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Posted
Alprazolam FAQ

quote:
Alprazolam FAQ
v2.3, June 2003



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TABLE OF CONTENTS

1.0 DESCRIPTION
1.1 BRAND NAMES
1.2 CATEGORIES
1.3 INACTIVE INGREDIENTS

2.0 CLINICAL PHARMACOLOGY
2.1 CLINICAL STUDIES
2.2 ANIMAL STUDIES

3.0 INDICATIONS AND USAGE
3.1 CONTRAINDICATIONS
3.2 WARNINGS
3.3 PRECAUTIONS
3.4 INTERACTIONS
3.5 ADVERSE REACTIONS

4.0 DOSAGE AND ADMINISTRATION
4.1 OVERDOSAGE

5.0 ABUSE AND DEPENDENCE

6.0 FREQUENTLY ASKED QUESTIONS

7.0 REVISION HISTORY


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1.0 DESCRIPTION

GENERIC NAME: alprazolam
DRUG CLASSIFICATION: Alprazolam is classified as a prescription drug.
CHEMICAL NAME: 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo (4,3-a)(1,4) benzodiazepine
STRUCTURAL FORMULA: C17H13ClN4
MOLECULAR WEIGHT: 308.7695

Alprazolam (al-PRAYZ-oh-lam) belongs to the class of psychoactive drugs called Central Nervous System Agents/Anxiolytics, Sedatives and Hypnotics/Benzodiazepines. It is a benzodiazepine anxiolytic used in the treatment of anxiety disorders. Benzodiazepines (ben-zoe-dye-AZ-e-peens) are the most commonly used anti-anxiety drugs because they are fairly safe, they rapidly reduce the symptoms of anxiety and they don't have to be taken on an ongoing basis in order to be effective. All benzodiazepines cause dose-related suppression of the central nervous system, varying from slight impairment to hypnosis.

Alprazolam tablets contain alprazolam which is a triazolo analog of the 1,4 benzodiazepine class of central nervous system-active compounds.

Alprazolam is a white crystalline powder, which is soluble in methanol or ethanol but which has no appreciable solubility in water at physiological pH.

Each alprazolam tablet, for oral administration, contains 0.25, 0.5, 1 or 2 mg of alprazolam.



Tablet, 0.25 mgFrownerwhite, ovoid-shaped tablet, imprint: "Upjohn 29") or (white, ovoid-shaped tablet, imprint: "XANAX 0.25")

Tablet, 0.5 mgFrownerpink, ovoid-shaped tablet, imprint: "Upjohn 55") or (peach, ovoid-shaped tablet, imprint: "XANAX 0.5")

Tablet, 1 mgFrownerlavender, ovoid-shaped tablet, imprint: "Upjohn 90") or (blue, ovoid-shaped tablet, imprint: "XANAX 1.0")

Tablet, 2 mgFrownerwhite, triscored tablet (3 scores), imprint: "2" on one side and "XANAX" on the other). These tablets can be broken into 4 equal parts of 0.5 mg each.

Alprazolam oral solution: 0.5 mg / 5 ml, 1 mg / 1 ml concentrate.
Alprazolam SR tablets.

Alprazolam is often preferable to other benzodiazepines, such as chlordiazepoxide, clorazepate and prazepam, because alprazolam has a relatively shorter half-life and does not have active metabolites that can lead to accumulation, particularly in the elderly. Alprazolam was approved by the FDA in 1981 and became available as a generic in 1993.

1.1 BRAND NAMES

Alcelam; Algad; Alpaz; Alplax; Alpram; Alprax; Alprazolam Intensol; Alprox; Alzam; Alzolam; Alzor; Anpress; Ansiopax; Apotex; Azor; Cassadan; Constan; Frontal; Kalma; Marzolam; Mialin; Panix; Pazolam; Pharnax; Prinox; Pruden; Ralozam; Relaxol; Restyl; Solanax; Tafil; Tensivan; Trankimazin; Tranquinal; Tricalma; Unilan; Valeans; Xanagis; Xanax; Xanor; Zacetin; Zanapam; Zenax; Zolarem; Zoldac; Zoldax; Zotran. (Foreign Brand names outside U.S. in italics)

