Alprazolam (Jamp Pharma) Product Monograph

ACTION AND CLINICAL PHARMACOLOGY

Alprazolam, a triazolo 1,4 benzodiazepine analog, binds with high affinity to the GABA benzodiazepine receptor complex. Considerable evidence suggests that the central pharmacologic/therapeutic actions of alprazolam are mediated via interaction with this receptor complex.

Pharmacokinetics

Absorption,

Orally administered alprazolam is readily absorbed in man. Plasma levels are proportional to the dose given; over the dose range of 0.5 to 3 mg, peak levels of 8.0 to 37 ng/ml were observed. The mean elimination half-life of alprazolam is about 11 hours in healthy adults.

With multiple doses, given 3 times daily, steady state is reached within 7 days.

Metabolism and Excretion

Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4

(CYP3A4). Degradation of alprazolam occurs mainly by oxidation yielding the primary metabolites αhydroxy-alprazolam and a benzophenone derivative. The α hydroxy-metabolite is further transformed to demethylalprazolam. Both αhydroxy-alprazolam and demethylalprazolam are active and appear to have half-lives similar to alprazolam but their plasma levels are low. Alprazolam metabolites are excreted primarily in the urine.

The table summarizes some pharmacokinetic parameters in healthy adults and healthy elderly subjects (mean age 70 years, range 62 to 78 years), as well as in obese subjects and in patients with impaired hepatic or renal function. Clearance was decreased and half-lives were increased in all special patient populations except in patients on hemodialysis. Time to peak plasma concentration was increased in patients with liver disease and CAPD.

^aCAPD: Continuous Ambulatory Peritoneal Dialysis

Cmax: peak plasma concentration

Tmax: time of peak concentration

C1: total clearance

t½ elimination half-life

Clinical Trial

In a placebo-controlled, 8-week trial, which included 526 patients with diagnoses of Panic

Disorder with or without Agoraphobia, alprazolam in a dosage range of 1 to 10 mg per day

(with a mean daily dosage of 5.7 ± 2.27 mg at the end of the treatment period) was found effective in blocking or attenuating panic attacks and reducing phobic avoidance.

Clinical Pharmacology:

A double blind, balanced, randomized, two treatment, two period, two sequence, single dose, crossover, bioequivalence study of Famlil-Alprazolam 1mg immediate release tablets versus Xanax (Alprazolam) tablets of Pharmacia & Upjohn Pfizer Canada Inc, Canada was conducted in 24 healthy, adult, human subjects under fasting conditions.

^* Alprazolam

^†Xanax manufactured by Pharmacia &Upjohn Pfizer Canada Inc., Canada

^& For t_max this is median (range) only

^§ Expressed as the arithmetic mean (CV%) only

INDICATIONS AND CLINICAL USE

ALPRAZOLAM (alprazolam) is indicated for the management of Anxiety Disorders or the short-term symptomatic relief of symptoms of excessive anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.

Generalized Anxiety Disorder

ALPRAZOLAM is indicated for the treatment of Generalized Anxiety Disorder (GAD).

GAD 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 lightheadedness; 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.

Panic Disorder with/without Agoraphobia

ALPRAZOLAM is also indicated for the management of Panic Disorder with or without

Agoraphobia. Panic disorder is an illness characterized by recurrent panic attacks.

Panic attacks are discrete periods of intense fear or discomfort, with at least four of the following symptoms: dyspnea; dizziness, unsteady feelings, or faintness; tachycardia;

trembling or shaking; sweating; choking; nausea or abdominal distress; depersonalization or derealization; paresthesias; flushes or chills; chest pain or discomfort, fear of dying;

fear of going crazy or of doing something uncontrolled.

Attacks are usually of a few minutes duration but can, more rarely, last up to a few hours.

The diagnosis of Panic Disorders requires that either four attacks must have occurred within a four-week period, or one or more attacks must have been followed by a period of at least one month of persistent fear of having another attack. The symptoms must not be attributable to known organic factors.

The panic attacks, at least initially, are unexpected. Later in the course of this disturbance certain situations, e.g., 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).

During the natural course of the illness, the patient often develops symptoms of

Agoraphobia. Agoraphobia is a fear of being in situations from which escape might be difficult or in which help might not be available in the event of an unexpected panic attack. As a result of this fear, the patient either restricts travel or needs a companion when away from home, or else endures agoraphobic situations despite intense anxiety. The severity varies from mild (able to travel to work or to shop), to severe (completely housebound).

Demonstrations of the effectiveness of alprazolam by systematic clinical studies 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 drug treatment in all patients.

Geriatrics (> 65 years of age)

Elderly patients may be especially sensitive to the effects of benzodiazepines and lower doses of ALPRAZOLAM are recommended (see ACTION AND CLINICAL

PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Geriatrics; and DOSAGE

AND ADMINISTRATION, Elderly and Debilitated Patients).

Pediatrics (< 18 years of age)

ALPRAZOLAM is not recommended for use in patients under the age of 18 years (see

PRECAUTIONS, Pediatrics).

CONTRAINDICATIONS

ALPRAZOLAM (alprazolam) is contraindicated in patients with known hypersensitivity to alprazolam or to any component of the product’s formulation, or other benzodiazepines.

ALPRAZOLAM is also contraindicated in patients with myasthenia gravis, severe hepatic insufficiency, severe respiratory insufficiency, sleep apnea syndrome, or acute narrow angle glaucoma. However, ALPRAZOLAM may be used in patients with open angle glaucoma who are receiving appropriate treatment.

Co-administration of ALPRAZOLAM with ketoconazole and itraconazole are contraindicated because these medications significantly impair the metabolism of alprazolam by CYP3A4 (see PRECAUTIONS, Drug Interactions).

