The information included in the subsection on Adverse Events Observed in Short-Term, Placebo-Controlled Trials with XANAX XR Tablets is based on pooled data of five 6- and 8-week placebo-controlled clinical studies in panic disorder.

Adverse event reports were elicited either by generaÅ? inÄ?uiry or by checklist, and were recorded by clinical investigators using terminology of their own choosing. The stated freÄ?uencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened during therapy following baseline evaluation. In the tables and tabulations that follow, standard MedDRA terminology (version 4.0) was used to classify reported adverse events.

Adverse Events Observed in Short-Term, Placebo-Controlled Trials of XANAX XR

Adyerse Eyents Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials

Approximately 17% of the 531 patients who received XANAX XR in placebo-controlled clinical trials for panic disorder had at least one adverse event that led to discontinuation compared to 8% of 349 placebo-treated patients. The most common events leading to discontinuation and considered to be drug-related (ie, leading to discontinuation in at least 1% of the patients treated with XANAX XR at a ratÄ? at least twice that of placebo) are shown in the following table.

Common Adverse Events Leading to Discontinuation of Treatment in Placebo-Controlled Trials

Adyerse Eyents Occurring at an Incidence of 1% or MorÄ? Among Patients Treated with XANAX XR

The prescriber should be aware that adyerse event incidence cannot be used to predict the incidence of adyerse eyents in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited freÄ?uencies cannot be compared with event incidence obtained from other clinical investigations involving different treatments, uses, and investigators. The cited values, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence ratÄ? in the population studied.

The following table shows the incidence of treatment-emergent adverse events that occurred during 6- to 8-week placebo-controlled trials in 1% or morÄ? of patients treated with XANAX XR where the incidence in patients treated with XANAX XR was greater than the incidence in placebo-treated patients. The most commonly observed adverse events in panic disorder patients treated with XANAX XR (incidence of 5% or greater and at least twice the incidence in placebo patients) were: sedation, somnolence, memory impairment, dysarthria, coordination abnormal, ataxia, libido decreased (see table).

Treatment-Emergent Adverse Events: Incidence in Short-Term, Placebo-Controlled Clinical Trials with

XANAXXR

Other Adyerse Eyents Obseryed During the Premarketing Eyaluation of XANAX XR Tablets Following is a list of MedDRA terms that reflect treatment-emergent adverse events reported by 531 patients with panic disorder treated with XANAX XR. Ali potentially important reported events are included except those already listed in the above table or elsewhere in labeling, those events for which a drug cause was remote, those event terms that were so generaÅ? as to be uninformative, and those events that occurred at rates similar to background rates in the generaÅ? population. It is important to emphasize that, although the events reported occurred during treatment with XANAX XR, they were not necessarily caused by the drug. Events are further categorized by body system and listed in order of decreasing freÄ?uency according to the following definitions: freÄ?uent adverse events are those occurring on 1 or morÄ? occasions in at least 1/100 patients; infreÄ?uent adverse events are those occurring in less than 1/100 patients but at least 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

Cardiac disorders: FreÄ?uent: palpitation; InfreÄ?uent: sinus tachycardia

Ear and Labyrinth disorders: FreÄ?uent: Yertigo; InfreÄ?uent: tinnitus, ear pain Eye

disorders: FreÄ?uent: blurred vision; InfreÄ?uent: mydriasis, photophobia

Gastrointestinal disorders. FreÄ?uent: diarrhea, vomiting, dyspepsia, abdominal pain;

InfreÄ?uent: dysphagia, salivary hypersecretion

GeneraÅ? disorders and administration site conditions: FreÄ?uent: malaise, weakness, chest pains;

InfreÄ?uent: fali, pyrexia, thirst, feeling hot and cold, edema, feeling jittery, sluggishness, asthenia, feeling drunk, chest tightness, increased energy, feeling of relaxation, hangover, loss of control of legs, rigors

Musculoskeletal and connecÅ?ve tissue disorders: FreÄ?uent: back pain, muscle cramps, muscle twitching

