XANAX® CIV
alprazolam tablets, USP
DESCRIPTION
XANAX Tablets contain alprazolam which is a triazolo analog of the 1,4 benzodiazepine
class of central nervous system-active compounds.
The chemical name of alprazolam is 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-Ι] [1,4]
benzodiazepine.
CLINICAL PHARMACOLOGY
Pharmacodynamics
CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo
specific receptors at several sites within the central nervous system. Their exact mechanism of
action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system
depressant activity varying from mild impairment of task performance to hypnosis.
Pharmacokinetics
Absorption
Following oral administration, alprazolam is readily absorbed. Peak concentrations in the
plasma occur in 1 to 2 hours following administration. Plasma levels are proportionate to the
dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were
observed. Using a specific assay methodology, the mean plasma elimination half-life of
alprazolam has been found to be about 11.2 hours (range: 6.3-26.9 hours) in healthy adults.
Distribution
In vitro, alprazolam is bound (80 percent) to human serum protein. Serum albumin accounts
for the majority of the binding.
Metabolism/Elimination
Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4
(CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and α-
hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans.
Their half-lives appear to be similar to that of alprazolam. The plasma concentrations of 4-
hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged alprazolam concentration
were always less than 4%. The reported relative potencies in benzodiazepine receptor binding
experiments and in animal models of induced seizure inhibition are 0.20 and 0.66,
respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. Such low concentrations
and the lesser potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam suggest that they
are unlikely to contribute much to the pharmacological effects of alprazolam. The
benzophenone metabolite is essentially inactive.
Alprazolam and its metabolites are excreted primarily in the urine.
Special Populations
Changes in the absorption, distribution, metabolism and excretion of benzodiazepines have
been reported in a variety of disease states including alcoholism, impaired hepatic function
and impaired renal function. Changes have also been demonstrated in geriatric patients. A
mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects
(range: 9.0-26.9 hours, n=16) compared to 11.0 hours (range: 6.3-15.8 hours, n=16) in healthy
adult subjects. In patients with alcoholic liver disease the half-life of alprazolam ranged
between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and 26.9
hours (mean=11.4 hours, n=17) in healthy subjects. In an obese group of subjects the half-life
of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8 hours, n=12) as compared to
between 6.3 and 15.8 hours (mean=10.6 hours, n=12) in healthy subjects.
Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes
transplacental passage and that it is excreted in human milk.
Race — Maximal concentrations and half-life of alprazolam are approximately 15% and 25%
higher in Asians compared to Caucasians.
Pediatrics — The pharmacokinetics of alprazolam in pediatric patients have not been studied.
Gender — Gender has no effect on the pharmacokinetics of alprazolam.
Cigarette Smoking — Alprazolam concentrations may be reduced by up to 50% in smokers
compared to non-smokers.
Drug-Drug Interactions
Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most
of the interactions that have been documented with alprazolam are with drugs that inhibit or
induce CYP3A4.
Compounds that are potent inhibitors of CYP3A would be expected to increase plasma
alprazolam concentrations. Drug products that have been studied in vivo, along with their
effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole,
2.70 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold (see
CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS–Drug Interactions).
CYP3A inducers would be expected to decrease alprazolam concentrations and this has been
observed in vivo. The oral clearance of alprazolam (given in a 0.8 mg single dose) was
increased from 0.90±0.21 mL/min/kg to 2.13±0.54 mL/min/kg and the elimination t1/2 was
shortened (from 17.1±4.9 to 7.7 ±1.7 h) following administration of 300 mg/day
carbamazepine for 10 days (see PRECAUTIONS–Drug Interactions). However, the
carbamazepine dose used in this study was fairly low compared to the recommended doses
(1000-1200 mg/day); the effect at usual carbamazepine doses is unknown.
The ability of alprazolam to induce human hepatic enzyme systems has not yet been
determined. However, this is not a property of benzodiazepines in general. Further, alprazolam
did not affect the prothrombin or plasma warfarin levels in male volunteers administered
sodium warfarin orally.
CLINICAL STUDIES
Anxiety Disorders
XANAX Tablets were compared to placebo in double blind clinical studies (doses up to 4
mg/day) in patients with a diagnosis of anxiety or anxiety with associated depressive
symptomatology. XANAX was significantly better than placebo at each of the evaluation
periods of these 4-week studies as judged by the following psychometric instruments:
Physician’s Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient’s
Global Impressions and Self-Rating Symptom Scale.
Panic Disorder
Support for the effectiveness of XANAX in the treatment of panic disorder came from three
short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely
corresponding to DSM-III-R criteria for panic disorder.
