NDC 67296-0431 Alprazolam

NDC Product Code 67296-0431

NDC 67296-0431-1

Package Description: 10 TABLET in 1 BOTTLE

NDC 67296-0431-2

Package Description: 30 TABLET in 1 BOTTLE

This product is EXCLUDED from the official NDC directory because the listing data was inactivated by the FDA.

NDC Product Information

Alprazolam with NDC 67296-0431 is a product labeled by Redpharm Drug Inc.. The generic name of Alprazolam is . The product's dosage form is and is administered via form.

Labeler Name: Redpharm Drug Inc.

Dosage Form: -

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Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • DOCUSATE SODIUM (UNII: F05Q2T2JA0)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
  • SODIUM BENZOATE (UNII: OJ245FE5EU)
  • STARCH, CORN (UNII: O8232NY3SJ)

Product Labeler Information

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Labeler Name: Redpharm Drug Inc.
Labeler Code: 67296
Start Marketing Date: 02-01-2008 What is the Start Marketing Date?
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Listing Expiration Date: 12-31-2017 What is the Listing Expiration Date?
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Exclude Flag: I What is the NDC Exclude Flag?
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Information for Patients

Alprazolam

Alprazolam is pronounced as (al pray' zoe lam)

Why is alprazolam medication prescribed?
Alprazolam is used to treat anxiety disorders and panic disorder (sudden, unexpected attacks of extreme fear and worry about these attacks). Alprazolam is in a class of m...
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Alprazolam Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Description

Alprazolam 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-α] [1,4] benzodiazepine. The structural
formula is:Alprazolam is a white to off-white crystalline powder, which is soluble in
alcohol but which has no appreciable solubility in water at physiological
pH.Each alprazolam tablet, for oral administration, contains 0.25, 0.5, or 1 mg
of alprazolam. Inactive ingredients: docusate sodium, lactose monohydrate,
magnesium stearate, microcrystalline cellulose, pregelatinized starch, and
sodium benzoate.Alprazolam is a white to off-white crystalline powder, which is soluble in
alcohol but which has no appreciable solubility in water at physiological
pH. Additionally, the 0.5 mg also contains
FD and C Yellow No. 6 Aluminum Lake, and the 1 mg also
contains FD and C Blue No. 2 Aluminum Lake.

Clinical Pharmacology

PharmacodynamicsCNS 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.PharmacokineticsAbsorptionFollowing 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 mg, peak levels of 8 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 to 26.9 hours) in healthy
adults.DistributionIn vitro, alprazolam is bound (80
percent) to human serum protein. Serum albumin accounts for the majority of the
binding.Metabolism/EliminationAlprazolam 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 0.2 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 PopulationsChanges 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 to 26.9
hours, n = 16) compared to 11 hours (range: 6.3 to 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.RaceMaximal concentrations and half-life of alprazolam are
approximately 15% and 25% higher in Asians compared to Caucasians.PediatricsThe pharmacokinetics of alprazolam in pediatric patients have not
been studied.GenderGender has no effect on the pharmacokinetics of alprazolam.Cigarette SmokingAlprazolam 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, 2.7 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 0.9±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 to 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 DisordersAlprazolam 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. Alprazolam 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 DisorderSupport for the effectiveness of alprazolam 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 alprazolam was 5 to 6 mg/day in two of the studies, and
the doses of alprazolam were fixed at 2 and 6 mg/day in the third study. In all
three studies, alprazolam was superior to placebo on a variable defined as “the
number of patients with zero panic attacks” (range, 37 to 83% met this
criterion), as well as on a global improvement score. In two of the three
studies, alprazolam was superior to placebo on a variable defined as “change
from baseline on the number of panic attacks per week” (range, 3.3 to 5.2), and
also on a phobia rating scale. A subgroup of patients who were improved on
alprazolam 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 DisordersAlprazolam tablets 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 alprazolam.Panic DisorderAlprazolam 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 alprazolam 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

