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Xanax Side Effects, and Drug Interactions - Alprazolam

Xanax Side Effects, and Drug Interactions - Alprazolam

SIDE EFFECTS

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 (e.g., drowsiness or light-headedness).

The data cited in TABLE 1 and TABLE 2 are estimates of untoward clinical event incidence among patients who participated under the following clinical conditions: relatively short duration (i.e., 4 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 10 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 (e.g., increased surveillance, decreased dosage or discontinuation of drug therapy) may be necessary because of the untoward clinical event (see TABLE 1).

TABLE 1 Anxiety Disorders
	Treatment-Emergent Symptom Incidence *		Incidence of Intervention Because of Symptom
	Alprazolam	Placebo	Alprazolam
Number of Patients	565	505	565
	% of Patients Reporting
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	†
* Events reported by 1% or more of alprazolam patients are included.
† None reported.

In addition to the relatively common (i.e., greater than 1%) untoward events enumerated in TABLE 1, 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 (see TABLE 2).

TABLE 2 Panic Disorders
	Treatment-Emergent Symptom Incidence*
	Alprazolam	Placebo
Number of Patients	1388	1231
	% of Patients Reporting
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 alprazolam patients are included.

In addition to the relatively common (i.e., greater than 1%) untoward events enumerated in TABLE 2, 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.

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 3 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.

Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Therefore, the same precaution must be exercised when using doses of alprazolam greater than 4 mg/day in treating patients with panic disorders as is exercised with the use of any psychotropic drug in treating depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans.

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 post¾traumatic stress disorder.

Laboratory analyses were performed on patients participating in the clinical program for alprazolam. The following incidences of abnormalities shown in TABLE 3 were observed in patients receiving alprazolam and in patients in the corresponding placebo group. Few of these abnormalities were considered to be of physiological significance.

TABLE 3
	Alprazolam		Placebo
	Low	High	Low	High
Hematology
Hematocrit	*	*	*	*
Hemoglobin	*	*	*	*
Total WBC Count	1.4	2.3	1.0	2.0
Neutrophil Count	2.3	3.0	4.2	1.7
Lymphocyte Count	5.5	7.4	5.4	9.5
Monocyte Count	5.3	2.8	6.4	*
Eosinophil Count	3.2	9.5	3.3	7.2
Basophil Count	*	*	*	*
Urinalysis
Albumin	¾	*	¾	*
Sugar	¾	*	¾	*
RBC/HPF	¾	3.4	¾	5.0
WBC/HPF	¾	25.7	¾	25.9
Blood Chemistry
Creatinine	2.2	1.9	3.5	1.0
Bilirubin	*	1.6	*	*
SGOT	*	3.2	1.0	1.8
Alkaline Phosphatase	*	1.7	*	1.8
* Less than 1%.

When treatment with alprazolam is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are advisable.

Minor changes in EEG patterns, usually low-voltage fast activity have been observed in patients during therapy with alprazolam and are of no known significance.

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: liver enzyme elevations, hepatitis, hepatic failure, Stevens¾Johnson 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 occurred following discontinuance of benzodiazepines, including alprazolam. 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 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 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 alprazolam at doses within the recommended range for the treatment of anxiety (e.g., 0.75-4 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 alprazolam. It is recommended that all patients on alprazolam 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 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 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 alprazolam tablets have been assigned to Schedule IV.

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: sertraline and paroxetine. Data from 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).

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