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XANAX® XR, CIV (alprazolam) Adverse Reactions

ADVERSE REACTIONS

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 general inquiry or by checklist, and were recorded by clinical investigators using terminology of their own choosing. The stated frequencies 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

Adverse Events 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 rate at least twice that of placebo) are shown in the following table.

Common Adverse Events Leading to Discontinuation of Treatment in Placebo-Controlled Trials
System Organ Class/Adverse EventPercentage of Patients Discontinuing Due to Adverse Events
XANAX XR
(n=531)
Placebo
(n=349)
Nervous system disorders
  Sedation7.50.6
  Somnolence3.20.3
  Dysarthria2.10
  Coordination abnormal1.90.3
  Memory impairment1.50.3
General disorders/administration site conditions
  Fatigue1.70.6
Psychiatric disorders
  Depression2.51.2

Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated with XANAX XR

The prescriber should be aware that adverse event incidence cannot be used to predict the incidence of adverse events 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 frequencies 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 rate 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 more 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 XANAX XR
System Organ Class/Adverse EventPercentage of Patients Reporting Adverse Event
XANAX XR
(n=531)
Placebo
(n=349)
Nervous system disorders
  Sedation45.222.6
  Somnolence23.06.0
  Memory impairment15.46.9
  Dysarthria10.92.6
  Coordination abnormal9.40.9
  Mental impairment7.25.7
  Ataxia7.23.2
  Disturbance in attention3.20.6
  Balance impaired3.20.6
  Paresthesia2.41.7
  Dyskinesia1.71.4
  Hypoesthesia1.30.3
  Hypersomnia1.30
General disorders/administration site conditions
  Fatigue13.99.2
  Lethargy1.70.6
Infections and infestations
  Influenza2.42.3
  Upper respiratory tract infections1.91.7
Psychiatric disorders
  Depression12.19.2
  Libido decreased6.02.3
  Disorientation1.50
  Confusion1.50.9
  Depressed mood1.30.3
  Anxiety1.10.6
Metabolism and nutrition disorders
  Appetite decreased7.37.2
  Appetite increased7.06.0
  Anorexia1.50
Gastrointestinal disorders
  Dry mouth10.29.7
  Constipation8.14.3
  Nausea6.03.2
  Pharyngolaryngeal pain3.22.6
Investigations
  Weight increased5.14.3
  Weight decreased4.33.7
Injury, poisoning, and procedural complications
  Road traffic accident1.50
Reproductive system and breast disorders
  Dysmenorrhea3.62.9
  Sexual dysfunction2.41.1
  Premenstrual syndrome1.70.6
Musculoskeletal and connective tissue disorders
  Arthralgia2.40.6
  Myalgia1.51.1
  Pain in limb1.10.3
Vascular disorders
  Hot flushes1.51.4
Respiratory, thoracic, and mediastinal disorders
  Dyspnea1.50.3
  Rhinitis allergic1.10.6
Skin and subcutaneous tissue disorders
  Pruritis1.10.9

Other Adverse Events Observed During the Premarketing Evaluation 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. All 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 general as to be uninformative, and those events that occurred at rates similar to background rates in the general 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 frequency according to the following definitions: frequent adverse events are those occurring on 1 or more occasions in at least l/l00 patients; infrequent adverse events are those occurring in less than l/100 patients but at least l/1000 patients; rare events are those occurring in fewer than l/1000 patients.

Cardiac disorders: Frequent: palpitation; Infrequent: sinus tachycardia

Ear and Labyrinth disorders: Frequent: Vertigo; Infrequent: tinnitus, ear pain

Eye disorders: Frequent: blurred vision; Infrequent: mydriasis, photophobia

Gastrointestinal disorders: Frequent: diarrhea, vomiting, dyspepsia, abdominal pain; Infrequent: dysphagia, salivary hypersecretion

General disorders and administration site conditions: Frequent: malaise, weakness, chest pains; Infrequent: fall, 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 connective tissue disorders: Frequent: back pain, muscle cramps, muscle twitching

Nervous system disorders: Frequent: headache, dizziness, tremor; Infrequent: amnesia, clumsiness, syncope, hypotonia, seizures, depressed level of consciousness, sleep apnea syndrome, sleep talking, stupor

Psychiatric system disorders: Frequent: irritability, insomnia, nervousness, derealization, libido increased, restlessness, agitation, depersonalization, nightmare; Infrequent: 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: Frequent: difficulty in micturition; Infrequent: urinary frequency, urinary incontinence

Respiratory, thoracic, and mediastinal disorders: Frequent: nasal congestion, hyperventilation; Infrequent: choking sensation, epistaxis, rhinorrhea

Skin and subcutaneous tissue disorders: Frequent: sweating increased; Infrequent: clamminess, rash, urticaria

Vascular disorders: Infrequent: hypotension

The categories of adverse events reported in the clinical development program for XANAX Tablets in the treatment of panic disorder differ somewhat from 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 Adverse Events Occurring at an Incidence of 5% or More Among Patients Treated with XANAX XR

The following table shows the incidence of discontinuation-emergent adverse events that occurred during short-term, placebo-controlled trials in 5% or more 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
System Organ Class/AdverseEventPercentage of Patients Reporting Adverse Event
XANAX XR
(n=422)
Placebo
(n=261)
Nervous system disorders
  Tremor28.210.7
  Headache26.512.6
  Hypoesthesia7.82.3
  Paraesthesia7.12.7
Psychiatric disorders
  Insomnia24.29.6
  Nervousness21.88.8
  Depression10.95.0
  Derealization8.03.8
  Anxiety7.82.7
  Depersonalization5.71.9
Gastrointestinal disorders
  Diarrhea12.13.1
Respiratory, thoracic and mediastinal disorders
  Hyperventilation8.52.7
Metabolism and nutrition disorders
  Appetite decreased9.53.8
Musculosketal and connective tissue disorders
  Muscle twitching7.42.7
Vascular disorders
  Hot flushes5.92.7

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 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 Tablets 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 Tablets cannot be readily determined. Reported events include: gastrointestinal disorder, hypomania, mania, liver enzyme elevations, hepatitis, jaundice, hepatic failure, Stevens-Johnson syndrome, photosensitivity reaction, angioedema, peripheral edema, menstruation irregular, hyperprolactinemia, gynecomastia, and galactorrhea (see PRECAUTIONS).

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