The average dose of XANAX was 5-6 mg/day in two of the studies, and the doses of XANAX
were fixed at 2 and 6 mg/day in the third study. In all three studies, XANAX was superior to
placebo on a variable defined as "the number of patients with zero panic attacks" (range, 37-
83% met this criterion), as well as on a global improvement score. In two of the three studies,
XANAX was superior to placebo on a variable defined as "change from baseline on the
number of panic attacks per week" (range, 3.3-5.2), and also on a phobia rating scale. A
subgroup of patients who were improved on XANAX during short-term treatment in one of
these trials was continued on an open basis up to 8 months, without apparent loss of benefit.
INDICATIONS AND USAGE
Anxiety Disorders
XANAX Tablets (alprazolam) are indicated for the management of anxiety disorder (a
condition corresponding most closely to the APA Diagnostic and Statistical Manual [DSM-IIIR]
diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety.
Anxiety or tension associated with the stress of everyday life usually does not require
treatment with an anxiolytic.
Generalized anxiety disorder is characterized by unrealistic or excessive anxiety and worry
(apprehensive expectation) about two or more life circumstances, for a period of 6 months or
longer, during which the person has been bothered more days than not by these concerns. At
least 6 of the following 18 symptoms are often present in these patients: Motor Tension
(trembling, twitching, or feeling shaky; muscle tension, aches, or soreness; restlessness; easy
fatigability); Autonomic Hyperactivity (shortness of breath or smothering sensations;
palpitations or accelerated heart rate; sweating, or cold clammy hands; dry mouth; dizziness or
light-headedness; nausea, diarrhea, or other abdominal distress; flushes or chills; frequent
urination; trouble swallowing or 'lump in throat’); Vigilance and Scanning (feeling keyed up
or on edge; exaggerated startle response; difficulty concentrating or 'mind going blank’
because of anxiety; trouble falling or staying asleep; irritability). These symptoms must not be
secondary to another psychiatric disorder or caused by some organic factor.
Anxiety associated with depression is responsive to XANAX.
Panic Disorder
XANAX is also indicated for the treatment of panic disorder, with or without agoraphobia.
Studies supporting this claim were conducted in patients whose diagnoses corresponded
closely to the DSM-III-R/IV criteria for panic disorder (see CLINICAL STUDIES).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, ie, a discrete
period of intense fear or discomfort in which four (or more) of the following symptoms
develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or
accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of
breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or
abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization
(feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing
control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or
hot flushes.
Demonstrations of the effectiveness of XANAX by systematic clinical study are limited to 4
months duration for anxiety disorder and 4 to 10 weeks duration for panic disorder; however,
patients with panic disorder have been treated on an open basis for up to 8 months without
apparent loss of benefit. The physician should periodically reassess the usefulness of the drug
for the individual patient.
CONTRAINDICATIONS
XANAX Tablets are contraindicated in patients with known sensitivity to this drug or other
benzodiazepines. XANAX may be used in patients with open angle glaucoma who are
receiving appropriate therapy, but is contraindicated in patients with acute narrow angle
glaucoma.
XANAX is contraindicated with ketoconazole and itraconazole, since these medications
significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A)
(see WARNINGS and PRECAUTIONS–Drug Interactions).
WARNINGS
Dependence and Withdrawal Reactions, Including Seizures
Certain adverse clinical events, some life-threatening, are a direct consequence of physical
dependence to XANAX. These include a spectrum of withdrawal symptoms; the most
important is seizure (see DRUG ABUSE AND DEPENDENCE). Even after relatively shortterm
use at the doses recommended for the treatment of transient anxiety and anxiety disorder
(ie, 0.75 to 4.0 mg per day), there is some risk of dependence. Spontaneous reporting system
data suggest that the risk of dependence and its severity appear to be greater in patients treated
with doses greater than 4 mg/day and for long periods (more than 12 weeks). However, in a
controlled postmarketing discontinuation study of panic disorder patients, the duration of
treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to
zero dose. In contrast, patients treated with doses of XANAX greater than 4 mg/day had more
difficulty tapering to zero dose than those treated with less than 4 mg/day.
The importance of dose and the risks of XANAX as a treatment for panic disorder: Because
the management of panic disorder often requires the use of average daily doses of XANAX
above 4 mg, the risk of dependence among panic disorder patients may be higher than that
among those treated for less severe anxiety. Experience in randomized placebo-controlled
discontinuation studies of patients with panic disorder showed a high rate of rebound and
withdrawal symptoms in patients treated with XANAX compared to placebo-treated patients.