WARNINGS

ALPRAZOLAM (alprazolam) is not effective in patients with Personality Disorders.

ALPRAZOLAM is not recommended for the management of Mood or Psychotic

Disorders.

Dependence and Withdrawal Reactions, Including Seizures: Physical dependence with withdrawal symptoms may occur with benzodiazepine discontinuation and can be severe

(eg, seizures) if benzodiazepines are suddenly discontinued or upon rapid dose decrease

(See DOSAGE AND ADMINISTRATION - Discontinuation). Even after relatively short-term use at the doses recommended for the treatment of transient anxiety and anxiety disorder (ie, 0.75 to 3.0 mg per day), there is some risk of dependence. Post-marketing surveillance data suggest that the risk of dependence and its severity appear to be greater in patients treated with relatively high doses (above 4 mg per day) and for long periods

(more than 8-12 weeks).

The Importance of Dose and the Risks of ALPRAZOLAM as a Treatment for Panic

Disorder: Because the management of Panic Disorder often requires the use of average daily doses of alprazolam above 3 mg, the risk of dependence among Panic Disorder patients may be higher than that among those treated for less severe anxiety. Randomized placebo-controlled discontinuation studies 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 a return of illness, rebound or withdrawal.

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:

From the studies cited, it has not been determined whether these symptoms are clearly related to the dose and duration of therapy with alprazolam in patients with Panic Disorder. In two

controlled trials of six to eight weeks duration where the ability of patients to discontinue medication was measured, 71% - 93% of patients treated with alprazolam tapered completely off therapy compared to 89% - 96% of placebo treated patients. The ability of patients to completely discontinue therapy with alprazolam after long-term therapy has not been reliably determined.

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 daily 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 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 alprazolam. The risk of seizure seems to be greatest 24-72 hours after discontinuation. (see DOSAGE AND ADMINISTRATION – Discontinuation;

Adverse Reactions – Post-Marketing Events).

Status Epilepticus and its Treatment: The 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. 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.

Depression and suicide: Panic-related disorders have been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients.

Therefore, the same precaution that is exercised with the use of any psychotropic drug in treating

depressed patients or those in whom there is reason to suspect concealed suicidal ideation or plans must be exercised when using the higher doses of alprazolam in treating patients with panic-related disorders. Prescriptions for alprazolam should be written for the smallest quantity of drug consistent with good patient management.

Interdose Symptoms: Early 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 inter-dosing 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 includes inadvertent reduction of dose

(eg, the patient forgets, the patient is admitted to hospital, etc.). Therefore, the dosage of alprazolam should be reduced or discontinued gradually (See DOSAGE AND

ADMINISTRATION).

Driving and Hazardous Activities: Because of its central nervous system depressant effect, patients receiving alprazolam should be cautioned not to undertake activities requiring mental alertness, judgment and physical coordination such as driving or operating machinery.

This is particularly true in the early phases of dose adjustment, and until it has been established that they do not become drowsy or dizzy while taking alprazolam. Alcohol or central nervous system depressant drugs should not be ingested during treatment with alprazolam.

PRECAUTIONS Dependence Liability: Physical and psychological dependence may occur with

benzodiazepines, including alprazolam. The risk of dependence increases with higher doses and long-term use. Patients who are prone to abuse drugs should be under careful surveillance when receiving alprazolam. Patients with a history of alcohol or drug abuse are at higher risk for developing psychological dependence.

Once physical dependence has developed, abrupt discontinuation of treatment will be accompanied by withdrawal symptoms. Although the severity and incidence of withdrawal symptoms may 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 (see WARNINGS, Dependence and Withdrawal

Reactions, Including Seizures). Withdrawal symptoms can range from mild dysphoria and insomnia to a major syndrome that may include irritability, nervousness, insomnia, agitation, diarrhea, abdominal cramps, vomiting, sweating, tremors and convulsions. Since symptoms may be similar to those for which the patient is being treated, it may be difficult to differentiate between relapse and withdrawal upon discontinuation. Since the risk of withdrawal symptoms is greater after abrupt discontinuation of treatment, abrupt withdrawal of the drug should be avoided and treatment - even if only of short duration - should be terminated by gradually reducing the daily dose to minimize withdrawal reactions.

Mania: Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression. New onset hypomania or mania were also reported with alprazolam treatment in the absence of a history of significant psychiatric disorders or concomitant medications.

Discontinuation of Treatment:

To discontinue treatment in patients taking alprazolam, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction. A decrease of 0.5 mg every 2 to 3 weeks is more appropriate when a dose of 6 mg daily or more has been administered even for only a few months. Once a dose of 2 mg daily

is achieved, the dose should be decreased by 0.25 mg per 2 to 3 weeks. (see DOSAGE AND

ADMINISTRATION).

Special Populations

Pregnant Women

The safety of the use of alprazolam in pregnancy has not been established. Therefore, alprazolam are not recommended for use during pregnancy.

Teratogenic Effects: Benzodiazepines can potentially cause fetal harm when administered to pregnant women. Several studies have suggested an increased risk of congenital malformations associated with the use of benzodiazepines during the first trimester of pregnancy. Later studies with the benzodiazepine class of drugs have provided no clear evidence of any type of defect.

Since alprazolam is also a benzodiazepine derivative, the administration of alprazolam is rarely justified in women of child-bearing potential. Women of child-bearing potential should be warned to consult their physician regarding the discontinuation of the drug due to the potential hazard to the fetus if they are pregnant or intend to become pregnant.

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 during late third trimester of pregnancy or during labour.

Labor and Delivery

Alprazolam has no established use in labor or delivery.

Nursing Mothers

Studies in rats have indicated that alprazolam and its metabolites are secreted into the milk.