Alcelam (Thailand)
Algad (Israel)
Alpaz (Peru)
Alplax (Argentina)
Alpram (Korea)
Alprax (India)
Alprox (Israel)
Alzam (South-Africa)
Alzolam (India; Malaysia)
Anpress (Thailand)
Ansiopax (Chile)
Apotex (Canada)
Azor (South-Africa)
Cassadan (Germany)
Constan (Japan)
Frontal (Brazil)
Kalma (Australia; New-Zealand)
Marzolam (Thailand)
Mialin (Italy)
Panix (South-Africa)
Pazolam (Portugal)
Pharnax (Thailand)
Prinox (Argentina)
Pruden (Chile)
Ralozam (Australia; New-Zealand)
Relaxol (Peru)
Restyl (Bahrain; Cyprus; Egypt; Iran; Iraq; Jordan; Kuwait; Lebanon; Libya; Oman; Qatar; Republic-of-Yemen; Saudi-Arabia; Syria; United-Arab-Emirates)
Solanax (Japan)
Tafil (Costa-Rica; Denmark; El-Salvador; Germany; Guatemala; Honduras; Mexico; Nicaragua; Panama; Venezuela)
Tensivan (Colombia)
Trankimazin (Spain)
Tranquinal (Ecuador; Peru)
Tricalma (Chile)
Unilan (Portugal)
Valeans (Italy)
Xanagis (Israel)
Xanor (Finland; Philippines; South-Africa; Sweden)
Zacetin (Korea)
Zanapam (Korea)
Zenax (India)
Zolarem (Bahrain; Benin; Burkina-Faso; Cyprus; Egypt; Ethiopia; Gambia; Ghana; Guinea; Iran; Iraq; Israel; Ivory-Coast; Jordan; Kenya; Kuwait; Lebanon; Liberia; Libya; Malawi; Mali; Mauritania; Mauritius; Morocco; Niger; Nigeria; Oman; Qatar; Republic-Of-Yemen; Saudi-Arabia; Senegal; Seychelles; Sierra-Leone; South-Africa; Sudan; Syria; Tanzania; Tunia; Uganda; United-Arab-Emirates; Zambia; Zimbabwe)
Zoldac (Benin; Burkina-Faso; Ethiopia; Gambia; Ghana; Guinea; India; Ivory-Coast; Kenya; Liberia; Malawi; Mali; Mauritania; Mauritius; Morocco; Niger; Nigeria; Senegal; Seychelles; Sierra-Leone; South-Africa; Sudan; Tanzania; Tunia; Uganda; Zambia; Zimbabwe)
Zotran (Chile)

1.2 CATEGORIES

Anti-anxiety Drugs; Anxiety; Anxiolytics; Sedatives; Hypnotics; Benzodiazepines; Central Nervous System Agents; Depression; Nausea; Pain; Panic Disorder; Social Phobia; Psychotropic Agents; Tension; Tinnitus*; Schedule C-IV controlled substance; Pregnancy Category D; Top 200 Drugs; FDA Approval 1981 Oct; Patent Expiration 1993 Sep.
*Indication not approved by FDA

1.3 INACTIVE INGREDIENTS

Cellulose, corn starch, docusate sodium, lactose, magnesium stearate, silicon dioxide and sodium benzoate; In addition, the 0.5 mg tablet contains FD&C yellow no. 6 and the 1 mg tablet contains FD&C blue no. 2.


2.0 CLINICAL PHARMACOLOGY

Benzodiazepines act at the level of the limbic, thalamic and hypothalamic regions of the CNS and can produce any level of CNS depression required including sedation, hypnosis, skeletal muscle relaxation, anticonvulsant activity and coma. The action of these drugs is mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Central benzodiazepine receptors interact allosterically with GABA receptors, potentiating the effects of GABA and increasing the inhibition of the ascending reticular activating system. Benzodiazepines block the cortical and limbic arousal that occurs following stimulation of the reticular pathways.

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 1-2 hours following administration. Plasma levels are proportionate to the dose given; over the dose range of 0.5 to 3.0 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: 6.3-26.9 hours) in healthy adults.

The predominant metabolites are a-hydroxy-alprazolam and a benzophenone derived from alprazolam. The biological activity of a-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. Both the active and inactive derivatives of the drug are excreted in the urine.

Alprazolam is administered orally and is rapidly absorbed following an oral dose. The drug is widely distributed and is 90% plasma protein-bound. Alprazolam may cross the placenta and distribute into breast milk. Alprazolam undergoes oxidative metabolism in the liver, producing metabolites with little or no activity.

