Alprazolam: Package Insert and Label Information (Page 3 of 5)

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.

Treatment-Emergent Adverse Events Reported in Placebo-Controlled Trials of Anxiety Disorders
ANXIETY DISORDERS
Treatment-Emergent Symptom Incidence * Incidence of Intervention Because of Symptom
ALPRAZOLAM PLACEBO ALPRAZOLAM
Number of Patients % of Patients Reporting: 565 505 565

Central Nervous System Drowsiness Light-headedness Depression Headache Confusion Insomnia Nervousness Syncope Dizziness Akathisia Tiredness/Sleepiness

41.0 20.8 13.9 12.9 9.9 8.9 4.1 3.1 1.8 1.6 †

21.6 19.3 18.1 19.6 10.0 18.4 10.3 4.0 0.8 1.2 † 15.1 1.2 2.4 1.1 0.9 1.3 1.1 † 2.5 † 1.8
Gastrointestinal Dry Mouth Constipation Diarrhea Nausea/Vomiting Increased Salivation 14.7 10.4 10.1 9.6 4.2 13.3 11.4 10.3 12.8 2.4 0.7 0.9 1.2 1.7 †
Cardiovascular Tachycardia/Palpitations Hypotension 7.7 4.7 15.6 2.2 0.4 †

SensoryBlurred Vision

6.2 6.2 0.4
Musculoskeletal Rigidity Tremor 4.2 4.0 5.3 8.8 † 0.4

Cutaneous Dermatitis/Allergy

3.8 3.1 0.6
Other Nasal Congestion Weight Gain Weight Loss

7.3 2.7 2.3

9.3 2.7 3.0 † † †

* Events reported by 1% or more of alprazolam patients are included. None reported

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

DISCONTINUATION-EMERGENT SYMPTOM INCIDENCE Percentage of 641 Alprazolam-Treated Panic Disorder Patients Reporting Events
Body System/Event
Neurologic Insomnia Light-headedness Abnormal involuntary movement Headache Muscular twitching Impaired coordination Muscle tone disorders Weakness

Psychiatric Anxiety Fatigue and Tiredness Irritability Cognitive Disorder Memory impairment Depression Confusional state

29.5 19.3 17.3 17.0 6.9 6.6 5.9 5.8 19.2 18.4 10.5 10.3 5.5 5.1 5.0 Gastrointestinal Nausea/Vomiting Diarrhea Decreased salivation

Metabolic-Nutritional Weight loss Decreased appetite

Dermatological Sweating

Cardiovascular Tachycardia

Special Senses Blurred vision

16.5 13.6 10.6 13.3 12.8 14.4

12.2

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

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

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