Levels of benzodiazepines, including alprazolam, in breast milk are low. Therefore, nursing should not be undertaken while a patient is receiving alprazolam.

Pediatrics (< 18 years of age)

The safety and efficacy of alprazolam in patients under the age of 18 years have not been established. Alprazolam is not recommended for use in patients under the age of 18 years.

Geriatrics (<65 years of age)

Elderly and debilitated patients have been found to be prone to the CNS depressant activity of benzodiazepines, even after low doses. Manifestations of this CNS depressant activity include ataxia, over sedation and hypotension. Therefore, medication should be administered with caution to these patients, particularly if a drop in blood pressure might lead to cardiac complications. Initial doses should be low and increments should be made gradually, depending on the response of the patient, in order to avoid over sedation, neurological impairment and other possible adverse reactions. (see ACTION AND CLINICAL PHARMACOLOGY,

Pharmacokinetics and DOSAGE AND ADMINISTRATION, Geriatrics).

Renal or Hepatic Impairment

If treatment is necessary in patients with impaired hepatic or renal function, therapy should be initiated at a very low dose and the dosage increased only to the extent that it is compatible with the degree of residual function of these organs. Such patients should be followed closely and have periodic laboratory assessments. (see ACTION AND CLINICAL PHARMACOLOGY and

DOSAGE AND ADMINISTRATION).

Laboratory Tests: If alprazolam is administered for repeated cycles of therapy, periodic blood counts and liver function tests are advisable.

Drug Interactions:

Pharmacodynamic Drug-Drug Interactions

CNS – acting drugs

Benzodiazepines, including alprazolam, may potentiate or produce additive central nervous system depressant effects when combined with other psychotropic medication, alcohol, narcotics, barbiturates, antihistamines or anticonvulsants. Therefore, if alprazolam is to be

combined with other drugs acting on the CNS, careful consideration should be given to the pharmacology of the agents involved because of the possible additive or potentiating effects. Patients should also be advised against the simultaneous use of other CNS depressant drugs and should be cautioned not to take alcohol during the administration of alprazolam.

Pharmacokinetic Drug-Drug Interactions

CYP3A Inhibitors

Pharmacokinetic interactions can occur when alprazolam is administered along with drugs that interfere with its metabolism. Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450 3A4) may increase the concentration of alprazolam and enhance its activity. Data from clinical studies with alprazolam, in vitro studies with alprazolam, and clinical studies with drugs metabolized similarly to alprazolam provide evidence for varying degrees of interaction and possible interaction with alprazolam for a number of drugs.

Antifungal agents

Ketoconazole and itraconazole are potent inhibitors of CYP3A. The co-administration of alprazolam with ketoconazole, itraconazole, or other azole-type antifungals is not recommended (see CONTRAINDICATIONS). This is based on results of drug interaction studies of triazolam and midazolam, benzodiazepines metabolized similarly to alprazolam, with ketoconazole and itraconazole. In addition, an in vitro study showed ketoconazole to be a potent inhibitor of alprazolam metabolism.

Caution and consideration of dose reduction is recommended when alprazolam is co-administered with nefazodone, fluvoxamine, and cimetidine.

Nefazodone

When alprazolam (1 mg bid) and nefazodone (200 mg bid) were co-administered to steady state, peak concentrations, AUC and half-life values for alprazolam increased by approximately 2 fold. Nefazodone plasma concentrations were unaffected by alprazolam, although levels of the mCPP metabolite were increased. The concomitant use of alprazolam and nefazodone was also associated with an increase in psychomotor impairment presumably due to increased alprazolam plasma concentrations.

If alprazolam is co-administered with nefazodone, a reduction in the alprazolam dosage may be

appropriate; no dosage adjustment is required for nefazodone. The interactive effects of higher doses of these agents, such as the dosage levels of alprazolam used in panic disorder, have not been studied.

Fluvoxamine

When alprazolam 1.0 mg and fluvoxamine (50 mg qd for 3 days followed by 100 mg qd for 7 days) were co-administered the AUC of alprazolam was approximately doubled, the Cmax of alprazolam increased by about 50% and the half life of alprazolam increased from 19.8 hours to 33.9 hours. Cmax and AUC of fluvoxamine were decreased by about 25%. Psychomotor performance tests on day 10 showed significant decreases in performance.

Cimetidine

In healthy volunteers, a single 1 mg dose of alprazolam was administered with and without concurrent administration of cimetidine (300 mg) every 6 hours. Cimetidine significantly impaired the clearance of alprazolam and prolonged its half-life. Cimetidine significantly reduced total metabolic clearance (1.05 versus 1.66 ml/min/kg). Co-administration of alprazolam and cimetidine resulted in an approximate doubling of the Cmax of alprazolam and a statistically significant increase in the AUC of alprazolam. The half-life of alprazolam increased from 12.2 hours to 14.2 hours.

Oral contraceptives

The effect of oral contraceptives on the pharmacokinetics of a single 1 mg dose of alprazolam was studied in healthy women. Alprazolam clearance was lower in subjects taking oral contraceptives (0.95 ml/min/kg) than in the control group (1.21 ml/min/kg) while its half-life was prolonged (12.4 hours versus 9.6 hours). Caution is recommended when alprazolam is co-administered with oral contraceptives.

HIV Protease Inhibitors

Interactions involving HIV protease inhibitors (eg, ritonavir) and alprozolam are complex and time dependent. Low doses of ritonavir resulted in a large impairment of alprazolam clearance, prolonged its elimination half-life and enhanced clinical effects. However, upon extended exposure to ritonavir, CYP3A induction offset this inhibition. This interaction will require a dose-adjustment or discontinuation of alprazolam.