Dependence and Withdrawal Reactions, Including
SeizuresCertain adverse clinical events, some life-threatening, are a
direct consequence of physical dependence to alprazolam. 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 (i.e., 0.75 to 4 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 alprazolam 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 alprazolam as
a treatment for panic disorderBecause the management of panic disorder often requires the use
of average daily doses of alprazolam 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 alprazolam 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
alprazolam 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% to 93% of patients treated
with alprazolam tapered completely off therapy compared to 89% to 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 alprazolam 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 alprazolam 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 alprazolam. The
risk of seizure seems to be greatest 24 to 72 hours after discontinuation (see
DOSAGE AND ADMINISTRATION for
recommended tapering and discontinuation schedule).Status Epilepticus and Its TreatmentThe medical event voluntary reporting system shows that
withdrawal seizures have been reported in association with the discontinuation
of alprazolam. In most cases, only a single seizure was reported; however,
multiple seizures and status epilepticus were reported as well.Interdose SymptomsEarly morning anxiety and emergence of anxiety symptoms between
doses of alprazolam have been reported in patients with panic disorder taking
prescribed maintenance doses of alprazolam. 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 ReductionWithdrawal reactions may occur when dosage reduction occurs for
any reason. This includes purposeful tapering, but also inadvertent reduction of
dose (e.g., the patient forgets, the patient is admitted to a hospital).
Therefore, the dosage of alprazolam should be reduced or discontinued gradually
(see DOSAGE AND
ADMINISTRATION).CNS Depression and Impaired PerformanceBecause of its CNS depressant effects, patients receiving
alprazolam 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 alprazolam.Risk of Fetal HarmBenzodiazepines can potentially cause fetal harm when
administered to pregnant women. If alprazolam 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, alprazolam 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 3AThe 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 InhibitorsAzole Antifungal AgentsKetoconazole and itraconazole are potent CYP3A inhibitors and
have been shown in vivo to increase plasma alprazolam
concentrations 3.98 fold and 2.7 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 CYP3A 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)NefazodoneCoadministration of nefazodone increased alprazolam concentration
two-fold.FluvoxamineCoadministration of fluvoxamine approximately doubled the maximum
plasma concentration of alprazolam, decreased clearance by 49%, increased
half-life by 71%, and decreased measured psychomotor performance.CimetidineCoadministration 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
MetabolismOther drugs possibly affecting alprazolam metabolism by
inhibition of CYP3A are discussed in the PRECAUTIONS section (see PRECAUTIONS: Drug
Interactions).

Precautions

GeneralSuicideAs 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.ManiaEpisodes of hypomania and mania have been reported in association
with the use of alprazolam in patients with depression.Uricosuric EffectAlprazolam 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 alprazolam.Use in Patients with Concomitant IllnessIt 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
alprazolam. A decreased systemic alprazolam elimination rate (eg, increased
plasma half-life) has been observed in both alcoholic liver disease patients and
obese patients receiving alprazolam (see CLINICAL PHARMACOLOGY).

Information For Patients

  • For All Users of AlprazolamTo assure safe and effective use of benzodiazepines, all patients
  • Prescribed alprazolam should be provided with the following guidance.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.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.Inform your physician if you are nursing.Until you experience how this medication affects you, do not drive a car or
  • Operate potentially dangerous machinery, etc.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.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 patientsThe use of alprazolam 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, alprazolam 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 alprazolam did not completely taper
  • Off therapy. In a controlled postmarketing discontinuation study of panic
  • Disorder patients, the patients treated with doses of alprazolam 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 alprazolam.In addition, the extended use at doses greater than 4 mg/day appears to
  • Increase the incidence and severity of withdrawal reactions when alprazolam 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.
However, when treatment is protracted, periodic blood counts, urinalysis, and
blood chemistry analyses are advisable in keeping with good medical practice.

Drug Interactions

Use with Other CNS DepressantsIf alprazolam 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. 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.Use with Imipramine and DesipramineThe 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 3AThe initial step in alprazolam metabolism is hydroxylation
catalyzed by cytochrome P450 3A (CYP3A). 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 CYP3A inhibitors of possible
clinical significance on the basis of clinical studies involving alprazolam
(caution is recommended during coadministration with alprazolam)FluoxetineCoadministration 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.PropoxypheneCoadministration of propoxyphene decreased the maximum plasma
concentration of alprazolam by 6%, decreased clearance by 38%, and increased
half-life by 58%.Oral ContraceptivesCoadministration 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 CYP3A
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. However, data from an
in vivo drug interaction study involving a single
dose of alprazolam 1 mg and steady state dose of sertraline (50 to 150 mg/day)
did not reveal any clinically significant changes in the pharmacokinetics of
alprazolam. 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).Drugs demonstrated to be inducers of CYP3ACarbamazepine can increase alprazolam metabolism and therefore
can decrease plasma levels of alprazolam.

