ALPRAZOLAM
DESCRIPTION:
ALPRAX 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-(alpha)) (1,4) benzodiazepine.
Alprazolam is a white crystalline powder, which is soluble in methanol or
ethanol but which has no appreciable solubility in water at physiological pH.
Each ALPRAX Tablet, for oral administration, contains 0.25, 0.5, 1 or 2 mg of
alprazolam.
ALPRAX Tablets, 2 mg, are multi-scored and may be divided as shown below:
Inactive ingredients: Cellulose, corn starch, docusate sodium, lactose,
magnesium stearate, silicon dioxide and sodium benzoate. In addition, the 0.5 mg
tablet contains FD&C Yellow No. 6 and the 1 mg tablet contains FD&C Blue No. 2.
ACTIONS/CLINICAL PHARMACOLOGY:
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.
Following oral administration, alprazolam is readily absorbed. Peak
concentrations in the plasma occur in one to two 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.
The predominant metabolites are (alpha)-hydroxy- alprazolam and a benzophenone
derived from alprazolam. The biological activity of (alpha)-hydroxy-alprazolam
is approximately one- half that of alprazolam. The benzophenone metabolite is
essentially inactive. Plasma levels of these metabolites are extremely low, thus
precluding precise pharmacokinetic description. However, their half-lives appear
to be of the same order of magnitude as that of alprazolam. Alprazolam and its
metabolites are excreted primarily in the urine.
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.
In Vitro, alprazolam is bound (80 percent) to human serum protein.
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.
INDICATIONS AND USAGE:
ALPRAX Tablets (alprazolam) are indicated for the management of anxiety disorder
(a condition corresponding most closely to the APA Diagnostic and Statistical
Manual (DSM-III-R) 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 six 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 ALPRAX.
ALPRAX 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 criteria for panic disorder (see CLINICAL
STUDIES).
Panic disorder is an illness characterized by recurrent panic attacks. The panic
attacks, at least initially, are unexpected. Later in the course of this
disturbance certain situations, eg, driving a car or being in a crowded place,
may become associated with having a panic attack. These panic attacks are not
triggered by situations in which the person is the focus of others' attention
(as in social phobia). The diagnosis requires four such attacks within a four
week period, or one or more attacks followed by at least a month of persistent
fear of having another attack. The panic attacks must be characterized by at
least four of the following symptoms: dyspnea or smothering sensations;
dizziness, unsteady feelings, or faintness; palpitations or tachycardia;
trembling or shaking; sweating; choking; nausea or abdominal distress;
depersonalization or derealization; paresthesias; hot flashes or chills; chest
pain or discomfort; fear of dying; fear of going crazy or of doing something
uncontrolled. At least some of the panic attack symptoms must develop suddenly,
and the panic attack symptoms must not be attributable to some known organic
factors. Panic disorder is frequently associated with some symptoms of
agoraphobia.
Demonstrations of the effectiveness of ALPRAX by systematic clinical study are
limited to four months duration for anxiety disorder and four to ten weeks
duration for panic disorder; however, patients with panic disorder have been
treated on an open basis for up to eight months without apparent loss of
benefit. The physician should periodically reassess the usefulness of the drug
for the individual patient.
CONTRAINDICATIONS:
ALPRAX Tablets are contraindicated in patients with known sensitivity to this
drug or other benzodiazepines. ALPRAX may be used in patients with open angle
glaucoma who are receiving appropriate therapy, but is contraindicated in
patients with acute narrow angle glaucoma.