Nervous system disorders: FreÄ?uent: headache, dizziness, tremor; InfreÄ?uent: amnesia, clumsiness, syncope, hypotonia, seizures, depressed level of consciousness, sleep apnea syndrome, sleep talking, stupor

Psychiatrie system disorders: FreÄ?uent: irritability, insomnia, nervousness, derealization, libido increased, restlessness, agitation, depersonalization, nightmare; InfreÄ?uent: abnormal dreams, apathy, aggression, anger, bradyphrenia, euphoric mood, logorrhea, mood swings, dysphonia, hallucination, homicidal ideation, mania, hypomania, impulse control, psychomotor retardation, suicidal ideation

Renal and urinary disorders: FreÄ?uent: difficulty in micturition; InfreÄ?uent: urinary freÄ?uency, urinary incontinence

Respiratory, thoracic, and mediastinal disorders: FreÄ?uent: nasal congestion, hyperventilation; InfreÄ?uent: choking sensation, epistaxis, rhinorrhea

Skin and subcutaneous tissue disorders: FreÄ?uent: sweating increased; InfreÄ?uent: clamminess, rash, urticaria

Vascular disorders: InfreÄ?uent: hypotension

The categories of adverse events reported in the clinical development program for XANAX Tablets in the treatment of panic disorder differ somewhat firom those reported for XANAX XR Tablets because the clinical trials with XANAX Tablets and XANAX XR Tablets used different standard medical nomenclature for reporting the adverse events. Nevertheless, the types of adverse events reported in the clinical trials with XANAX Tablets were generally the same as those reported in the clinical trials with XANAX XR Tablets.

Discontinuation-Emergent Adyerse Eyents Occurring at an Incidence of 5% or MorÄ? Among Patients Treated with XANAX XR

The following table shows the incidence of discontinuation-emergent adyerse events that oceurred during short-term, placebo-controlled trials in 5% or morÄ? of patients treated with XANAX XR where the incidence in patients treated with XANAX XR was two times greater than the incidence in placebo-treated patients.

Discontinuation-Emergent Symptoms: Incidence in Short-Term, Placebo-Controlled Trials with XANAX XR

There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam (see WARNINGS).

To discontinue treatment in patients taking XANAX XR Tablets, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of XANAX XR Tablets be decreased by no morÄ? 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, inereased muscle spasticity, sleep disturbances, hallucinations, and other adverse behavioral effects such as agitation, ragÄ?, 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 psychiatrie conditions. Should any of the above events oceur, alprazolam should be discontinued. Isolated published reports involving smali 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 Tablets siÅ?ce market introduction. The majority of these reactions were reported through the medical event voluntary reporting system. Because of the spontaneous naturÄ? of the reporting of medical events and the lack of controls, a causal relationship to the use of XANAX Tablets cannot be readily determined. Reported events include: liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson syndrome, hyperprolactinemia, gynecomastia, and galactorrhea.

DRUG ABUSE AND DEPENDENCE

Physical and Psychological Dependence

Withdrawal symptoms similar in character to those noted with sedative/hypnotics and alcohol have oceurred following discontinuance of benzodiazepines, including alprazolam. The symptoms can rangÄ? 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 reÄ?uires re-institution of treatment at doses of alprazolam 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 inadeÄ?uate 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 naturÄ? of the symptoms may be helpful. A withdrawal syndrome typically includes the oceurrence 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 alprazolam at doses within the recommended rangÄ? for the treatment of anxiety (eg, 0.75 to 4 mg/day). Signs and symptoms of withdrawal are often morÄ? 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 alprazolam. It is recommended that all patients on alprazolam who reÄ?uire a dosage reduction be gradually tapered under close supervision (see WARNINGS and DOSAGE AND ADMINISTRATION).

Psychological dependence is a risk with all benzodiazepines, including alprazolam. 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 alprazolam, especially those receiving higher doses for extended periods. Addiction-prone individuals should be under careful surveillance when receiving alprazolam. As with all amriolytics, 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 XR Tablets have been assigned to Schedule IV.