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All about: Alprazolam

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Generic Name: alprazolam
Dosage Form: Tablets, usp civ

Alprazolam 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-striazolo [ 4 , 3 -α] [1,4] benzodiazepine.

The structural formula is represented below:

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.

Alprazolam tablets, 2 mg, are multi-scored and may be divided as shown below:

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.

Alprazolam - 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 3.0 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 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: 9.0–26.9 hours, n=16) compared to 11.0 hours (range: 6.3 – 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.

Indications and Usage for Alprazolam

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 is also indicated for the treatment of panic disorder, with or without agoraphobia.

Studies support ing 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 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.

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 tablets are contraindicated with ketoconazole and itraconazole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP 3A) (see WARNINGS and PRECAUTIONS–Drug Interactions).

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 (see DRUG ABUSE AND DEPENDENCE). Even after relatively short-term use at the doses recommended for the treatment of transient anxiety and anxiety disorder (ie, 0.75 to 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 (three months compared to six 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 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 alprazolaman data greater rate than the placebo treated group were as follows:

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 coordination 6.6 Decreased appetite 12.8
Muscle tone disorders 5.9
Weakness 5.8 Dermatological
Psychiatric Sweating 14.4
Anxiety 19.2
Fatigue and Tiredness 18.4 Cardiovascular
Irritability 10.5 Tachycardia 12.2
Cognitive disorder 10.3
Memory impairment 5.5 Special Senses
Depression 5.1 Blurred vision 10.0
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. In a controlled postmarketing discontinuation study of panic disorder patients, the duration of treatment (three months compared to six months) had no effect on the ability of patients 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 doses of Alprazolam greater than 4 mg/day 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 1 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 8 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 (see DOSAGE AND ADMINISTRATION for recommended tapering and discontinuation schedule).

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 (see DOSAGE AND ADMINISTRATION).

Risk of dose reduction

Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes purposeful tapering, but also in advertent reduction of dose (eg, the patient forgets, the patient is admitted to a hospital, etc.). Therefore, the dosage of Alprazolam should be reduced or discontinued gradually (see DOSAGE ANDADMINISTRATION).

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 fetal 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 ofdiscontinuing 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 vivo interaction data with Alprazolam are not available, ketoconazole and itraconazole are potent CYP 3A inhibitors and the coadministration of Alprazolam with them is not recommended. Other azole-type antifungal agents should also be considered potent CYP 3A inhibitors and the coadministration of Alprazolam with them is not recommended (see CONTRAINDICATIONS).

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 coadministration with the following drugs):

Nefazodone—Coadministration of nefazodone increased Alprazolam concentration two-fold.

Fluvoxavine—Coadministration 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—Coadministration 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

Other drugs possibly affecting Alprazolam metabolism by inhibition of CYP 3A are discussed in the PRECAUTIONS section (see PRECAUTIONS – Drug Interactions).

Precautions

General

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 (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.

Information for Patients

For all users of alprazolam

To assure safe and effective use of benzodiazepines, all patients prescribed Alprazolam should be provided with the following guidance. In addition, panic disorder patients, for whom doses greater than 4 mg/day are typically prescribed, should be advised about the risks associated with the use of higher doses.

  1. Inform your physician about any alcohol consumption and medicine you are taking now, including medication you may buy without a prescription. Alcohol should generally not be used during treatment with benzodiazepines.
  2. Not recommended for use in pregnancy. Therefore, inform your physician if you are pregnant, if you are planning to have a child, or if you become pregnant while you are taking this medication.
  3. Inform your physician if you are nursing.
  4. Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery, etc.
  5. Do not increase the dose even if you think the medication "does not work anymore" without consulting your physician. Benzodiazepines, even when used as recommended, may produce emotional and/or physical dependence.
  6. Do not stop taking medication abruptly or decrease the dose without consulting your physician, since withdrawal symptoms can occur.

Additional advice for panic disorder patients

The use of Alprazolam at doses greater than 4 mg/day, often necessary to treat panic disorder, is accompanied by risks that you need to carefully consider. When used at doses greater than 4 mg/day, which may or may not be required for your treatment, Alprazolam has the potential to cause severe emotional and physical dependence in some patients and these patients may find it exceedingly difficult to terminate treatment. In two controlled trials of six to eight weeks duration where the ability of patients to discontinue medication was measured, 7 to 29% of patients treated with Alprazolam did not completely taper off therapy. In a controlled postmarketing discontinuation study of panic disorder patients, the patients treated with doses of Alprazolam greater than 4 mg/day had more difficulty tapering to zero dose than patients treated with less than 4 mg/day. In all cases, it is important that your physician help you discontinue this medication in a careful and safe manner to avoid overly extended use of alprazolam.

In addition, the extended use at doses greater than 4 mg/day appears to increase the incidence and severity of withdrawal reactions when Alprazolam is discontinued. These are generally minor but seizure can occur, especially if you reduce the dose too rapidly or discontinue the medication abruptly. Seizure can be life-threatening.