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%) 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: 9.0-26.9 hours, n = 16) compared to 11.0 hours (range: 6.3-15.8 hours, n = 16) in healthy adult subjects. The co-administration of oral contraceptives to healthy women increased the half-life of alprazolam as compared to that in healthy control women (mean: 12.4 hours, n = 11 versus 9.6 hours, n = 9). There was a prolongation in the mean half-life of alprazolam from 12.4 hours (range: 7.2-18.4 hours, n = 9) to 16.6 hours (range: 10.0- 24.3 hours, n = 9) by the co-administration of cimetidine to the same healthy adults. 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.

2.1 CLINICAL STUDIES

ANXIETY DISORDERS: Alprazolam tablets were compared to placebo in double blind clinical studies (doses up to 4 mg/day) in patients with a diagnosis of anxiety or anxiety with associated depressive symptomatology. Alprazolam was significantly better than placebo at each of the evaluation periods of these four week studies as judged by the following psychometric instruments: Physician's Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient's Global Impressions and Self-Rating Symptom Scale.PANIC DISORDER: Support for the effectiveness of alprazolam in the treatment of panic disorder came from three short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely corresponding to DSM-III-R criteria for panic disorder.

The average dose of alprazolam was 5-6 mg/day in two of the studies and the doses of alprazolam were fixed at 2 and 6 mg/day in the third study. In all three studies, alprazolam was superior to placebo on a variable defined as "the number of patients with zero panic attacks" (range, 37-83% met this criterion), as well as on a global improvement score. In two of the three studies, alprazolam was superior to placebo on a variable defined as "change from baseline on the number of panic attacks per week" (range, 3.3-5.2) and also on a phobia rating scale. A subgroup of patients who were improved on alprazolam during short-term treatment in one of these trials was continued on an open basis up to 8 months, without apparent loss of benefit.

2.2 ANIMAL STUDIES

When rats were treated with alprazolam at 3, 10 and 30 mg/kg/day (15 to 150 times the maximum recommended human dose) orally for 2 years, a tendency for a dose related increase in the number of cataracts was observed in females and a tendency for a dose related increase in corneal vascularization was observed in males. These lesions did not appear until after 11 months of treatment.


3.0 INDICATIONS AND USAGE

Alprazolam is 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 lightheadedness; 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 is 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.

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 (e.g., driving a car or being in a crowded place) may become associated with having a panic attack. 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; pounding heart or accelerated heart rate; trembling or shaking; sweating; choking; nausea or abdominal distress; depersonalization (being detached from oneself) or derealization (feelings of unreality); paresthesias (numbness or tingling sensations); 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 attributable to some known 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.

3.1 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 should be used with extreme caution in patients with respiratory depression, pulmonary disease such as severe COPD (chronic obstructive pulmonary disease) or sleep apnea because the drug can exacerbate ventilatory failure.

Alprazolam should be used with extreme caution in patients with myasthenia gravis because the drug can exacerbate this condition.

Patients with late stage Parkinson's disease may experience worsening of their psychosis or impaired cognition with administration of benzodiazepines. Benzodiazepines may also cause incoordination or paradoxical reactions that may worsen symptoms of Parkinson's disease.

The administration of alprazolam can exacerbate acute intermittent porphyria, so the drug should be used with caution in patients with this condition.

Alprazolam is occasionally beneficial for patients with major depression, psychosis or suicidal ideation. The drug should be administered to these patients with careful monitoring.

Alprazolam is classified as pregnancy category D because it could harm the fetus when administered to pregnant women. Positive evidence of human fatal risk exists based on investigational, marketing or human studies, but the potential benefit to the mother may outweigh the potential risks to the fetus. Many benzodiazepines distribute into breast milk. Because of the potential for adverse effects in the nursing infant, such as sedation, feeding difficulties and weight loss, alprazolam generally is not recommended during breast-feeding.

Alprazolam should be administered cautiously to patients with severe hepatic disease because the elimination half-life of the drug can be prolonged, possibly resulting in toxicity. Patients with hepatic disease are more likely to experience adverse CNS reactions and should receive reduced initial dosages. Concomittant administration of alprazolam and potent inhibitors of CYP 3A4 such as ketoconazole and itraconazole are contraindicated. Concurrent administration of alprazolam and drugs that inhibit cytochrome P450 3A (CYP 3A) should be approached with caution.

