DailyMed Label: Gabazolamine-0.5

DailyMed Label: Gabazolamine

2011

DailyMed Prescription

Gabazolamine

ALPRAZOLAM, CHOLINE

Physician Therapeutics LLC

NDC: 68405-024

NDC: 68405-024

DESCRIPTION Alprazolam is a triazolo analog of the 1,4 benzodiazepine class of central nervous system-active compounds. The chemical name of alprazolam is 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-α] [1,4] benzodiazepine, and its structural formula is: Alprazolam is a white to off-white crystalline powder, which is soluble in alcohol but which has no appreciable solubility in water at physiological pH. Each tablet, for oral administration, contains 0.25 mg, 0.5 mg, 1 mg, and 2 mg of alprazolam. The 2 mg tablets are multiscored, and may be divided in half to provide two 1 mg segments, or quarters to provide four 0.5 mg segments. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, docusate sodium, lactose (hydrous), magnesium stearate, microcrystalline cellulose, and sodium benzoate. The 0.5 mg tablet also contains FD C yellow #6 aluminum lake (sunset yellow lake). The 1 mg tablet also contains FD C blue #2 aluminum lake. The 2 mg tablet also contains D C yellow #10 aluminum lake. Alprazolam Structural Formula

INDICATIONS AND USAGE Alprazolam tablets are indicated for the management of anxiety disorder (a condition corresponding most closely to the APA Diagnostic and Statistical Manual (DSM-III-R) diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. Generalized anxiety disorder is characterized by unrealistic or excessive anxiety and worry (apprehensive expectation) about two or more life circumstances, for a period of six months or longer, during which the person has been bothered more days than not by these concerns. At least 6 of the following 18 symptoms are often present in these patients: Motor Tension (trembling, twitching, or feeling shaky; muscle tension, aches, or soreness; restlessness; easy fatigability); Autonomic Hyperactivity (shortness of breath or smothering sensations; palpitations or accelerated heart rate; sweating, or cold clammy hands; dry mouth; dizziness or light-headedness; nausea, diarrhea, or other abdominal distress; flushes or chills; frequent urination; trouble swallowing or ‘lump in throat’); Vigilance and Scanning (feeling keyed up or on edge; exaggerated startle response; difficulty concentrating or ‘mind going blank’ because of anxiety; trouble falling or staying asleep; irritability). These symptoms must not be secondary to another psychiatric disorder or caused by some organic factor. Anxiety associated with depression is responsive to alprazolam. Alprazolam tablets are also indicated for the treatment of panic disorder, with or without agoraphobia. Studies supporting this claim were conducted in patients whose diagnoses corresponded closely to the DSM-III-R criteria for panic disorder (see CLINICAL STUDIES ). Panic disorder is an illness characterized by recurrent panic attacks. The panic attacks, at least initially, are unexpected. Later in the course of this disturbance certain situations, eg, driving a car or being in a crowded place, may become associated with having a panic attack. These panic attacks are not triggered by situations in which the person is the focus of others’ attention (as in social phobia). The diagnosis requires four such attacks within a four week period, or one or more attacks followed by at least a month of persistent fear of having another attack. The panic attacks must be characterized by at least four of the following symptoms: dyspnea or smothering sensations; dizziness, unsteady feelings, or faintness; palpitations or tachycardia; trembling or shaking; sweating; choking; nausea or abdominal distress; depersonalization or derealization; paresthesias; hot flashes or chills; chest pain or discomfort; fear of dying; fear of going crazy or of doing something uncontrolled. At least some of the panic attack symptoms must develop suddenly, and the panic attack symptoms must not be attributed to some know organic factors. Panic disorder is frequently associated with some symptoms of agoraphobia. Demonstrations of the effectiveness of alprazolam by systematic clinical study are limited to four months duration for anxiety disorder and four to ten weeks duration for panic disorder; however, patients with panic disorder have been treated on an open basis for up to eight months without apparent loss of benefit. The physician should periodically reassess the usefulness of the drug for the individual patient.