CYP3A Inducers

Carbamazepine

A pharmacokinetic interaction has been noted between alprazolam and carbamazepine; significant reductions in alprazolam concentration have been noted after carbamazepine treatment has been initiated. Pharmacokinetic interactions between alprazolam and phenytoin have not been observed.

Other drugs

Imipramine and desipramine

The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam tablets in doses up to 4 mg/day. The clinical significance of these changes is unknown.

Warfarin

Alprazolam 0.5 mg, administered 3 times a day for 14 days, did not affect prothrombin times or plasma warfarin levels in male volunteers administered sodium warfarin orally.

Caution is recommended when alprazolam is co-administered with fluoxetine, propoxyphene, diltiazem, or macrolide antibiotics such as erythromycin and troleandomycin.

Digoxin

Increased digoxin concentrations have been reported when alprazolam was given, especially in elderly (>65 years if age). Patients who receive alprazolam and digoxin should therefore be monitored for signs and symptoms related to digoxin toxicity.

ADVERSE REACTIONS

Side effects to alprazolam if they occur, are generally observed at the beginning of therapy and usually disappear upon continued medication or decreased dosage.

The data cited in the following two tables are estimates of untoward clinical event incidence among patients who participated under the following clinical conditions: relatively short duration

(ie, four weeks) placebo-controlled clinical studies with dosages up to 4 mg/day of alprazolam

(for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety)

and short-term (up to ten weeks) placebo-controlled clinical studies with dosages up to 10 mg/day of alprazolam in patients with panic disorder, with or without agoraphobia.

In addition to the relatively common (i.e. greater than 1%) untoward events listed in the tables, the following events have been reported to occur with alprazolam and other benzodiazepines:

seizures, loss of coordination, concentration difficulties, memory impairment/transient amnesia, hallucinations, depersonalization, taste alterations, dystonia, irritability, anorexia, fatigue, sedation, slurred speech, musculoskeletal weakness, changes in libido, menstrual irregularities, incontinence, urinary retention, abnormal liver function, elevated hepatic enzymes, elevated bilirubin, jaundice, pruritus and diplopia and hyperprolactemia. Increased intraocular pressure has been rarely reported.

As with all benzodiazepines, paradoxical reactions such as stimulation, agitation, rage, aggressive or hostile behavior, increased muscle spasticity, sleep disturbances, hallucinations and other adverse behavioral effects may occur in rare instances and in a random fashion. Should these occur, use of the drug should be discontinued.

ANXIETY DISORDERS

PANIC DISORDERS

PANIC DISORDERS (cont/...)

In some of the spontaneous case reports of adverse behavioral effects such as stimulation, agitation, concentration difficulties, confusion and hallucinations, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Patients with borderline personality disorder, a prior history of violent or aggressive behaviour, or alcohol or substance abuse may be a risk for such events.

Instances of irritability, hostility and intrusive thoughts have been reported during discontinuance of alprazolam in patients with post-traumatic stress disorder.

Post-Marketing Adverse Events: Various adverse events have been reported in association with the use of alprazolam since market introduction. The majority of these reactions were reported through the medical event voluntary reporting system. Because of the spontaneous nature of the reporting of medical events and the lack of controls, a causal relationship to the use of alprazolam cannot be readily determined. Events include:

gastrointestinal disorder, hypomania, mania, hepatitis, angioedema, peripheral edema, liver enzyme elevations, hepatic failure, Stevens-Johnson syndrome, gynecomastia, galactorrhea, aggression, anger, libido disorder, psychomotor hyperactivity, dystonia, autonomic nervous system imbalance, dermatitis, and photosensitivity reaction.

Withdrawal seizures have been reported for patients taking alprazolam alone.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

For management of suspected drug overdose, contact your regional Poison Control Centre.

Symptoms:

Overdose of alprazolam is manifested as an extension of its pharmacologic activity. Thus, varying degrees of CNS depression effects such as somnolence, confusion, drowsiness, slurred speech, impaired coordination, diminished reflexes, respiratory depression and coma may ensue. As in the management of overdose with any drug, the possibility of multiple drug ingestion should be considered.

Serious sequela are rare unless other drugs and/or ethanol are concomitantly ingested. 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 over-dosed 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.

Treatment:

Vomiting may be induced if the patient is fully awake. Vital signs should be monitored and general supportive measures should be employed as indicated. Gastric lavage should be instituted as soon as possible. Intravenous fluids may be administered and an adequate airway should be maintained.

Experiments in animals have indicated that cardiopulmonary collapse can occur with massive intravenous doses of alprazolam. This could be reversed with positive mechanical respiration and the intravenous infusion of levarterenol. Animal experiments with alprazolam and related compounds have suggested that hemodialysis and forced diuresis are probably of little value.

Treatment of overdosage is primarily supportive of respiratory and cardiovascular function.

Flumazenil, a benzodiazepine receptor antagonist, may be used as an adjunct to the management of respiratory and cardiovascular function associated with overdose.

DOSAGE AND ADMINISTRATION:

Dosage should be individualized for maximal benefit. The lowest possible effective dose should be administered and the need for continued treatment reassessed frequently. The risk of dependence may increase with dose and duration of treatment. In general, patients who have not previously received psychotropic medication will require somewhat lower doses than those previously treated with minor tranquilizers, antidepressants, or hypnotics.

Anxiety Disorders

Adult Dosage:

The initial adult dosage of ALPRAZOLAM (alprazolam) is 0.25 mg given 2 or 3 times daily. If required, increases may be made in 0.25 mg increments according to the severity of symptoms and patient response. It is recommended that the evening dose be increased

before the daytime doses. Very severe manifestations of anxiety may require larger initial daily doses. The optimal dosage is one that permits symptomatic control of excessive anxiety without impairment of mental and motor function. Exceptionally, it may be necessary to increase dosage to a maximum of 3.0 mg daily, given in divided doses.