Patients with renal impairment should be carefully monitored during prolonged treatment with benzodiazepines to avoid the adverse reactions that may occur from drug accumulation.

The clearance and/or elimination of many drugs are reduced in the elderly. Delayed elimination can either intensify or prolong the actions of adverse reactions of the drug. Benzodiazepines have been associated with falls in the elderly. The impairment of cognitive and motor function may be more marked in this patient group and lower initial dosage is recommended together with close monitoring.

The safe and effective use of alprazolam in individuals below 18 years of age has not been established.

3.2 WARNINGS

DEPENDENCE AND WITHDRAWAL REACTIONS, INCLUDING SEIZURES: Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to alprazolam. These include a spectrum of withdrawal symptoms; the most important is seizure. Even after relatively short-term use at the doses recommended for the treatment of transient anxiety and anxiety disorder (i.e., 0.75-4.0 mg per day), there is some risk of dependence. Spontaneous reporting system data suggest that the risk of dependence and its severity appear to be greater in patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks). However, in a controlled postmarketing discontinuation study of panic disorder patients, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose. In contrast, patients treated with doses of alprazolam greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day.

THE IMPORTANCE OF DOSE AND THE RISKS OF ALPRAZOLAM AS A TREATMENT FOR PANIC DISORDER: Because the management of panic disorder often requires the use of average daily doses of alprazolam above 4 mg, the risk of dependence among panic disorder patients may be higher than that among those treated for less severe anxiety. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder showed a high rate of rebound and withdrawal symptoms in patients treated with alprazolam compared to placebo treated patients.

Relapse or return of illness was defined as a return of symptoms characteristic of panic disorder (primarily panic attacks) to levels approximately equal to those seen at baseline before active treatment was initiated. Rebound refers to a return of symptoms of panic disorder to a level substantially greater in frequency or more severe in intensity than seen at baseline. Withdrawal symptoms were identified as those which baseline. Withdrawal symptoms were identified as those which were generally not characteristic of panic disorder and which occurred for the first time more frequently during discontinuation than at baseline.

In a controlled clinical trial in which 63 patients were randomized to alprazolam and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound or withdrawal.

In a larger database comprised of both controlled and uncontrolled studies in which 641 patients received alprazolam, discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with alprazolam and at a greater rate than the placebo treated group were as follows (TABLE 1):

--------------------------------------------------------------------------
TABLE 1
Discontinuation-Emergent Symptom Incidence
Percentage of 641 Alprazolam-Treated Panic Disorder Patients
Reporting Events
--------------------------------------------------------------------------
Body System/Event
--------------------------------------------------------------------------
NEUROLOGIC GASTROINTESTINAL
Insomnia 29.5 Nausea/Vomiting 16.5
Light-headedness 19.3 Diarrhea 13.6
Abnormal involuntary movement 17.3 Decreased salivation 10.6
Headache 17.0 METABOLIC-NUTRITIONAL
Muscular twitching 6.9 Weight loss 13.3
Impaired Co-ordination 6.6 Decreased appetite 12.8
Muscle tone disorders 5.9
Weakness 5.8 DERMATOLOGICAL
PSYCHIATRIC Sweating 14.4
Anxiety 19.2 CARDIOVASCULAR
Fatigue and Tiredness 18.4 Tachycardia 12.2
Irritability 10.5 SPECIAL SENSES
Cognitive disorder 10.3 Blurred vision 10.0
Memory impairment 5.5
Depression 5.1
Confusional state 5.0
--------------------------------------------------------------------------

From the studies cited, it has not been determined whether these symptoms are clearly related to the dose and duration of therapy with alprazolam in patients with panic disorder.

In two controlled trials of six to eight weeks duration where the ability of patients to discontinue medication was measured, 71%-93% of alprazolam treated patients tapered completely off therapy compared to 89%-96% of placebo treated patients. The ability of patients to completely discontinue therapy with alprazolam after long-term therapy has not been reliably determined. However, in a controlled post marketing discontinuation study of panic disorder patients, the duration of treatment (three months compared to six months) had no effect on the ability to taper to zero dose.