ALPRAX is contraindicated with ketoconazole and itraconazole, since these
medications significantly impair the oxidative metabolism mediated by cytochrome
P450 3A (CYP 3A) (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 ALPRAX. These include a spectrum of
withdrawal symptoms; the most important is seizure (see DRUG ABUSE AND
DEPENDENCE). Even after relatively short-term 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 (three months compared to six
months) had no effect on the ability of patients to taper to zero dose. In
contrast, patients treated with doses of ALPRAX 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 ALPRAX AS A TREATMENT FOR PANIC DISORDER:
Because the management of panic disorder often requires the use of average daily
doses of ALPRAX 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 ALPRAX 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 ALPRAX 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 a larger database comprised of both controlled and uncontrolled studies in
which 641 patients received ALPRAX, discontinuation-emergent symptoms which
occurred at a rate of over 5% in patients treated with ALPRAX and at a greater
rate than the placebo treated group were as follows:
DISCONTINUATION-EMERGENT SYMPTOM INCIDENCE
PERCENTAGE OF 641 ALPRAX-TREATED PANIC DISORDER
PATIENTS REPORTING EVENTS
____________________________________________________________________________________________________________
BODY SYSTEM/EVENT
____________________________________________________________________________________________________________
NEUROLOGIC GASTROINTESTINAL
____________________________________________________________________________________________________________
Insomnia 29.5 Nausea/Vomiting 16.5
Light-headedness 19.3 Diarrhea 13.6
Abnormal involuntary movement 17.3 Decreased salivation 10.6
Headache 17.0 METABOLIC-NUTRITIONAL
Muscular twitching 6.9 Weight loss 13.3
Impaired coordination 6.6 Decreased appetite 12.8
Muscle tone disorders 5.9
Weakness 5.8 DERMATOLOGICAL
Psychiatric Sweating 14.4
Anxiety 19.2
Fatigue and Tiredness 18.4 CARDIOVASCULAR
Irritability 10.5 Tachycardia 12.2
Cognitive disorder 10.3
Memory impairment 5.5 SPECIAL SENSES
Depression 5.1 Blurred vision 10.0
Confusional state 5.0
____________________________________________________________________________________________________________
From the studies cited, it has not been determined whether these symptoms are
clearly related to the dose and duration of therapy with ALPRAX in patients with
panic disorder.
In two controlled trials of six to eight weeks duration where the ability of
patients to discontinue medication was measured, 71%-93% of ALPRAX treated
patients 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 (three months compared to six months) had no
effect on the ability of patients to taper to zero dose.
Seizures attributable to ALPRAX 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 ALPRAX 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 1mg every
three 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 ALPRAX. 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 ALPRAX. In most cases,
only a single seizure was reported; however, multiple seizures and status
epilepticus were reported as well. Ordinarily, the treatment of status
epilepticus of any etiology involves use of intravenous benzodiazepines plus
phenytoin or barbiturates, maintenance of a patent airway and adequate
hydration. For additional details regarding therapy, consultation with an
appropriate specialist may be considered.
INTERDOSE SYMPTOMS:
Early morning anxiety and emergence of anxiety symptoms between doses of ALPRAX
have been reported in patients with panic disorder taking prescribed maintenance
doses of ALPRAX. 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, etc.). Therefore, the
dosage of ALPRAX should be reduced or discontinued gradually (see DOSAGE AND
ADMINISTRATION).
ALPRAX Tablets are not of value in the treatment of psychotic patients and should
not be employed in lieu of appropriate treatment for psychosis. Because of its
CNS depressant effects, patients receiving ALPRAX 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 ALPRAX.
Benzodiazepines can potentially cause fetal harm when administered to pregnant
women. If ALPRAX 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, ALPRAX 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 P450
3A: The initial step in alprazolam metabolism is hydroxylation catalyzed by
cytochrome P450 3A (CYP 3A). 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 CYP 3A. With
drugs inhibiting CYP 3A 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 CYP
3A.
POTENT CYP 3A INHIBITORS:
Azole antifungal agents-Although IN VIVO interaction data with alprazolam are
not available, ketoconazole and itraconazole are potent CYP 3A inhibitors and
the coadministration of alprazolam with them is not recommended. Other azole-
type antifungal agents should also be considered potent CYP 3A 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 CYP 3A are
discussed in the PRECAUTIONS section (see PRECAUTIONS-Drug Interactions).
PRECAUTIONS:
GENERAL:
If ALPRAX Tablets are to be combined with other psychotropic agents or
anticonvulsant drugs, careful consideration should be given to the pharmacology
of the agents to be employed, particularly with compounds which might potentiate
the action of benzodiazepines (see DRUG INTERACTIONS).