Elderly or Debilitated Patients: It is recommended that the general principle of using the lowest effective dose be followed in elderly or debilitated patients to preclude the development of ataxia or oversedation. The initial dosage is 0.125 mg given 2 or 3 times daily. If necessary, this dosage may be increased gradually depending on patient tolerance and response. The elderly may be especially sensitive to the effects of benzodiazepines.

Hepatic or Renal Function: In patients with advanced liver or renal disease, the usual dose is 0.125 to 0.25 mg, given two or three times daily. This may be gradually increased if needed and tolerated.

Panic Disorders

The usual starting dose is 0.5 mg to 1.0 mg at bedtime or 0.5 mg three times daily. The dose should be adjusted until the patient is free of panic attacks. Dosage adjustments should be in increments no greater than 1 mg every three to four days. Interdose symptoms may be lessened by using a schedule that provides for administration 3 or 4 times per day.

In controlled trials conducted to establish the efficacy of alprazolam in Panic Disorders, 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 maximum alprazolam doses of greater than 7 mg per day, including approximately 100 patients who received maximum dosages of greater than 9 mg per day. Occasional patients required as much as

10 mg per day to receive a successful response.

The necessary duration of treatment for Panic Disorder is unknown at this time. After a

period of extended freedom from panic attacks, a supervised tapered discontinuation may be attempted.

Discontinuation:

To discontinue treatment in patients taking alprazolam, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction. A decrease of 0.5 mg every 2 to 3 weeks is more appropriate when a dose of 6 mg daily or more has been administered even for only a few months. Once a dose of 2 mg daily is achieved, the dose should be decreased by 0.25 mg per 2 to 3 weeks.

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE

Proper name: Alprazolam

Chemical name: (1) 4H-[1,2,4}Triazolo[4,3-α][1,4]benzodiazepine, 8 chloro-1- methyl-6-phenyl-;

(2) 8-Chloro-1-methyl-6-phenyl-4H-1-s- triazolo[4,3-α][1,4]benzodiazepine

Molecular formula: Cl7H13CIN4

Molecular weight: 308.76

Description: Alprazolam is a white crystalline powder, soluble in methanol or ethanol but with no appreciable solubility in water and a melting point of 225-231 °C.

STABILITY AND STORAGE RECOMMENDATIONS

ALPRAZOLAM should be stored in tight, light-resistant containers at controlled room temperature (15°C to 30°C).

AVAILABILITY OF DOSAGE FORMS

ALPRAZOLAM (alprazolam) is available in:

0.25 mg, White colored, oval shape biconvex tablet one side debossed by ‘N’ on the left side and by ‘A’ on the right side of score line and other side debossed with ‘0.25’,

0.5 mg, Orange colored, oval shape biconvex tablet one side debossed by ‘N’ on the left side and by ‘A’ on the right side of score line and other side debossed with ‘0.5’,

1 mg, Blue colored, oval shape biconvex tablet one side debossed by ‘N’ on the left side

and by ‘A’ on the right side of score line and other side debossed with ‘1.0’ and

2 mg, White to off white oblong shaped multi scored debossed ‘2’ on one side and plain on other side.

The 2 mg tablets-scored (3 scores) and can be broken into 4 equal parts of 0.5 mg each.

ALPRAZOLAM 0.25 mg, 0.5 mg and 1 mg tablets are available in bottles of 100, 500 & 1000 tablets.

ALPRAZOLAM 2 mg tablets are available in bottles of 100& 500 tablets.

PHARMACOLOGY The anxiolytic activity of alprazolam was demonstrated in various tests in the mouse, rat, cat and monkey. Although alprazolam appeared qualitatively similar to diazepam, it was about 3 to 5 times more potent on an overall basis. In the mouse, alprazolam prolonged hypoxic survival, reduced rearing in the open-field test, and reduced footshock or isolation induced aggression.

Pentylenetetrazol-induced seizures were antagonized by alprazolam in the mouse, rat and cat.

Alprazolam attenuated conflict behaviour in rats and reduced plasma corticosteroid levels in stressed rats. In the cat and monkey alprazolam produced increased beta activity in the EEG similar to diazepam.

Alprazolam had CNS depressant relaxation activity in all species tested. These effects were observed over a large range of doses giving the compound an extremely flat dose response curve.

Except at near lethal doses, little change was observed in physiological measures such as heart rate, respiratory rate and body temperature.

In mice, alprazolam potentiated the actions of pentobarbital, chlorprothixene, ethanol and γ butyrolactone. Alprazolam promoted sleep in the monkey at doses that caused observable motor incoordination.

As with other benzodiazepines, direct physical dependence was induced when large doses of alprazolam were administered on a continuing basis to rats and mice. Alprazolam had weak but measurable reinforcing properties and showed very poor cross-dependence in phenobarbital-dependent animals.

Alprazolam increased the toxicity of glutethimide, methaqualone, pentobarbital, chlorpromazine, thioridazine, phenytoin and d-amphetamine in the mouse. Attempts to eliminate alprazolam by hemodialysis in nephrectomized dogs were unsuccessful.

Alprazolam readily entered the CNS in mice and rats. Alprazolam had no apparent effect on the cholinergic system. Brain levels of dopamine and serotonin were only slightly elevated in mice treated with alprazolam. When catecholamine synthesis was blocked, dopamine utilization was slowed. Alprazolam decreased the incorporation of tyrosine into brain dopamine and norepinephrine of rats.