Seizures attributable to alprazolam were seen after drug discontinuance or dose reduction in 8 of 1980 patients with panic disorder or in patients participating in clinical trials where alprazolam doses of greater than 4 mg daily for over 3 months were permitted. Five of these cases clearly occurred during abrupt dose reduction or discontinuation from daily doses of 2 to 10 mg. Three cases occurred in situations where there was not a clear relationship to abrupt dose reduction or discontinuation. In one instance, seizure occurred after discontinuation from a single dose of 1 mg after tapering at a rate of one mg every three days from 6 mg daily. In two other instances, the relationship to taper is indeterminate; in both of these cases the patients had been receiving doses of 3 mg daily prior to seizure. The duration of use in the above eight cases ranged from 4 to 22 weeks. There have been occasional voluntary reports of patients developing seizures while apparently tapering gradually from alprazolam. The risk of seizure seems to be greatest 24-72 hours after discontinuation.

STATUS EPILEPTICUS AND ITS TREATMENT: The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of alprazolam. In most cases, only a single seizure was reported; however, multiple seizures and status epilepticus were reported as well. Ordinarily, the treatment of status epilepticus of any etiology involves use of intravenous benzodiazepines plus phenytoin or barbiturates, maintenance of a patent airway and adequate hydration. For additional details regarding therapy, consultation with an appropriate specialist may be considered.

INTERDOSE SYMPTOMS: Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam have been reported in patients with panic disorder taking prescribed maintenance doses of alprazolam. These symptoms may reflect the development of tolerance or a time interval between doses, which is longer than the duration of clinical action of the administered dose. In either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels above those needed to prevent relapse, rebound or withdrawal symptoms over the entire course of the interdosing interval. In these situations, it is recommended that the same total daily dose be given divided as more frequent administrations.

RISK OF DOSE REDUCTION: Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes purposeful tapering, but also inadvertent reduction of dose (e.g., the patient forgets, the patient is admitted to a hospital, etc.). Therefore, the dosage of alprazolam should be reduced or discontinued gradually.

Alprazolam tablets are not of value in the treatment of psychotic patients and should not be employed in lieu of appropriate treatment for psychosis. Because of its CNS depressant effects, patients receiving alprazolam should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the simultaneous ingestion of alcohol and other CNS depressant drugs during treatment with alprazolam.

Benzodiazepines can potentially cause fatal harm when administered to pregnant women. If alprazolam is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Because of experience with other members of the benzodiazepine class, alprazolam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug.

ALPRAZOLAM INTERACTION WITH DRUGS THAT INHIBIT METABOLISM VIA CYTOCHROME P450 3A: The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP 3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP 3A. With drugs inhibiting CYP 3A to a lesser but still significant degree, alprazolam should be used only with caution and consideration of appropriate dosage reduction. For some drugs, an interaction with alprazolam has been quantified with clinical data; for other drugs, interactions are predicted from in vitro data and/or experience with similar drugs in the same pharmacologic class.

The following are examples of drugs known to inhibit the metabolism of alprazolam and/or related benzodiazepines, presumably through inhibition of CYP 3A.

POTENT CYP 3A INHIBITORS: Azole antifungal agents: Although in vitro interaction data with alprazolam are not available, ketoconazole and itraconazole are potent CYP 3A inhibitors and the co-administration of alprazolam with them is not recommended. Other azole-type antifungal agents should also be considered potent CYP 3A inhibitors and the co-administration of alprazolam with them is not recommended.

Drugs demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving alprazolam (caution and consideration of appropriate alprazolam dose reduction are recommended during co-administration with the following drugs):

Nefazodone: Co-administration of nefazodone increased alprazolam concentration twofold.

Fluvoxamine: Co-administration of fluvoxamine approximately doubled the maximum plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71% and decreased measured psychomotor performance.

Cimetidine: Co-administration of cimetidine increased the maximum plasma concentration of alprazolam by 86%, decreased clearance by 42% and increased half-life by 16%.

Other drugs possibly affecting alprazolam metabolism by inhibition of CYP 3A are discussed in DRUG INTERACTIONS.

3.3 PRECAUTIONS

If alprazolam tablets are 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.

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. 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 (e.g., increased plasma half-life) has been observed in both alcoholic liver disease patients and obese patients receiving alprazolam.

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.

LABORATORY TESTS: Laboratory tests are not ordinarily required in otherwise healthy patients.