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.
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
ALPRAX. A decreased systemic alprazolam elimination rate (eg, increased plasma
half-life) has been observed in both alcoholic liver disease patients and obese
patients receiving ALPRAX (see ACTIONS/CLINICAL PHARMACOLOGY).
Episodes of hypomania and mania have been reported in association with the use
of ALPRAX in patients with depression.
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
ALPRAX.
INFORMATION FOR PATIENTS:
FOR ALL USERS OF ALPRAX:
To assure safe and effective use of benzodiazepines, all patients prescribed
ALPRAX should be provided with the following guidance. In addition, panic
disorder patients, for whom doses greater than 4 mg/day are typically
prescribed, should be advised about the risks associated with the use of higher
doses.
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 ALPRAX 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, ALPRAX 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 six to eight weeks duration
where the ability of patients to discontinue medication was measured, 7 to 29%
of patients treated with ALPRAX did not completely taper off therapy. In a
controlled postmarketing discontinuation study of panic disorder patients, the
patients treated with doses of ALPRAX 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 ALPRAX.
In addition, the extended use at doses greater than 4 mg/day appears to increase
the incidence and severity of withdrawal reactions when ALPRAX 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.
LABORATORY TESTS:
Laboratory tests are not ordinarily required in otherwise healthy patients.
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 ALPRAX 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.
Propoxyphen-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).
DRUG/LABORATORY TEST INTERACTIONS:
Although interactions between benzodiazepines and commonly employed clinical
laboratory tests have occasionally been reported, there is no consistent pattern
for a specific drug or specific test.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY:
No evidence of carcinogenic potential was observed during 2-year bioassay
studies of alprazolam in rats at doses up to 30 mg/kg/day (150 times the maximum
recommended daily human dose of 10 mg/day) and in mice at doses up to 10
mg/kg/day (50 times the maximum recommended daily human dose).
Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100
mg/kg, which is 500 times the maximum recommended daily human dose of 10 mg/day.
Alprazolam also was not mutagenic In Vitro in the DNA Damage/Alkaline Elution
Assay or the Ames Assay.
Alprazolam produced no impairment of fertility in rats at doses up to 5
mg/kg/day, which is 25 times the maximum recommended daily human dose of 10
mg/day.
PREGNANCY: Teratogenic Effects:
Pregnancy Category D: (See WARNINGS Section).
NONTERATOGENIC EFFECTS:
It should be considered that the child born of a mother who is receiving
benzodiazepines may be at some risk for withdrawal symptoms from the drug during
the postnatal period. Also, neonatal flaccidity and respiratory problems have
been reported in children born of mothers who have been receiving
benzodiazepines.
LABOR AND DELIVERY:
ALPRAX has no established use in labor or delivery.
NURSING MOTHERS:
Benzodiazepines are known to be excreted in human milk. It should be assumed
that alprazolam is as well. Chronic administration of diazepam to nursing
mothers has been reported to cause their infants to become lethargic and to lose
weight. As a general rule, nursing should not be undertaken by mothers who must
use ALPRAX.
PEDIATRIC USE:
Safety and effectiveness of ALPRAX in individuals below 18 years of age have not
been established.
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 ALPRAX 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.
Propoxyphen-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).
DRUG/LABORATORY TEST INTERACTIONS:
Although interactions between benzodiazepines and commonly employed clinical
laboratory tests have occasionally been reported, there is no consistent pattern
for a specific drug or specific test.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
Side effects to ALPRAX 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 ALPRAX (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 ALPRAX 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.
ANXIETY DISORDERS
TREATMENT-EMERGENT SYMPTOM INCIDENCE OF INTERVENTION
INCIDENCE(**/* ) BECAUSE OF SYMPTOM
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ALPRAX PLACEBO ALPRAX
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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 (*)
____________________________________________________________________________________________________________
*NONE REPORTED
**/* EVENTS REPORTED BY 1% OR MORE OF ALPRAX PATIENTS ARE INCLUDED.
____________________________________________________________________________________________________________