DOSAGE AND ADMINISTRATION Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who require doses greater than 4 mg/day. In such cases, dosage should be increased cautiously to avoid adverse effects. Anxiety Disorders And Transient Symptoms Of Anxiety: Treatment for patients with anxiety should be initiated with a dose of 0.25 to 0.5 mg given three times daily. The dose may be increased to achieve a maximum therapeutic effect, at intervals of 3 to 4 days, to a maximum daily dose of 4 mg, given in divided doses. The lowest possible effective dose should be employed and the need for continued treatment reassessed frequently. The risk of dependence may increase with dose and duration of treatment. In elderly patients, in patients with advanced liver disease or in patients with debilitating disease, the usual starting dose is 0.25 mg, given two or three times daily. This may be gradually increased if needed and tolerated. The elderly may be especially sensitive to the effects of benzodiazepines. If side effects occur at the recommended starting dose, the dose may be lowered. In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every three days. Some patients may require an even slower dosage reduction. Panic Disorder: The successful treatment of many panic disorder patients has required the use of alprazolam at doses greater than 4 mg daily. In controlled trials conducted to establish the efficacy of alprazolam in panic disorder, doses in the range of 1 to 10 mg daily were used. The mean dosage employed was approximately 5 to 6 mg daily. Among the approximately 1700 patients participating in the panic disorder development program, about 300 received alprazolam in dosages of greater than 7 mg/day, including approximately 100 patients who received maximum dosages of greater than 9 mg/day. Occasional patients required as much as 10 mg a day to achieve a successful response. Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses in patients especially sensitive to the drug. Thereafter, the dose can be increased at intervals equal to at least 5 times the elimination half-life (about 11 hours in young patients, about 16 hours in elderly patients). Longer titration intervals should probably be used because the maximum therapeutic response may not occur until after the plasma levels achieve steady state. Dose should be advanced until an acceptable therapeutic response (ie, a substantial reduction in or total elimination of panic attacks) is achieved, intolerance occurs, or the maximum recommended dose is attained. For patients receiving doses greater than 4 mg/day, periodic reassessment and consideration of dosage reduction is advised. In a controlled postmarketing dose-response study, patients treated with doses of alprazolam greater than 4 mg/day for three months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit. Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided. (See WARNINGS , PRECAUTIONS , DRUG ABUSE AND DEPENDENCE ). The following regimen is one that follows the principles outlined above: Treatment may be initiated with a dose of 0.5 mg three times daily. Depending on the response, the dose may be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day. Slower titration to the dose levels greater than 4 mg/day may be advisable to allow full expression of the pharmacodynamic effect of alprazolam. To lessen the possibility of interdose symptoms, the times of administration should be distributed as evenly as possible throughout the waking hours, that is, on a three or four times per day schedule. The necessary duration of treatment for panic disorder patients responding to alprazolam is unknown. After a period of extended freedom from attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena. In any case, reduction of dose must be undertaken under close supervision and must be gradual. If significant withdrawal symptoms develop, the previous dosing schedule should be reinstituted and, only after stabilization, should a less rapid schedule of discontinuation be attempted. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. It is suggested that the dose be reduced by no more than 0.5 mg every three days, with the understanding that some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.

CONTRAINDICATIONS Alprazolam tablets are contraindicated in patients with known sensitivity to this drug or other benzodiazepines. Alprazolam may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in patients with acute narrow angle glaucoma. Alprazolam is contraindicated with ketoconazole and intraconazole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP 3A) (see WARNINGS and PRECAUTIONS-Drug Interactions ).

PRECAUTIONS General If alprazolam is to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines (see Drug Interactions ). As with other psychotropic medications, the usual precautions with respect to administration of the drug and size of the prescription are indicated for severely depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans. It is recommended that the dosage be limited to the smallest effective dose to preclude the development of ataxia or oversedation which may be a particular problem in elderly or debilitated patients. (see DOSAGE AND ADMINISTRATION ). The usual precautions in treating patients with impaired renal, hepatic or pulmonary function should be observed. There have been rare reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam. A decreased systemic alprazolam elimination rate (eg, increased plasma half-life) has been observed in both alcoholic liver disease patients and obese patients receiving alprazolam (see CLINICAL PHARMACOLOGY ). Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression. Alprazolam has a weak uricosuric effect. Although other medications with weak uricosuric effect have been reported to cause acute renal failure, there have been no reported instances of acute renal failure attributable to therapy with alprazolam.

Side effects to alprazolam, if they occur, are generally observed at the beginning of therapy and usually disappear upon continued medication. In the usual patient, the most frequent side effects are likely to be an extension of the pharmacological activity of alprazolam, eg, drowsiness or light-headedness.