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 EffectsPregnancy Category D(See WARNINGS
section).Nonteratogenic EffectsIt 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

Alprazolam 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 alprazolam.

Pediatric Use

Safety and effectiveness of alprazolam in individuals below 18 years of age have
not been established.

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, e.g., 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 (i.e., 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 (e.g., 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 DisordersANXIETY
DISORDERSTreatment-EmergentSymptom Incidence †Incidence of InterventionBecause of SymptomALPRAZOLAM
PLACEBO
ALPRAZOLAMNumber of Patients 565505565% of Patients Reporting:Central Nervous System
Drowsiness 41.021.615.1Light-headedness 20.819.31.2Depression 13.918.12.4Headache 12.919.61.1Confusion 9.910.00.9Insomnia 8.918.41.3Nervousness 4.110.31.1Syncope 3.14.0*Dizziness 1.80.82.5Akathisia 1.61.2*Tiredness/Sleepiness **1.8GastrointestinalDry Mouth 14.713.30.7Constipation 10.411.40.9Diarrhea 10.110.31.2Nausea/Vomiting 9.612.81.7Increased Salivation 4.22.4*CardiovascularTachycardia/Palpitations 7.715.60.4Hypotension 4.72.2*SensoryBlurred Vision 6.26.20.4MusculoskeletalRigidity 4.25.3*Tremor 4.08.80.4CutaneousDermatitis/Allergy 3.83.10.6OtherNasal Congestion 7.39.3*Weight Gain 2.72.7*Weight Loss 2.33.0** None reported† Events reported by 1% or more of alprazolam patients
are includedIn addition to the relatively common (i.e., 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 DisorderPANIC
DISORDERTreatment-EmergentSymptom Incidence*ALPRAZOLAMPLACEBONumber of Patients 13881231% of Patients Reporting:Central Nervous
SystemDrowsiness 76.842.7Fatigue and Tiredness 48.642.3Impaired Coordination 40.117.9Irritability 33.130.1Memory Impairment 33.122.1Light-headedness/Dizziness 29.836.9Insomnia 29.441.8Headache 29.235.6Cognitive Disorder 28.820.5Dysarthria 23.36.3Anxiety 16.624.9Abnormal Involuntary Movement 14.821.0Decreased Libido 14.48.0Depression 13.814.0Confusional State 10.48.2Muscular Twitching 7.911.8Increased Libido 7.74.1Change in Libido (Not specified) 7.15.6Weakness 7.18.4Muscle Tone Disorders 6.37.5Syncope 3.84.8Akathisia 3.04.3Agitation 2.92.6Disinhibition 2.71.5Paresthesia 2.43.2Talkativeness 2.21.0Vasomotor Disturbances 2.02.6Derealization 1.91.2Dream Abnormalities 1.81.5Fear 1.41.0Feeling Warm 1.30.5GastrointestinalDecreased Salivation 32.834.2Constipation 26.215.4Nausea/Vomiting 22.031.8Diarrhea 20.622.8Abdominal Distress 18.321.5Increased Salivation 5.64.4Cardio-RespiratoryNasal Congestion 17.416.5Tachycardia 15.426.8Chest Pain 10.618.1Hyperventilation 9.714.5Upper Respiratory Infection 4.33.7SensoryBlurred Vision 21.021.4Tinnitus 6.610.4MusculoskeletalMuscular Cramps 2.42.4Muscle Stiffness 2.23.3CutaneousSweating 15.123.5Rash 10.88.1OtherIncreased Appetite 32.722.8Decreased Appetite 27.824.1Weight Gain 27.217.9Weight Loss 22.616.5Micturition Difficulties 12.28.6Menstrual Disorders 10.48.7Sexual Dysfunction 7.43.7Edema 4.95.6Incontinence 1.50.6Infection 1.31.7* Events reported by 1% or more 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 EventsBody
System/EventNeurologic GastrointestinalInsomnia 29.5Nausea/Vomiting 16.5Light-headedness 19.3Diarrhea 13.6Abnormal involuntary movement 17.3Decreased Salivation 10.6Headache 17.0Metabolic-NutritionalMuscular twitching 6.9Weight loss 13.3Impaired coordination 6.6Decreased appetite 12.8Muscle tone disorders 5.9Weakness 5.8DermatologicalPsychiatricSweating 14.4Anxiety 19.2Fatigue and Tiredness 18.4CardiovascularIrritability 10.5Tachycardia 12.2Cognitive disorder 10.3Memory impairment 5.5Special SensesDepression 5.1Blurred vision 10.0Confusional state 5.0From 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
post-traumatic stress disorder.

