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Pharmacy Times
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Alprazolam Extendedrelease Tablets


In the United States, nearly 1 in 4 peoplecan be expected to have at least 1experience with a clinically significantanxiety disorder.Women are more oftenafflicted than men, and a concurrent psychiatriccondition is present nearly 75%of the time. Despite the statistics, lessthan one third of those suffering fromanxiety disorders seek treatment.

Particularly, the anxiety type known aspanic disorder includes any 4 of the followingsymptoms, as described in theDiagnostic and Statistical Manual ofMental Disorders, Fourth Edition: palpitations,sweating, trembling, sensations ofsuffocation, feeling of choking, chest painor discomfort, nausea or abdominal distress,feeling of fainting or light-headedness,feeling of being detached from oneself,fear of losing control, fear of imminentdeath, paresthesias, and chills orhot flushes.

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


All benzodiazepines, including alprazolam,act at gamma-aminobutyric acidreceptors in the central nervous system(CNS), causing dose-related depressantbehaviors. The extended-release versionhas a slower absorption rate, delivering arelatively consistent concentration for 5to 11 hours after dosing. Benzodiazepinesare indicated in moderate-toseverepanic disorders in order to hastentherapeutic benefits, especially duringthe first weeks of treatment.

Dosing and Administration

Individualized, once-daily dosing ofalprazolam generally begins at 0.5 to 1mg daily, with 1-mg increases at 3-to 4-day intervals, peaking at about 3 to 6 mgdaily. Morning dosing is preferred. Thetablets should not be chewed, crushed,or dissolved before swallowing. Dailydoses beyond 6 mg may be necessary(some patients require as much as 10mg), but these doses require carefulmonitoring to avoid adverse effects. Theelderly or those with liver disease shouldbegin with a daily dose of 0.5 mg andthen be carefully titrated to the desiredresponse.

For patients being converted to theextended-release version of alprazolamfrom the immediate-release version, thedose is the same total daily dose, onlynow taken once daily.

Side Effects and Interactions

All benzodiazepines are associatedwith sedation, breakthrough symptomsduring treatment, and rebound effectsonce therapy is stopped. Alprazolam isno exception.

Alprazolam is extensively metabolizedby the CYP 3A4 enzyme. Ketoconazole,itraconazole, and erythromycin are allassociated with an elevation in alprazolamconcentrations.The increase in serumconcentrations is dramatic enough withketoconazole and itraconazole to establishspecific contraindications for theirconcurrent use with alprazolam. Oral contraceptivesincrease the half-life of alprazolam,and carbamazepine increases thedrug's clearance. Alprazolam concentrationsmay be diminished by half amongusers of tobacco.

Alprazolam, whether in immediate-orextended-release form, is a controlledsubstance assigned to Schedule IV.Emotional and physical dependence onalprazolam is possible, and seizures orrebound symptoms have been reportedwithin 1 to 3 days following abrupt discontinuationof treatment. When weaningthe patient from therapy, daily dosesof the extended-release tablets shouldbe decreased by no more than 0.5 mgevery 3 days. Some patients benefit froman even slower tapering. Alcohol will addto the CNS depressant activity of alprazolam;chronic alcohol use can challengethe ability of the clinician to predict therapeuticresponse to treatment.

Clinical Outlook

The patient adherence benefit of oncedailydosing is a frequent goal amongpharmaceutical manufacturers. Extendedreleasealprazolam also affords a longertherapeutic concentration, thereby reducingbreakthrough symptoms duringtreatment.

Oxybutynin ExtendedreleaseTablets

Although often connected withmenopause, an overactive bladder hasno gender bias. It is associated with involuntarydetrusor muscle contractions thatmay occur spontaneously or by provocation.Ultimately, symptoms are describedas stress incontinence ordetrusor muscle sensitivitywith urgency.

Urinary incontinenceis a commonproblem, afflicting 17million patients in theUnited States,with an estimated annual management cost of $26 billion.An overactive bladder represents achallenge both as a societal misadventureand as a balanced treatment.Traditionally, anticholinergic agents havebeen employed, but with results temperedby equally difficult side effects.

Oxybutynin has been a mainstay oftreatment since its introduction in 1972.Its reformulation as an extended-releaseproduct from Mylan Pharmaceuticals hasdone much to reduce adverse effectsthat result in patient nonadherence.


Anticholinergics are competitiveinhibitors of acetylcholine.In the bladder, this inhibitionrestricts involuntarycontractions,relaxing pressure onthe bladder, therebycontrolling symptoms ofincontinence.

Dosage and Administration

In addition to creating a voiding diaryand having a focused physical examination,patients need to be examined toeliminate underlying pathologies such asdiabetes, Alzheimer's disease, Parkinson'sdisease, or multiple sclerosis.Whenthe need for drug treatment is determined,the once-daily convenience andcontrol afforded by extended-releaseversions of oxybutynin make it a primarycandidate for first-line therapy. The usualadult dose is 5 or 10 mg, taken once dailyat approximately the same time eachday. Pediatric patients aged 6 years andolder are generally dosed daily at 5 mg.Dosing may be increased, depending onpatient response, at 7-day intervals to adaily adult maximum of 30 mg, or a dailypediatric dose of 20 mg.

The administration of the extendedreleaseversion of oxybutynin with foodor antacids does not appear to have aneffect on drug absorption. Patientsshould be instructed not to chew thetablets. Patients also need to be awarethat the tablet shell may not dissolve andcan appear in the stool.

Precautions and Interactions

The side effects of oxybutynin are anticholinergicin nature—dry mouth andeyes, blurred vision, constipation, dizziness,drowsiness, heat intolerance, andthe potential for cardiac palpitations. Ingeneral, any anticholinergic therapy iscontraindicated among patients withuntreated closed-angle glaucoma or urinaryobstruction. Although oxybutyninpossesses the above side effects, its profileis not as dramatic as with earlier regimensinvolving propantheline, hyoscyamine,or tricyclic antidepressants.

Nevertheless, patients with existingnarrowing of the gastrointestinal tractmay experience intestinal blockage withoxybutynin, and those with ulcerativecolitis may potentially experience exacerbationof symptoms to the point of paralyticileus. Other preexisting conditionsrequiring additional monitoring includemyasthenia gravis, hyperthyroidism,hypertension, cardiac arrhythmia, andprostatic hypertrophy.

The extended-release version of oxybutyninhas greater absorption in thelarge intestine than in the stomach, theprimary absorption site for the earlier,immediate-release versions. This alteredabsorption process may explainthe lower frequency of dry mouth withthe extended-release version of oxybutynin.

The use of other drugs with anticholinergiceffects should be approachedwith caution, as should thoseagents with inhibitory effects on thehepatic enzyme CYP 3A4 (ketoconazole,clarithromycin, erythromycin, itraconazole,and miconazole).


Research in treating urinary incontinenceis exploring desmopressin, potassiumchannel openers, and even intravesicaluse of capsaicin as therapeuticalternatives. Recent reports even predictthat urologists may be employing genetherapy via cystoscopes as early as 2010.Until then, generic oxybutynin, as anextended-release tablet, is available tomanage symptoms of overactive bladderand its ensuing incontinence.

Mr. Middleton is an instructor of pharmacologyat Kellogg CommunityCollege in Battle Creek, Mich.

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