Cardiopulmonary studies in the dog showed that supratherapeutic intravenous doses of alprazolam decreased blood pressure by a modest amount but had little effect on other cardiovascular measures. Respiratory function was modestly decreased in these studies.

In rats, large doses of alprazolam and diazepam tended to prolong prothrombin times and lower plasma warfarin levels.

Pharmacokinetics:

When alprazolam was administered orally as a compressed tablet formulation, the average time of peak plasma concentration in several studies ranged from 0.9 to 2.4 hours. Based on urinary 14C excretion after oral alprazolam-14C, the minimal drug absorption was 79%. Over a dosage range of 0.5 mg dose to 2.0 mg, serum alprazolam levels were proportional to dose. Average peak serum levels of alprazolam ranged from 8.0 ng/mL for a 0.5 mg dose to 26.5 ng/mL for a

2.0 mg dose. Average elimination half-life values in several studies ranged from 9.5 to 15.0 hr., based on serum levels fit to a one-compartment model. Protein binding studies with human serum, at 37°C showed that over a concentration range of 30 to 1000 ng/mL, alprazolam binding was independent of concentration and amounted to 80%; alprazolam was 68% bound to human serum albumin.

Alprazolam serum levels increased after daily three times a day dosing and reached steady-state

levels within 7 days.

Drug-related materials were excreted predominantly in the urine. After a 2.0 mg dose of alprazolam-14C, average recoveries of 14C in urine and feces were 79% and 7%, respectively.

Average renal clearance of alprazolam was 371 mL/hr compared to a normal glomerular filtration rate of 7500 mL/hr. Renal excretion apparently involves glomerular filtration with extensive reabsorption.

Alprazolam was extensively metabolized and evidence was obtained for 29 metabolites in urine.

Three pathways of metabolism have been identified: (1) oxidation of the 1-methyl group to yield the major metabolite, α-hydroxyalprazolam, followed by further oxidation and decarboxylation to yield 1-demethylalprazolam, (2) oxidation of the C-4 methylene to yield 4-

hydroxyalprazolam, and (3) cleavage of the 5,6 azomethine bond with subsequent oxidation to yield a 3-hydroxymethy1-5- methyl-triazolyl-substituted benzophenone. These metabolites of alprazolam are present in only very low levels in the plasma, thus precluding rigorous pharmacokinetic treatment of the data. However, their excretion half-lives are likely to be similar to that of alprazolam.

Tissue distribution of alprazolam-14C was studied in mice by whole body-slice autoradiography after 2.2 mg/kg oral and intravenous doses. Drug-related material penetrated the central nervous system rapidly and was widely distributed in other tissues without long-term retention. In pregnant mice, low levels of drug-related materials were observed in the fetus.

Following a 0.3 mg/kg oral dose of alprazolam-14C in lactating rats, average drug equivalent levels of 17 and 18 ng/mL were found in milk 6 and 12 hours, respectively, after dosing.

TOXICOLOGY

Acute Toxicity:

In studies in mice, the LD₅₀ of intraperitoneal alprazolam was found to be 500 to 682 mg/kg. In studies in the rat, the oral LD₅₀ and intraperitoneal LD₅₀ ranged from 331 to 2171 mg/kg and 409 to 819 mg/kg, respectively. Signs of toxicity were rapid sleep induction and convulsions.

Subacute and Chronic Toxicity:

Rat:

Alprazolam was administered orally to rats at a dosage of 300 mg/kg/day for 6 days. Depression and ataxia were observed in all treated rats and ulcers were found in 4 of 5 treated female rats.

In two 1-month studies (0,10, 30, 100 and 300 mg/kg/day oral alprazolam), depression and ataxia resulting in decreased food consumption and lower body weights were observed at all dose levels. Stomach ulcers were observed at 100 and 300 mg/kg/day, and at 300 mg/kg/day haemorrhages from the stomach lesions resulted in lower haematocrit and hemoglobin levels and the presence of nucleated red blood cells in blood smears. Multinucleated giant cells in the testicular tubules (2 of 4 males) and degeneration of the testicular tubular cells (4 of 4 males)

were observed at the 300 mg/kg/day dose level.

In two-3 month studies (0, 10, 30 and 100 mg/kg/day oral alprazolam) depression and ataxia were seen at all dose levels. Atrophy of the thymus, stomach ulcers and reduced hemoglobin, haematocrit and red blood cell counts secondary to haemorrhages from these stomach lesions, were observed in the 100 mg/kg/day group. In one study, testicular atrophy (15 of 15 males) and a reduced number of spermatozoa in the epididymis (11 of 15 males) were observed at the 100 mg/kg/day dose. In the other study, atrophy of a few testicular tubules (1 of 2 males) and multinucleated giant cells in the tubules (2 of 2 males) were observed at this dose.

In a 2-year study (0, 3, 10 and 30 mg/kg/day oral alprazolam), treatment was associated with dose and time-related convulsions at 10 and 30 mg/kg/day. A significantly shorter survival period for males and females at 30 mg/kg/day for males at 10 mg/kg/day was observed. Atrophy of the testes and decreased mature spermatozoa in the epididymis were seen in 18 of 44 males at the 30 mg/kg/day dose level. There was a significant positive dose trend of telangiectasis in females. Telangiectasis appeared grossly as sporadic red spots, about 1 mm in diameter.

Histologically, the hepatic sinusoids were dilated and filled with blood. . A tendency for a dose related increase in the number of cataracts (females) and corneal vascularisation (males) was observed. These lesions did not appear until after 11 months of treatment.

Dog:

Dogs were administered alprazolam orally for 10 days at dose levels of 10 to 300 mg/kg/day.

Sedation and ataxia were seen at all dose levels and cholesterol, glucose, alkaline phosphatase and SGPT were slightly elevated.