Drug Abuse And Dependence

Physical and Psychological DependenceWithdrawal 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 to 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 ClassAlprazolam is a controlled substance under the Controlled
Substance Act by the Drug Enforcement Administration and alprazolam tablets have
been assigned to Schedule IV.

Overdosage

Clinical ExperienceManifestations of alprazolam overdosage include somnolence,
confusion, impaired coordination, diminished reflexes and coma. Death has been
reported in association with overdoses of alprazolam by itself, as it has with
other benzodiazepines. In addition, fatalities have been reported in patients
who have overdosed with a combination of a single benzodiazepine, including
alprazolam, and alcohol; alcohol levels seen in some of these patients have been
lower than those usually associated with alcohol-induced fatality.The acute oral LD50 in rats is 331 to 2171 mg/kg.
Other experiments in animals have indicated that cardiopulmonary collapse can
occur following massive intravenous doses of alprazolam (over 195 mg/kg; 975
times the maximum recommended daily human dose of 10 mg/day). Animals could be
resuscitated with positive mechanical ventilation and the intravenous infusion
of norepinephrine bitartrate.Animal experiments have suggested that forced diuresis or hemodialysis are
probably of little value in treating overdosage.General Treatment of OverdoseOverdosage reports with alprazolam tablets are limited. As in all
cases of drug overdosage, respiration, pulse rate, and blood pressure should be
monitored. General supportive measures should be employed, along with immediate
gastric lavage. Intravenous fluids should be administered and an adequate airway
maintained. If hypotension occurs, it may be combated by the use of
vasopressors. Dialysis is of limited value. As with the management of
intentional overdosing with any drug, it should be borne in mind that multiple
agents may have been ingested.Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for
the complete or partial reversal of the sedative effects of benzodiazepines and
may be used in situations when an overdose with a benzodiazepine is known or
suspected. Prior to the administration of flumazenil, necessary measures should
be instituted to secure airway, ventilation, and intravenous access. Flumazenil
is intended as an adjunct to, not as a substitute for, proper management of
benzodiazepine overdose. Patients treated with flumazenil should be monitored
for re-sedation, respiratory depression, and other residual benzodiazepine
effects for an appropriate period after treatment. The
prescriber should be aware of a risk of seizure in association with flumazenil
treatment, particularly in long-term benzodiazepine users and in cyclic
antidepressant overdose. The complete flumazenil package insert including
CONTRAINDICATIONS, WARNINGS,
and PRECAUTIONS should be consulted prior to
use.