Drug Interactions The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression. The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam in doses up to 4 mg/day. The clinical significance of these changes is unknown. Drugs That Inhibit Alprazolam Metabolism Via Cytochrome P450 3A: The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP 3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam (see CONTRAINDICATIONS and WARNINGS for additional drugs of this type. Drugs Demonstrated To Be CYP 3A Inhibitors Of Possible Clinical Significance On The Basis Of Clinical Studies Involving Alprazolam (Caution Is Recommended During Coadministration With Alprazolam: Fluoxetine --Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased measured psychomotor performance. Propoxyphene --Coadministration of propoxyphene decreased the maximum plasma concentration of alprazolam by 6%, decreased clearance by 38%; and increased half-life by 58%. Oral contraceptives --Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased half-life by 29%. Drugs And Other Substances Demonstrated To Be CYP 3A Inhibitors On The Basis Of Clinical Studies Involving Benzodiazepines Metabolized Similarly To Alprazolam Or On The Basis Of In Vitro Studies With Alprazolam Or Other Benzodiazepines (Caution Is Recommended During Coadministration With Alprazolam): Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction with alprazolam for the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro studies of alprazolam suggest a possible drug interaction with alprazolam for the following: sertraline and paroxetine. Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during the coadministration of any of these with alprazolam (see WARNINGS ).

HOW SUPPLIED Alprazolam Tablets, USP are supplied as follows: 0.25 mg — Each white, round tablet imprinted with  on one side and 027 and bisect on the other contains 0.25 mg of Alprazolam, USP. Tablets are supplied in bottles of 100 (NDC 0228-2027-10), 500 (NDC 0228-2027-50), and 1000 (NDC 0228-2027-96). 0.5 mg — Each peach, round tablet imprinted with  on one side and 029 and bisect on the other contains 0.5 mg of Alprazolam, USP. Tablets are supplied in bottles of 100 (NDC 0228-2029-10), 500 (NDC 0228-2029-50), and 1000 (NDC 0228-2029-96). 1 mg — Each blue, round tablet imprinted with  on one side and 031 and bisect on the other contains 1 mg of Alprazolam, USP. Tablets are supplied in bottles of 100 (NDC 0228-2031-10), 500 (NDC 0228-2031-50), and 1000 (NDC 0228-2031-96). 2 mg — Each yellow, rectangle shaped, flat faced, beveled edge tablet imprinted with  and 039 on one side and multiscored on both sides contains 2 mg of Alprazolam, USP. Tablets are supplied in bottles of 100 (NDC 0228-2039-10), and 500 (NDC 0228-2039-50). Dispense in tight, light-resistant containers as defined in the USP. Keep container tightly closed. Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

CLINICAL PHARMACOLOGY CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis. Following oral administration, alprazolam is readily absorbed. Peak concentrations in the plasma occur in one to two hours following administration. Plasma levels are proportionate to the dose given; over the dose range of 0.5 to 3 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults. The predominant metabolites are α -hydroxy-alprazolam and a benzophenone derived from alprazolam. The biological activity of α -hydroxy-alprazolam is approximately one-half that of alprazolam. The benzophenone metabolite is essentially inactive. Plasma levels of these metabolites are extremely low, thus precluding precise pharmacokinetic description. However, their half-lives appear to be of the same order of magnitude as that of alprazolam. Alprazolam and its metabolites are excreted primarily in the urine. The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined. However, this is not a property of benzodiazepines in general. Further, alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally. In vitro , alprazolam is bound (80 percent) to human serum protein. Changes in the absorption, distribution, metabolism and excretion of benzodiazepines have been reported in a variety of disease states including alcoholism, impaired hepatic function and impaired renal function. Changes have also been demonstrated in geriatric patients. A mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9.0 to 26.9 hours, n=16) compared to 11.0 hours (range: 6.3 to 15.8 hours, n=16) in healthy adult subjects. In patients with alcoholic liver disease the half-life of alprazolam ranged between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and 26.9 hours (mean=11.4 hours, n=17) in healthy subjects. In an obese group of subjects the half-life of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8 hours, n=12) as compared to between 6.3 and 15.8 hours (mean=10.6 hours, n=12) in healthy subjects. Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes transplacental passage and that it is excreted in human milk.

CLINICAL EXPERIENCE Patients taking GABAdone have demonstrated significant functional improvements when this therapeutic agent is used for the dietary management of the metabolic processes associated with sleep disorders. The administration of GABAdone results in the induction and maintenance of sleep in patients with sleep disorders. GABAdone has no effect on normal blood pressure.