DRUG/LABORATORY TEST INTERACTIONS: Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test.

CARCINOGENESIS, MUTAGENESIS AND IMPAIRMENT OF FERTILITY: No evidence of carcinogenic potential was observed during 2-year bioassay studies of alprazolam in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum recommended daily human dose). Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which is 500 times the maximum recommended daily human dose of 10 mg/day. Alprazolam also was not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay.

Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg/day, which is 25 times the maximum recommended daily human dose of 10 mg/day.

PREGNANCY:

TERATOGENIC EFFECTS: Pregnancy Category D. - Positive evidence of risk.

NONTERATOGENIC EFFECTS: It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.

LABOR AND DELIVERY: Alprazolam has no established use in labor or delivery.

NURSING MOTHERS: Benzodiazepines are known to be excreted in human milk. It should be assumed that alprazolam is as well. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. As a general rule, nursing should not be under taken by mothers who must use alprazolam.

PEDIATRIC USE: Safety and effectiveness of alprazolam in individuals below 18 years of age have not been established.

3.4 INTERACTIONS

The benzodiazepines, including alprazolam, produce additive CNS depressant effects when co-administered 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 tablets 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.

Drugs demonstrated to be CYP 3A inhibitors of possible clinical significance on the basis of clinical studies involving alprazolam (caution is recommended during co-administration with alprazolam):

Fluoxetine (Prozac): Co-administration 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: Co-administration of propoxyphene decreased the maximum plasma concentration of alprazolam by 6%, decreased clearance by 38% and increased half-life by 58%.

Digoxin (Lanoxin): May increase serum digoxin levels, increasing toxicity. An interaction between digoxin with alprazolam has been reported. Digoxin toxicity has occurred in a patient receiving alprazolam and digoxin. This interaction may be the result of increased plasma protein binding of digoxin and/or an effect of the benzodiazepine at the renal tubules that results in decreased digoxin elimination. Pending further clarification of this interaction, patients receiving alprazolam and digoxin concurrently should be monitored for increased serum digoxin levels.

Oral Contraceptives: Co-administration 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 co-administration 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 co-administration of any of these with alprazolam.

3.5 ADVERSE REACTIONS

Side effects of alprazolam tablets, 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 (e.g., drowsiness or light-headedness).

The data cited in the two tables below (TABLE 2, TABLE 3) are estimates of untoward clinical event incidence among patients who participated under the following clinical conditions: relatively short duration (i.e., four weeks) placebo-controlled clinical studies with dosages up to 4 mg/day of alprazolam (for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety) and short-term (up to ten weeks) placebo-controlled clinical studies with dosages up to 10 mg/day of alprazolam in patients with panic disorder, with or without agoraphobia.

These data cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors often differ from those in clinical trials. These figures cannot be compared with those obtained from other clinical studies involving related drug products and placebo as each group of drug trials are conducted under a different set of conditions.

Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the relative contributions of drug and non-drug factors to the untoward event incidence in the population studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient but induce it in others. (For example, an anxiolytic drug may relieve dry mouth (a symptom of anxiety) in some subjects but induce it (an untoward event) in others.) Additionally, for anxiety disorders the cited figures can provide the prescriber with an indication as to the frequency with which physician intervention (e.g., increased surveillance, decreased dosage or discontinuation of drug therapy) may be necessary because of the untoward clinical event (TABLE 2).

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TABLE 2
ANXIETY DISORDERS
Treatment-Emergent Incidence of
Symptom Incidence x intervention
Because of Symptom
Alprazolam Placebo Alprazolam
--------------------------------------------------------------------------
Number of Patients 565 505 565
% of Patients Reporting:
CENTRAL NERVOUS SYSTEM
Drowsiness 41.0 21.6 15.1
Light-headedness 20.8 19.3 1.2
Depression 13.9 18.1 2.4
Headache 12.9 19.6 1.1
Confusion 9.9 10.0 0.9
Insomnia 8.9 18.4 1.3
Nervousness 4.1 10.3 1.1
Syncope 3.1 4.0 *
Dizziness 1.8 0.8 2.5
Akathisia 1.6 1.2 *
Tiredness/Sleepiness * * 1.8
GASTROINTESTINAL
Dry Mouth 14.7 13.3 0.7
Constipation 10.4 11.4 0.9
Diarrhea 10.1 10.3 1.2
Nausea/Vomiting 9.6 12.8 1.7
Increased Salivation 4.2 2.4 *
CARDIOVASCULAR
Tachycardia/Palpitations 7.7 15.6 0.4
Hypotension 4.7 2.2 *
SENSORY
Blurred Vision 6.2 6.2 0.4
MUSCULOSKELETAL
Rigidity 4.2 5.3 *
Tremor 4.0 8.8 0.4
CUTANEOUS
Dermatitis/Allergy 3.8 3.1 0.6
OTHER
Nasal Congestion 7.3 9.3 *
Weight Gain 2.7 2.7 *
Weight Loss 2.3 3.0 *
* None reported.
x Events reported by 1% or more of alprazolam patients are included.
--------------------------------------------------------------------------
In addition to the relatively common (i.e., greater than 1%) untoward events enumerated in the table above, the following adverse events have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention (TABLE 3).

