Alprazolam Extendedrelease Tablets

Introduction

In the United States, nearly 1 in 4 people can be expected to have at least 1 experience with a clinically significant anxiety disorder.Women are more often afflicted than men, and a concurrent psychiatric condition is present nearly 75% of the time. Despite the statistics, less than one third of those suffering from anxiety disorders seek treatment.

Particularly, the anxiety type known as panic disorder includes any 4 of the following symptoms, as described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition: palpitations, sweating, trembling, sensations of suffocation, feeling of choking, chest pain or discomfort, nausea or abdominal distress, feeling of fainting or light-headedness, feeling of being detached from oneself, fear of losing control, fear of imminent death, paresthesias, and chills or hot flushes.

Barr Laboratories Inc has received FDA approval to market alprazolam extended- release tablets in 0.5-, 1-, 2-, and 3-mg strengths for the treatment of panic disorder, with or without agoraphobia.

Pharmacology

All benzodiazepines, including alprazolam, act at gamma-aminobutyric acid receptors in the central nervous system (CNS), causing dose-related depressant behaviors. The extended-release version has a slower absorption rate, delivering a relatively consistent concentration for 5 to 11 hours after dosing. Benzodiazepines are indicated in moderate-tosevere panic disorders in order to hasten therapeutic benefits, especially during the first weeks of treatment.

Dosing and Administration

Individualized, once-daily dosing of alprazolam generally begins at 0.5 to 1 mg daily, with 1-mg increases at 3-to 4- day intervals, peaking at about 3 to 6 mg daily. Morning dosing is preferred. The tablets should not be chewed, crushed, or dissolved before swallowing. Daily doses beyond 6 mg may be necessary (some patients require as much as 10 mg), but these doses require careful monitoring to avoid adverse effects. The elderly or those with liver disease should begin with a daily dose of 0.5 mg and then be carefully titrated to the desired response.

For patients being converted to the extended-release version of alprazolam from the immediate-release version, the dose is the same total daily dose, only now taken once daily.

Side Effects and Interactions

All benzodiazepines are associated with sedation, breakthrough symptoms during treatment, and rebound effects once therapy is stopped. Alprazolam is no exception.

Alprazolam is extensively metabolized by the CYP 3A4 enzyme. Ketoconazole, itraconazole, and erythromycin are all associated with an elevation in alprazolam concentrations.The increase in serum concentrations is dramatic enough with ketoconazole and itraconazole to establish specific contraindications for their concurrent use with alprazolam. Oral contraceptives increase the half-life of alprazolam, and carbamazepine increases the drug's clearance. Alprazolam concentrations may be diminished by half among users of tobacco.

Alprazolam, whether in immediate-or extended-release form, is a controlled substance assigned to Schedule IV. Emotional and physical dependence on alprazolam is possible, and seizures or rebound symptoms have been reported within 1 to 3 days following abrupt discontinuation of treatment. When weaning the patient from therapy, daily doses of the extended-release tablets should be decreased by no more than 0.5 mg every 3 days. Some patients benefit from an even slower tapering. Alcohol will add to the CNS depressant activity of alprazolam; chronic alcohol use can challenge the ability of the clinician to predict therapeutic response to treatment.

Clinical Outlook

The patient adherence benefit of oncedaily dosing is a frequent goal among pharmaceutical manufacturers. Extendedrelease alprazolam also affords a longer therapeutic concentration, thereby reducing breakthrough symptoms during treatment.

Oxybutynin Extendedrelease Tablets

Although often connected with menopause, an overactive bladder has no gender bias. It is associated with involuntary detrusor muscle contractions that may occur spontaneously or by provocation. Ultimately, symptoms are described as stress incontinence or detrusor muscle sensitivity with urgency.

Urinary incontinence is a common problem, afflicting 17 million patients in the United States,with an estimated annual management cost of $26 billion. An overactive bladder represents a challenge both as a societal misadventure and as a balanced treatment. Traditionally, anticholinergic agents have been employed, but with results tempered by equally difficult side effects.

Oxybutynin has been a mainstay of treatment since its introduction in 1972. Its reformulation as an extended-release product from Mylan Pharmaceuticals has done much to reduce adverse effects that result in patient nonadherence.

Pharmacology

Anticholinergics are competitive inhibitors of acetylcholine. In the bladder, this inhibition restricts involuntary contractions, relaxing pressure on the bladder, thereby controlling symptoms of incontinence.

Dosage and Administration

In addition to creating a voiding diary and having a focused physical examination, patients need to be examined to eliminate underlying pathologies such as diabetes, Alzheimer's disease, Parkinson's disease, or multiple sclerosis.When the need for drug treatment is determined, the once-daily convenience and control afforded by extended-release versions of oxybutynin make it a primary candidate for first-line therapy. The usual adult dose is 5 or 10 mg, taken once daily at approximately the same time each day. Pediatric patients aged 6 years and older are generally dosed daily at 5 mg. Dosing may be increased, depending on patient response, at 7-day intervals to a daily adult maximum of 30 mg, or a daily pediatric dose of 20 mg.

The administration of the extendedrelease version of oxybutynin with food or antacids does not appear to have an effect on drug absorption. Patients should be instructed not to chew the tablets. Patients also need to be aware that the tablet shell may not dissolve and can appear in the stool.

Precautions and Interactions

The side effects of oxybutynin are anticholinergic in nature—dry mouth and eyes, blurred vision, constipation, dizziness, drowsiness, heat intolerance, and the potential for cardiac palpitations. In general, any anticholinergic therapy is contraindicated among patients with untreated closed-angle glaucoma or urinary obstruction. Although oxybutynin possesses the above side effects, its profile is not as dramatic as with earlier regimens involving propantheline, hyoscyamine, or tricyclic antidepressants.

Nevertheless, patients with existing narrowing of the gastrointestinal tract may experience intestinal blockage with oxybutynin, and those with ulcerative colitis may potentially experience exacerbation of symptoms to the point of paralytic ileus. Other preexisting conditions requiring additional monitoring include myasthenia gravis, hyperthyroidism, hypertension, cardiac arrhythmia, and prostatic hypertrophy.

The extended-release version of oxybutynin has greater absorption in the large intestine than in the stomach, the primary absorption site for the earlier, immediate-release versions. This altered absorption process may explain the lower frequency of dry mouth with the extended-release version of oxybutynin.

The use of other drugs with anticholinergic effects should be approached with caution, as should those agents with inhibitory effects on the hepatic enzyme CYP 3A4 (ketoconazole, clarithromycin, erythromycin, itraconazole, and miconazole).

Outlook

Research in treating urinary incontinence is exploring desmopressin, potassium channel openers, and even intravesical use of capsaicin as therapeutic alternatives. Recent reports even predict that urologists may be employing gene therapy via cystoscopes as early as 2010. Until then, generic oxybutynin, as an extended-release tablet, is available to manage symptoms of overactive bladder and its ensuing incontinence.

Mr. Middleton is an instructor of pharmacology at Kellogg Community College in Battle Creek, Mich.