Laboratory Tests

Laboratory tests are not ordinarily required in otherwise healthy patients.

Drug 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 (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: setraline and paroxetine . Data fron 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).

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, 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

(See WARNINGS section).

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 undertaken by mothers who must use alprazolam.

Pediatric Use

Safety and effectiveness of Alprazolam tablets in individuals below 18 years of age have not been established.

Geriatric Use

The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma Alprazolam concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. The smallest effective dose of Alprazolam should be used in the elderly to preclude the development of ataxia and oversedation (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Adverse Reactions

Side effects to 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, eg, drowsiness or light-headedness.

The data cited in the two tables below are estimates of untoward clinical event incidence among patients who participated under the following clinical conditions: relatively short duration (ie, 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 (eg, increased surveillance, decreased dosage or discontinuation of drug therapy) may be necessary because of the untoward clinical event.

ANXIETY DISORDERS
Treatment-Emergent Symptom Incidence* Incidence of Intervention Because of Symptom
Alprazolam Placebo Alprazolam
*
Events reported by 1% or more of Alprazolam patients are included.
None reported
Number of Patients % of Patients Reporting: 565 505 565
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

In addition to the relatively common (ie, 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.

PANIC DISORDER
Treatment-Emergent Symptom Incidence*
Alprazolam Placebo
*
Events reported by 1% or more of Alprazolam patients are included.
Number of Patients
% of Patients Reporting:
1388 1231
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
  Derealization 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
Cardio-Respiratory
  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

In addition to the relatively common (ie, 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 a

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Apo-Acetaminophen Apo-Acetaminophen
Some commonly used brand names are: In the U.S.— Aceta Elixir 1 Aceta Tablets 1 Acetaminophen Uniserts 1 Actamin 1 Actamin Extra 1 Actamin Super 2 Aminofen 1 Aminofen Max 1 Apacet Capsules 1 Apacet Elixir 1 Apacet Extra Strength Caplets 1 Apacet Extra Strength Tablets 1 Apacet, Infants' 1 more...

caffeine citrate caffeine citrate
Generic Name: caffeine citrate (oral) (KAF een SIT rate) Brand Names: Cafcit What is this drug? Caffeine citrate is a central nervous system stimulant. It also has effects on the lungs and metabolism. Caffeine citrate is used to treat breathing problems in premature infants. Caffeine ci more...

cromolyn sodium oral cromolyn sodium oral
Generic Name: cromolyn sodium oral (KRO mo lin SO dee um) Brand Names: Gastrocrom What is cromolyn sodium oral? Cromolyn sodium is an anti-inflammatory medication. It works by preventing the release of substances in the body that cause inflammation. Cromolyn sodium oral is used to trea more...

fluoxetine and olanzapine fluoxetine and olanzapine
Generic Name: fluoxetine and olanzapine (floo OX eh teen and oh LAN za peen) Brand Names: Symbyax What is fluoxetine and olanzapine? Fluoxetine is an antidepressant in a group of drugs called selective serotonin reuptake inhibitors (SSRIs). Olanzapine is an antipsychotic medication. The more...

Latanoprost Ophthalmic Latanoprost Ophthalmic
Some commonly used brand names are: In the U.S.— Xalatan Category Antiglaucoma agent (ophthalmic) antihypertensive, ocular Description Latanoprost (la-TA-noe-prost) is used to treat certain kinds of glaucoma. It is also used to treat a condition called hypertension of the eye. La more...

Norfloxacin Norfloxacin
Pronouncation: (nor-FLOX-uh-SIN) Class: Fluoroquinolone Trade Names: Chibroxin - Solution 3 mg/mL Trade Names: Noroxin - Tablets 400 mg Apo-Norflox (Canada) Novo-Norfloxacin (Canada) Mechanism of Action Pharmacology Interferes with microbial DNA synthesis. Pharmacokinetics Absorption Norfloxacin is more...

PanOxyl 20 Gel Topical PanOxyl 20 Gel Topical
Some commonly used brand names are: In the U.S.— Acne-Aid Vanishing Cream Acne-Aid Aqua Gel Ambi 10 Acne Medication Benoxyl 5 Lotion Benoxyl 10 Lotion Benzac AC 21/2 Gel Benzac AC 5 Gel Benzac AC 10 Gel Benzac AC Wash 21/2 Benzac AC Wash 5 Benzac AC Wash 10 Benzac 5 Gel Benzac 10 Gel Benz more...

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Some commonly used brand names are: In the U.S.— Advanced Formula Di-Gel 29 Alamag 2 Alamag Plus 9 Alenic Alka 15 Alenic Alka Extra Strength 18 Alka-Mints 27 Alkets 27 Alkets Extra Strength 27 Almacone 9 Almacone II 9 AlternaGEL 21 Alu-Cap 25 Aludrox 9 Alu-Tab 25 Amitone 27 Amphojel 25 An more...