blocks muscarinic acetylcholine receptors (anticholinergic action) and thus helps to reduce parasympathetic tone in those bladder muscles. Actually, it is the active metabolite of fesoterodine that is responsible for the therapeutic actions of the drug.
New, once-daily Toviaz extended release tablets will be available in doses of 4 and 8 mgs. The recommended starting dose is 4 mgs, which can be increased to 8 mgs if needed, based upon individual response and tolerability. Fesoterodine is not recommended for use in patients with severe renal or hepatic impairment. Since it is inactivated via cytochrome P450 (CYP3A4 and CYP 2D6), caution and dose limitations should be exercised if patients are also taking P450 inhibitors such as imidazole antifungals or macrolides (3A4), fluoxetine, or paroxetine (2D6).
Like other drugs used for urge incontinence, the side effects associated with Toviaz are the anticholinergic package, most commonly including dry mouth and constipation. In that regard, Toviaz should be used with caution in patients who suffer from decreased gastrointestinal motility, such as those with severe constipation. Less frequently reported side effects include dry eyes and urinary hesitancy/retention. Remember also, that in the central nervous system, anticholinergics can produce drowsiness, dizziness, and affect cognition, especially in the elderly.
According to the manufacturer, Toviaz will be available in the United States in the first half of 2009.
The FDA has approved LoSeasonique (levonorgrstrel/ethinyl estradiol tablets 0.10 mg/0.02 mg and ethinyl estradiol tablets 0.01 mg) extended-cycle oral contraceptive. LoSeasonique is the first lower-dose, extended-cycle oral contraceptive indicated for the prevention of pregnancy.
The clinical data supporting the LoSeasonique NDA resulted from a 12-month, multi-centered, open label clinical trial that concluded in June 2007. The clinical trial involved over 2,100 female subjects between the ages of 18 and 41 at 56 sites throughout the United States, and subjects completed an equivalent of nearly 21,000 28-day cycles of exposure.
Under the LoSeasonique extended-cycle regimen, women take combination tablets containing 0.10 mg levonorgestrel/0.02 mg of ethinyl estradiol daily for 84 consecutive days, followed 0.01 mg ethinyl estradiol tablets for seven days. The regimen is designed to reduce the number of withdrawal bleeding periods from 13 to four per year.
The most common adverse events in the clinical trial were headache, irregular and/or heavy uterine bleeding, dysmenorrhea, nausea and/or vomiting, and back pain.
It is expected that LoSeasonique will be shipped to trade customers and available by prescription to women in the first quarter of 2009.
Vimpat (lacosamide) is a new antiepileptic drug (AED) indicated as add-on therapy for the treatment of partial-onset seizures in adults. Interestingly, less than 50% of patients with partial-onset seizures will attain seizure control with their first AED, and more than 30% will continue to experience seizures despite trying two or more AEDs.
The precise mechanism by which lacosamide exerts its antiepileptic effect in humans remains to be fully elucidated. It appears that Vimpat has a dual mode of action that is different from all other available AEDs. Vimpat's mechanism of action is believed to reduce sodium channel over-activity by prolonging the longer lasting resting state (slow inactivation) of the channel, a different action compared with current sodium channel blocking drugs. This means that lacosamide only affects neurons which are depolarized or active for long periods of time, typical of neurons at the core of an epileptic focus.
Additionally, lacosamide binds to "collapsin response mediator protein 2" (CRMP 2), a phosphoprotein which is expressed in the nervous system and appears to be involved in neuronal differentiation and control of axonal outgrowth. How that translates into an antiepileptic action is not currently known. Perhaps it will diminish the "kindling" effect that can occur in epilepsy (recruitment, over time, of surrounding normal cells into the epileptic focus).
In clinical studies, the most common treatment-related adverse events were dizziness, nausea, headache, fatigue, and tremor.
Although Vimpat has not been approved for diabetic peripheral neuropathy (DPN) or other types of neuropathy, there have been numerous studies reporting promising results for this condition. We'll see where this goes in time.
Astepro is a new formulation of Astelin. The active substance in both these products is azelastine - the only nasal antihistamine approved for the treatment of rhinitis in the U.S. According to the manufacturer, Astepro Nasal Spray is an improvement over the currently marketed Astelin Nasal Spray and appears to be better tolerated by patients.
Fewer reports of bitter taste and nasal discomfort were recorded by Astepro users and it was, in general, better tolerated than Astelin. Symptom relief, as recorded by patients, was also better. In total, about 1,400 patients were involved in Meda's phase III studies.
Ethex Corporation and the FDA notified healthcare professionals of a voluntary recall of three lots of Dextroamphetamine Sulfate 5mg tablets. The product was recalled due to the potential presence of oversized tablets that may contain as much as twice the labeled amount of the active ingredient. Taking a higher than expected dose of Dextroamphetamine Sulfate may be associated with an increased risk of adverse effects such as tachycardia, hypertension, tremors, decreased appetite, headache, insomnia, dizziness, blurred vision, stomach upset, and dry mouth. Consumers and their caregivers should not use any Dextroamphetamine Sulfate tablets that appear to be oversized and should consult their healthcare professional with concerns.
The psoriasis drug Raptiva is getting a "black box" warning regarding the risk of life-threatening infections. Raptiva is given by injection once a week to treat moderate to severe plaque psoriasis in adults who are candidates for systemic (whole body) therapy or phototherapy (light therapy) to control their psoriasis.
Raptiva works by suppressing the immune system to reduce psoriasis flare-ups. Obviously, suppressing the immune system can raise the risk of serious infections and malignancies. Raptiva's new warning will highlight the risk of opportunistic infections including bacterial sepsis, viral meningitis, invasive fungal disease, and progressive multifocal leukoencephalopathy (PML). The FDA acknowledges that Raptiva does not cause any illnesses and while they are not telling patients to stop taking Raptiva, they recommend that doctors and other prescribers carefully evaluate and weigh the risk/benefit profile of Raptiva for patients who would be more susceptible to the risks.
Remember Vitamin D3 (dietary or photoconverted) needs two more activation steps before it has biological activity? The first step takes place in the liver (via the 25 hydoxylase enzyme) and the second enzymatic step takes place primarily in the kidneys to produce 1,25-dihydroxyvitamin D3. In recent years, however, tissue and organs such as skin, intestines, breast, and prostate have also been shown to express the second enzyme that completes vitamin D3 conversion. Now, a new University of Iowa study has reported that lung airway cells can also do it. The researchers report that while the Vitamin D3 converted by the kidneys circulates systemically, it appears that vitamin D3 converted by other organs, including cells lining the trachea and main bronchi, appears to stay within those tissues and regulates specific genes that help protect those cells from infection from a variety of pathogens, as well as dampening inflammation. This is certainly an interesting finding and adds to a rapidly growing list of yet another potential benefit of Vitamin D. Obviously, further research is needed in this particular area.
The diagnosis of fibromyalgia has long been controversial since musculoskeletal imaging and other objective diagnostic measures are consistently negative. Recently, however, researchers in France, using single photon emission computed tomography (SPECT), were able to detect functional abnormalities in certain regions in the brains of patients diagnosed with fibromyalgia, These studies confirmed earlier imaging studies of patients with the syndrome which showed brain perfusion abnormalities in patients compared to healthy subjects. An increase in perfusion (hyperperfusion) was found in that region of the brain known to discriminate pain intensity, and a decrease (hypoperfusion) was found within those areas thought to be involved in emotional response to pain. Further, these abnormalities were found to be directly correlated with the severity of the disease.