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Side effects to XANAX 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 XANAX (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 XANAX 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.

Treatment-Emergent Adverse Events Reported in Placebo-Controlled Trials of Anxiety Disorders

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

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.

Treatment-Emergent Adverse Events Reported in Placebo-Controlled Trials of Panic Disorder

Number of Patients % of Patients Reporting: PANIC DISORDER
Treatment-Emergent
Symptom Incidence*
XANAX 1388 PLACEBO 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
*Events reported by 1% or more of XANAX patients are included.

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 XANAX: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice.

Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients (see PRECAUTIONS, General).

Adverse Events Reported as Reasons for Discontinuation in Treatment of Panic Disorder in Placebo-Controlled Trials

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

DISCONTINUATION-EMERGENT SYMPTOM INCIDENCE

Percentage of 641 XANAX-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 Dermatological
Weakness 5.8
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 XANAX in patients with panic disorder. There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of XANAX Tablets (see WARNINGS).

To discontinue treatment in patients taking XANAX, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of XANAX be decreased by no more than 0.5 mg every three days (see DOSAGE AND ADMINISTRATION). Some patients may benefit from 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.

As with all benzodiazepines, paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous case reports of adverse behavioral effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder.

Post Introduction Reports

Various adverse drug reactions have been reported in association with the use of XANAX since market introduction. The majority of these reactions were reported through the medical event voluntary reporting system. Because of the spontaneous nature of the reporting of medical events and the lack of controls, a causal relationship to the use of XANAX cannot be readily determined. Reported events include: gastrointestinal disorder, hypomania, mania, liver enzyme elevations, hepatitis, hepatic failure, Stevens- Johnson syndrome, photosensitivity reaction, angioedema, peripheral edema, hyperprolactinemia, gynecomastia, and galactorrhea (see PRECAUTIONS).

Drug Abuse And Dependence

Physical and Psychological Dependence

Withdrawal symptoms similar in character to those noted with sedative/hypnotics and alcohol have occurred following discontinuance of benzodiazepines, including XANAX. The symptoms can range from mild dysphoria and insomnia to a major syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors and convulsions. Distinguishing between withdrawal emergent signs and symptoms and the recurrence of illness is often difficult in patients undergoing dose reduction. The long term strategy for treatment of these phenomena will vary with their cause and the therapeutic goal. When necessary, immediate management of withdrawal symptoms requires re-institution of treatment at doses of XANAX sufficient to suppress symptoms. There have been reports of failure of other benzodiazepines to fully suppress these withdrawal symptoms. These failures have been attributed to incomplete cross-tolerance but may also reflect the use of an inadequate dosing regimen of the substituted benzodiazepine or the effects of concomitant medications.

While it is difficult to distinguish withdrawal and recurrence for certain patients, the time course and the nature of the symptoms may be helpful. A withdrawal syndrome typically includes the occurrence of new symptoms, tends to appear toward the end of taper or shortly after discontinuation, and will decrease with time. In recurring panic disorder, symptoms similar to those observed before treatment may recur either early or late, and they will persist.

While the severity and incidence of withdrawal phenomena appear to be related to dose and duration of treatment, withdrawal symptoms, including seizures, have been reported after only brief therapy with XANAX at doses within the recommended range for the treatment of anxiety (eg, 0.75 to 4 mg/day). Signs and symptoms of withdrawal are often more prominent after rapid decrease of dosage or abrupt discontinuance. The risk of withdrawal seizures may be increased at doses above 4 mg/day (see WARNINGS).

Patients, especially individuals with a history of seizures or epilepsy, should not be abruptly discontinued from any CNS depressant agent, including XANAX. It is recommended that all patients on XANAX who require a dosage reduction be gradually tapered under close supervision (see WARNINGS and DOSAGE AND ADMINISTRATION).

Psychological dependence is a risk with all benzodiazepines, including XANAX. The risk of psychological dependence may also be increased at doses greater than 4 mg/day and with longer term use, and this risk is further increased in patients with a history of alcohol or drug abuse. Some patients have experienced considerable difficulty in tapering and discontinuing from XANAX, especially those receiving higher doses for extended periods. Addiction-prone individuals should be under careful surveillance when receiving XANAX. As with all anxiolytics, repeat prescriptions should be limited to those who are under medical supervision.

Controlled Substance Class

Alprazolam is a controlled substance under the Controlled Substance Act by the Drug Enforcement Administration and XANAX Tablets have been assigned to Schedule IV.