Relapse or return of illness was defined as a return of symptoms characteristic of panic
disorder (primarily panic attacks) to levels approximately equal to those seen at baseline
before active treatment was initiated. Rebound refers to a return of symptoms of panic
disorder to a level substantially greater in frequency, or more severe in intensity than seen at
baseline. Withdrawal symptoms were identified as those which were generally not
characteristic of panic disorder and which occurred for the first time more frequently during
discontinuation than at baseline.
In a controlled clinical trial in which 63 patients were randomized to XANAX and where
withdrawal symptoms were specifically sought, the following were identified as symptoms of
withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded
sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite
decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were frequently
seen during discontinuation, but it could not be determined if they were due to return of
illness, rebound, or withdrawal.
In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue
medication was measured, 71%-93% of patients treated with XANAX tapered completely off
therapy compared to 89%-96% of placebo-treated patients. In a controlled postmarketing
discontinuation study of panic disorder patients, the duration of treatment (3 months compared
to 6 months) had no effect on the ability of patients to taper to zero dose.
Seizures attributable to XANAX were seen after drug discontinuance or dose reduction in 8 of
1980 patients with panic disorder or in patients participating in clinical trials where doses of
XANAX greater than 4 mg/day for over 3 months were permitted. Five of these cases clearly
occurred during abrupt dose reduction, or discontinuation from daily doses of 2 to 10 mg.
Three cases occurred in situations where there was not a clear relationship to abrupt dose
reduction or discontinuation. In one instance, seizure occurred after discontinuation from a
single dose of 1 mg after tapering at a rate of 1 mg every 3 days from 6 mg daily. In two other
instances, the relationship to taper is indeterminate; in both of these cases the patients had
been receiving doses of 3 mg daily prior to seizure. The duration of use in the above 8 cases
ranged from 4 to 22 weeks. There have been occasional voluntary reports of patients
developing seizures while apparently tapering gradually from XANAX. The risk of seizure
seems to be greatest 24-72 hours after discontinuation (see DOSAGE AND
ADMINISTRATION for recommended tapering and discontinuation schedule).
Status Epilepticus and its Treatment
The medical event voluntary reporting system shows that withdrawal seizures have been
reported in association with the discontinuation of XANAX. In most cases, only a single
seizure was reported; however, multiple seizures and status epilepticus were reported as well.
Interdose Symptoms
Early morning anxiety and emergence of anxiety symptoms between doses of XANAX have
been reported in patients with panic disorder taking prescribed maintenance doses of
XANAX. These symptoms may reflect the development of tolerance or a time interval
between doses which is longer than the duration of clinical action of the administered dose. In
either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels
above those needed to prevent relapse, rebound or withdrawal symptoms over the entire
course of the interdosing interval. In these situations, it is recommended that the same total
daily dose be given divided as more frequent administrations (see DOSAGE AND
ADMINISTRATION).
Risk of Dose Reduction
Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes
purposeful tapering, but also inadvertent reduction of dose (eg, the patient forgets, the patient
is admitted to a hospital). Therefore, the dosage of XANAX should be reduced or
discontinued gradually (see DOSAGE AND ADMINISTRATION).
CNS Depression and Impaired Performance
Because of its CNS depressant effects, patients receiving XANAX should be cautioned
against engaging in hazardous occupations or activities requiring complete mental alertness
such as operating machinery or driving a motor vehicle. For the same reason, patients should
be cautioned about the simultaneous ingestion of alcohol and other CNS depressant drugs
during treatment with XANAX.
Risk of Fetal Harm
Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If
XANAX is used during pregnancy, or if the patient becomes pregnant while taking this drug,
the patient should be apprised of the potential hazard to the fetus. Because of experience with
other members of the benzodiazepine class, XANAX is assumed to be capable of causing an
increased risk of congenital abnormalities when administered to a pregnant woman during the
first trimester. Because use of these drugs is rarely a matter of urgency, their use during the
first trimester should almost always be avoided. The possibility that a woman of childbearing
potential may be pregnant at the time of institution of therapy should be considered. Patients
should be advised that if they become pregnant during therapy or intend to become pregnant
they should communicate with their physicians about the desirability of discontinuing the
drug.
Alprazolam Interaction with Drugs that Inhibit Metabolism via Cytochrome P4503A
The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A
(CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the
clearance of alprazolam. Consequently, alprazolam should be avoided in patients receiving
very potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser but still significant
degree, alprazolam should be used only with caution and consideration of appropriate dosage
reduction. For some drugs, an interaction with alprazolam has been quantified with clinical
data; for other drugs, interactions are predicted from in vitro data and/or experience with
similar drugs in the same pharmacologic class.