--------------------------------------------------------------------------
TABLE 3
Panic Disorders
Treatment-Emergent Symptom Incidence*
Alprazolam PLACEBO
--------------------------------------------------------------------------
Number of Patients 1388 1231
--------------------------------------------------------------------------
% of Patients Reporting:
CENTRAL NERVOUS SYSTEM
Drowsiness 76.8 42.7
Fatigue and Tiredness 48.6 42.3
Impaired Coordination 40.1 17.9
Irritability 33.1 30.1
Memory Impairment 33.1 22.1
Light-headedness /Dizziness 29.8 36.9
Insomnia 29.4 41.8
Headache 29.2 35.6
Cognitive Disorder 28.8 20.5
Dysarthria 23.3 6.3
Anxiety 16.6 24.9
Abnormal Involuntary Movement 14.8 21.0
Decreased Libido 14.4 8.0
Depression 13.8 14.0
Confusional State 10.4 8.2
Muscular Twitching 7.9 11.8
Increased Libido 7.7 4.1
Change in Libido (Not Specified) 7.1 5.6
Weakness 7.1 8.4
Muscle Tone Disorders 6.3 7.5
Syncope 3.8 4.8
Akathisia 3.0 4.3
Agitation 2.9 2.6
Disinhibition 2.7 1.5
Paresthesia 2.4 3.2
Talkativeness 2.2 1.0
Vasomotor Disturbances 2.0 2.6
Derealisation 1.9 1.2
Dream Abnormalities 1.8 1.5
Fear 1.4 1.0
Feeling Warm 1.3 0.5
GASTROINTESTINAL
Decreased Salivation 32.8 34.2
Constipation 26.2 15.4
Nausea/Vomiting 22.0 31.8
Diarrhea 20.6 22.8
Abdominal Distress 18.3 21.5
Increased Salivation 5.6 4.4
CARDIORESPIRATORY
Nasal Congestion 17.4 16.5
Tachycardia 15.4 26.8
Chest Pain 10.6 18.1
Hyperventilation 9.7 14.5
Upper Respiratory Infection 4.3 3.7
SENSORY
Blurred Vision 21.0 21.4
Tinnitus 6.6 10.4
MUSCULOSKELETAL
Muscular Cramps 2.4 2.4
Muscle Stiffness 2.2 3.3
CUTANEOUS
Sweating 15.1 23.5
Rash 10.8 8.1
OTHER
Increased Appetite 32.7 22.8
Decreased Appetite 27.8 24.1
Weight Gain 27.2 17.9
Weight Loss 22.6 16.5
Micturition Difficulties 12.2 8.6
Menstrual Disorders 10.4 8.7
Sexual Dysfunction 7.4 3.7
Edema 4.9 5.6
Incontinence 1.5 0.6
Infection 1.3 1.7
--------------------------------------------------------------------------
* Events reported by 1% or more of alprazolam patients are included.
--------------------------------------------------------------------------

In addition to the relatively common (i.e., greater than 1%) untoward events enumerated in the table above, the following adverse events have been reported in association with the use of alprazolam: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes and jaundice.

There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam tablets.

To discontinue treatment in patients taking alprazolam, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.5 mg every three days. Some patients may require an even slower dosage reduction. 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.

Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Therefore, the same precaution must be exercised when using the higher doses of alprazolam in treating patients with panic disorders as is exercised with the use of any psychotropic drug in treating depressed patients or those in whom there is reason to expect concealed suicid


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