Dosage And Administration

Dosage should be individualized for maximum beneficial effect.
While the usual daily dosages given below will meet the needs of most patients,
there will be some who require doses greater than 4 mg/day. In such cases,
dosage should be increased cautiously to avoid adverse effects.Anxiety Disorders and Transient Symptoms of
AnxietyTreatment for patients with anxiety should be initiated with a
dose of 0.25 to 0.5 mg given three times daily. The dose may be increased to
achieve a maximum therapeutic effect, at intervals of 3 to 4 days, to a maximum
daily dose of 4 mg, given in divided doses. The lowest possible effective dose
should be employed and the need for continued treatment reassessed frequently.
The risk of dependence may increase with dose and duration of treatment.In all patients, dosage should be reduced gradually when discontinuing
therapy or when decreasing the daily dosage. Although there are no
systematically collected data to support a specific discontinuation schedule, it
is suggested that the daily dosage be decreased by no more than 0.5 mg every
three days. Some patients may require an even slower dosage reduction.Panic DisorderThe successful treatment of many panic disorder patients has
required the use of alprazolam at doses greater than 4 mg daily. In controlled
trials conducted to establish the efficacy of alprazolam in panic disorder,
doses in the range of 1 to 10 mg daily were used. The mean dosage employed was
approximately 5 to 6 mg daily. Among the approximately 1700 patients
participating in the panic disorder development program, about 300 received
alprazolam in dosages of greater than 7 mg/day, including approximately 100
patients who received maximum dosages of greater than 9 mg/day. Occasional
patients required as much as 10 mg a day to achieve a successful response.Dose TitrationTreatment may be initiated with a dose of 0.5 mg three times
daily. Depending on the response, the dose may be increased at intervals of 3 to
4 days in increments of no more than 1 mg per day. Slower titration to the dose
levels greater than 4 mg/day may be advisable to allow full expression of the
pharmacodynamic effect of alprazolam. To lessen the possibility of interdose
symptoms, the times of administration should be distributed as evenly as
possible throughout the waking hours, that is, on a three or four times per day
schedule.Generally, therapy should be initiated at a low dose to minimize the risk of
adverse responses in patients especially sensitive to the drug. Dose should be
advanced until an acceptable therapeutic response (ie, a substantial reduction
in or total elimination of panic attacks) is achieved, intolerance occurs, or
the maximum recommended dose is attained.Dose MaintenanceFor patients receiving doses greater than 4 mg/day, periodic
reassessment and consideration of dosage reduction is advised. In a controlled
postmarketing dose-response study, patients treated with doses of alprazolam
greater than 4 mg/day for 3 months were able to taper to 50% of their total
maintenance dose without apparent loss of clinical benefit. Because of the
danger of withdrawal, abrupt discontinuation of treatment should be avoided.
(See WARNINGS, PRECAUTIONS, DRUG ABUSE AND
DEPENDENCE.)The necessary duration of treatment for panic disorder patients responding to
alprazolam is unknown. After a period of extended freedom from attacks, a
carefully supervised tapered discontinuation may be attempted, but there is
evidence that this may often be difficult to accomplish without recurrence of
symptoms and/or the manifestation of withdrawal phenomena.Dose ReductionBecause of the danger of withdrawal, abrupt discontinuation of
treatment should be avoided (see WARNINGS, PRECAUTIONS, DRUG ABUSE AND DEPENDENCE).In all patients, dosage should be reduced gradually when discontinuing
therapy or when decreasing the daily dosage. Although there are no
systematically collected data to support a specific discontinuation schedule, it
is suggested that the daily dosage be decreased by no more than 0.5 mg every
three days. Some patients may require an even slower dosage reduction.In any case, reduction of dose must be undertaken under close supervision and
must be gradual. If significant withdrawal symptoms develop, the previous dosing
schedule should be reinstituted and, only after stabilization, should a less
rapid schedule of discontinuation be attempted. 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. It is suggested that the dose be reduced by no more than
0.5 mg every 3 days, with the understanding that some patients may benefit from
an even more gradual discontinuation. Some patients may prove resistant to all
discontinuation regimens.Dosing in Special PopulationsIn elderly patients, in patients with advanced liver disease or
in patients with debilitating disease, the usual starting dose is 0.25 mg, given
two or three times daily. This may be gradually increased if needed and
tolerated. The elderly may be especially sensitive to the effects of
benzodiazepines. If side effects occur at the recommended starting dose, the
dose may be lowered.

How Supplied

Alprazolam tablets, USP for oral administration are available
as:0.25 mg: Oval, white tablets debossed GG 256 on one
side and scored on the reverse side and supplied as:NDC 67296-0431-1 bottles of 10NDC 67296-0431-2 bottles of 30

Animal Studies

When rats were treated with alprazolam at 3, 10, and 30 mg/kg/day
(15 to 150 times the maximum recommended human dose) orally for 2 years, a
tendency for a dose related increase in the number of cataracts was observed in
females and a tendency for a dose related increase in corneal vascularization
was observed in males. These lesions did not appear until after 11 months of
treatment.12-2007M7132Sandoz Inc.Princeton, NJ 08540

Label

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