The following are examples of drugs known to inhibit the metabolism of alprazolam and/or
related benzodiazepines, presumably through inhibition of CYP3A.
Potent CYP3A Inhibitors
Azole antifungal agents— Ketoconazole and itraconazole are potent CYP3A inhibitors and
have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70
fold, respectively. The coadministration of alprazolam with these agents is not recommended.
Other azole-type antifungal agents should also be considered potent CYP3A inhibitors and the
coadministration of alprazolam with them is not recommended (see
CONTRAINDICATIONS).
Drugs demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving
alprazolam (caution and consideration of appropriate alprazolam dose reduction are
recommended during coadministration with the following drugs)
Nefazodone—Coadministration of nefazodone increased alprazolam concentration two-fold.
Fluvoxamine—Coadministration of fluvoxamine approximately doubled the maximum
plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71%,
and decreased measured psychomotor performance.
Cimetidine—Coadministration of cimetidine increased the maximum plasma concentration of
alprazolam by 86%, decreased clearance by 42%, and increased half-life by 16%.
Other drugs possibly affecting alprazolam metabolism
Other drugs possibly affecting alprazolam metabolism by inhibition of CYP3A are discussed
in the PRECAUTIONS section (see PRECAUTIONS–Drug Interactions).
PRECAUTIONS
General
Suicide
As with other psychotropic medications, the usual precautions with respect to administration
of the drug and size of the prescription are indicated for severely depressed patients or those in
whom there is reason to expect concealed suicidal ideation or plans. Panic disorder has been
associated with primary and secondary major depressive disorders and increased reports of
suicide among untreated patients.
Mania
Episodes of hypomania and mania have been reported in association with the use of XANAX
in patients with depression.
Uricosuric Effect
Alprazolam has a weak uricosuric effect. Although other medications with weak uricosuric
effect have been reported to cause acute renal failure, there have been no reported instances of
acute renal failure attributable to therapy with XANAX.
Use in Patients with Concomitant Illness
It is recommended that the dosage be limited to the smallest effective dose to preclude the
development of ataxia or oversedation which may be a particular problem in elderly or
debilitated patients. (See DOSAGE AND ADMINISTRATION.) The usual precautions in
treating patients with impaired renal, hepatic or pulmonary function should be observed. There
have been rare reports of death in patients with severe pulmonary disease shortly after the
initiation of treatment with XANAX. A decreased systemic alprazolam elimination rate (eg,
increased plasma half-life) has been observed in both alcoholic liver disease patients and
obese patients receiving XANAX (see CLINICAL PHARMACOLOGY).
Information for Patients
For all users of XANAX:
To assure safe and effective use of benzodiazepines, all patients prescribed XANAX should be
provided with the following guidance.
1. Inform your physician about any alcohol consumption and medicine you are taking now,
including medication you may buy without a prescription. Alcohol should generally not be
used during treatment with benzodiazepines.
2. Not recommended for use in pregnancy. Therefore, inform your physician if you are
pregnant, if you are planning to have a child, or if you become pregnant while you are taking
this medication.
3. Inform your physician if you are nursing.
4. Until you experience how this medication affects you, do not drive a car or operate
potentially dangerous machinery, etc.
5. Do not increase the dose even if you think the medication "does not work anymore" without
consulting your physician. Benzodiazepines, even when used as recommended, may produce
emotional and/or physical dependence.
6. Do not stop taking this medication abruptly or decrease the dose without consulting your
physician, since withdrawal symptoms can occur.
Additional advice for panic disorder patients:
The use of XANAX at doses greater than 4 mg/day, often necessary to treat panic disorder, is
accompanied by risks that you need to carefully consider. When used at doses greater than 4
mg/day, which may or may not be required for your treatment, XANAX has the potential to
cause severe emotional and physical dependence in some patients and these patients may find
it exceedingly difficult to terminate treatment. In two controlled trials of 6 to 8 weeks duration
where the ability of patients to discontinue medication was measured, 7 to 29% of patients
treated with XANAX did not completely taper off therapy. In a controlled postmarketing
discontinuation study of panic disorder patients, the patients treated with doses of XANAX
greater than 4 mg/day had more difficulty tapering to zero dose than patients treated with less
than 4 mg/day. In all cases, it is important that your physician help you discontinue this
medication in a careful and safe manner to avoid overly extended use of XANAX.
In addition, the extended use at doses greater than 4 mg/day appears to increase the incidence
and severity of withdrawal reactions when XANAX is discontinued. These are generally
minor but seizure can occur, especially if you reduce the dose too rapidly or discontinue the
medication abruptly. Seizure can be life-threatening.