In a three-month study, alprazolam was administered orally to dogs at dosage levels of 0, 1, 10 and 100 mg/kg/day. Incoordination and ataxia were seen at the 10 and 100 mg/kg/day dose.

In the high dose group (100 mg/kg/day) alkaline phosphatase was elevated, red blood cell count, haematocrit and hemoglobin were reduced and an increased number of foci in the liver containing degenerate hepatocytes with neutrophils and lymphocytes were observed.

Convulsions occurred in 2 of 4 dogs at this dose level.

In a twelve-month study, dogs were administered alprazolam orally at doses of 0, 0.3, 1.0, 3, 10 and 30 mg/kg/day. A slight to moderate impairment of coordination was noted in dogs treated with 3, 10 and 30 mg/kg/day. Convulsions occurred in all dogs at the 10 and 30 mg/kg/day dose level and in 4 of 6 dogs at the 3 mg/kg/day dose level. At the end of the treatment, the dogs were put on a 5-day withdrawal to evaluate drug dependence liability. Some inappetence and weight loss were encountered following drug withdrawal. Body temperature had dose-related increases.

All of the 10 and 30 mg/kg/day dogs that were alive during the withdrawal period convulsed, while only 1 of 5 dogs receiving 3 mg/kg/day convulsed.

REPRODUCTIVE AND TERATOLOGIC STUDIES:

Alprazolam was given by gastric intubation to pregnant rats on gestation days 6 through 15 at 5,

10, 30 and 100 mg/kg/day. All fetuses at 100 mg/kg/day were resorbed. There was a dose-related incidence of resorptions and a decrease in pup weights. The incidence of missing metacarpals at the 10 and 30 mg/kg/day doses and agenesis of sternebrae at the 5 and 10 mg/kg/day doses were significantly increased. However, there was no evidence of skeletal immaturity and all bones were present in two week old pups from dams that were allowed to deliver and nurse the offspring for that period. Cardiovascular abnormalities were observed in 4 of the 35 animals in one study at 30 mg/kg/day. These were not observed in two other studies at the same dose.

Alprazolam was administered at 2 and 5 mg/kg/day in the diet of female rats for 14 days prior to mating and throughout the subsequent pregnancy and for 21 days post-parturition. A slight increase in the average number of resorptions per litter was noted at the 5 mg/kg/day level and a slight increase in the average number of dead pups per litter was observed at both dose levels.

Pup weights at birth were lower and postnatal survival was slightly decreased at the 5 mg/kg/day dose. Treatment of male rats at 2 and 5 mg/kg/day for 60 days prior to mating resulted in a decrease in the percentage of dams conceiving at the 5 mg/kg/day dose.

Pregnant rabbits were administered alprazolam by gastric intubation at 10 and 30 mg/kg/day on gestation days 6 through 18. The 30 mg/kg/day level resulted in the death of 6 of 27 rabbits. The majority of fetuses were resorbed and those which survived had a lower birth weight. A dose-related increase in the number of animals with extra ribs was observed. A low incidence of rib malformations and fused vertebrae and sternebrae were noted in treated animals. The majority of the fetuses at the 30 mg/kg/day level had no ossification centers for the phalanges of the first digit on the forepaw and/or missing metacarpals on the same digit. Short tails and the reduction in the number of caudal vertebrae were observed at both dose levels. Five of 21 fetuses at the 30 mg/kg/day level had asymmetrical caudal vertebrae.

Pregnant rabbits were administered alprazolam by gastric intubation at 2 and 5 mg/kg/day on gestation days 6 through 18. An increase in the incidence rates of extra ribs was observed at the 5 mg/kg/day dose and first metacarpal agenesis and first proximal phalanx agenesis on the forelimb was observed at both dose levels. Fused ribs and vertebrae were noted at the 2 mg/kg/day level and vertebrae fusion and malposition were noted at the 5 mg/kg/day level.

Pregnant rabbits were administered alprazolam by gastric intubation at 2 and 5 mg/kg/day on gestation days 6 through 18. In this study, the does were allowed to kindle and nurse the pups for

4 days. There were no consistent drug or dose-related anomalies observed in the gross visceral and skeletal examination.

REFERENCES

1. 1. Abernethy DR, Greenblatt DJ, Divoll M, et al. The influence of obesity on the pharmacokinetics of oral alprazolam and triazolam. Clin Pharmacokinet 1984;9:177-83.
2. 2. Abernathy DR, Greenblatt DJ, Morse DS, Shader RI. Interaction of propoxyphene with diazepam, alprazolam and lorazepam. Br J Clin Pharmac 1985;19:51-7.
3. 3.

   Aden GC, Thein SG. Alprazolam compared to diazepam and placebo in the treatment of anxiety. J

   Clin Psychiatry 1980;41:245-8.

4. 4. Arana GW, Epstein S, Molloy M, Greenblatt DJ. Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. J Clin Psychiatry 1988;49:11
5. 5.

   Andersch S, Rosenberg NK, Kullingsjo H, et al. Efficacy and safety of alprazolam, imipramine and placebo in treating panic disorder. A Scandinavian multicenter study. Acta Psychiat Scand 1991;Suppl

   365:18-27.

6. 6. Backman JT, Olkkola KT, Aranko K, Himberg J, Neuvonen PJ. Dose of midazolam should be reduced during diltiazem and verapamil treatments. Br J Clin Pharmac 1994;37:221-5
7. 7.

   Baldesssarini RJ. Drugs and the treatment of psychiatric disorders: psychosis and anxiety. In Goodman and Gilman’s The Pharmacologic Basis of Therapeutics, 9th edition. Hardman JG, Gilman AG,

   Limbird LE eds. McGraw-Hill, New York, 1995.

8. 8.

   Ballenger JC. Efficacy of benzodiazepines in panic disorder and agoraphobia. J Psychiatry Res

   1990;24(Suppl 2):15-25.

9. 9. Ballenger JC, Burrows GD, DuPont RL, et al. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. I. Efficacy in short-term treatment. Arch Gen Psychiatry 1988;45:413-22.
10. 10. Bayer M et al. Treatment of Benzodiazepine overdose with flumazenil – The Flumazenil in benzodiazepine intoxication multicenter study group. Clin Ther 1992; 14:978-995.
11. 11. Dehlin O, Kullingsjo H, Liden A. Pharmacokinetics of alprazolam in geriatric patients with neurotic depression. Pharmacol Toxicol 1991;68:121-4.
12. 12.

    DuPont RL. Thinking about stopping treatment for panic disorder. J Clin Psychiatry 1990;51(Suppl

    A):38-45.

13. 13. Fabre LF, McLendon DM. A double blind study comparing the efficacy and safety of alprazolam with diazepam and placebo in anxious out-patients. Curr Ther Res 1979;25:519-26.
14. 14.

    Fawcett JA, Kravitz HM. Alprazolam: pharmacokinetics, clinical efficacy, and mechanism of action.

    Pharmacotherapy 1982;2:243-54.

15. 15. Fleishaker JC, Hulst LK. A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine. Eur J Clin Pharmacol 1994;46:35-9.
16. 16.

    Greenblatt DJ, Divoll M, Abernethy DR, et al. Alprazolam kinetics in the elderly. Arch Gen

    Psychiatry 1983;40:287-90.

17. 17. Greenblatt DJ, Preskorn SH, Cotreau MM, Horst WD, Harmatz JS. Fluoxetine impairs clearance of alprazolam but not of clonazepam. Clin Pharmacol Ther 1992;52:479-86.
18. 18.

    Greenblatt DJ, von Moltke LL, Harmatz JS, Durol ALB et al. Alprazolam-ritonavir interaction:

    Implication for product labelling. Clin Pharm & Ther 2000; 67:335-341.

19. 19.

    Greenblat DJ et. Al. Extensive Impairment of Triazolam and alprazolam clearance by short-term low dose ritonavir: The clinical dilemma of concurrent inhibition and induction. J Clin Psychopharm 1999;

    19:293-296.

20. 20.

    Hobbs WR, Rall TW, Verdoorn TA. Hypnotics and Sedatives; ethanol. In Goodman and Gilman’s The

    Pharmacologic Basis of Therapeutics, 9th edition. Hardman JG, Gilman AG, Limbird LE eds.

    McGraw-Hill, New York, 1995.

21. 21.

    Itil TM. Discrimination between some hypnotic and anxiolytic drugs by computer-analyzed sleep. In:

    Williams RL, Karacan I. eds. Pharmacology of sleep. New York: John Wiley and Sons, 1976:225-38

22. 22.

    Itil TM, Polvan N, Egilmez S, et al. Anxiolytic effects of a new triazolobenzodiazepine, U-31,889.

    Curr Ther Res 1973;15:603-15.

23. 23.

    Itil TM, Saletu B, Marasa J, Mucciardi AN. Digital computer analyzed awake and sleep EEG (sleep prints) in predicting the effects of a triazolobenzodiazepine (U-31,889).

    Pharmakopsychiatrie Neuropsychopharmakol 1972;5:225-40.

24. 24.

    Juhl RP, Van Thiel DH, Dittert LW. Alprazolam pharmacokinetics in alcoholic liver disease. J Clin

    Pharmacol 1984;24:113-19.

25. 25. Kroboth PD, McAuley JW, Smith RB. Alprazolam in the Elderly; Pharmacokinetics and pharmacodynamics during multiple dosing. Psychopharmacology 1990;100:477-84.
26. 26. Lydiard RB, Lesser IM, Ballenger JC, et al. A fixed-dose study of Y alprazolam 2 mg, alprazolam 6 mg, and placebo in panic disorder. J Clin Psychopharmacol 1992;12:96-103.
27. 27.

    Maletzky BM. Anxiolytic efficacy of alprazolam compared to diazepam and placebo. J Int Med Res

    1980;8:139-43.

28. 28.

    McElhatton PR. The effects of benzodiazepine use during pregnancy and lactation. Repro Tox Review

    1994; 8:461-475.

29. 29. Noyes R, DuPont RL, Pecknold JC, et al. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. II. Patient acceptance, side effects and safety. Arch Gen Psychiatry 1988;45:423-8.
30. 30. Noyes, R, Garvey MJ, Cook B, et al. Controlled discontinuation of benzodiazepine treatment for patients with panic disorder. Am J Psychiatry 1991;148:517-23.
31. 31.

    Oo CY, Kuhn RJ, Desai N, Wright CE and McNamara PJ. Pharmacokinetics in lactating women:

    prediction of alprazolam transfer into milk. Br J Clin Pharm 1995;40:231-236.

32. 32. Patrias JM, DiPiro JT, Cheung RPF, Townsend RJ. Effect of alprazolam on phenytoin pharmacokinetics. Drug Intell Clin Pharm 1987;21:2A32
33. 33.

    Pecknold JC, Swinson RP, Kuch K, Lewis CP. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. III. Discontinuation effects. Arch Gen Psychiatry 1988;45:429-

    36.

34. 34. Pecknold JC, Swinson RP. Taper withdrawal studies with alprazolam in patients with panic disorder and agoraphobia. Psychopharmacol Bull 1986;22:173-6.
35. 35. Phillips JP, Antal EJ, Smith RB. A pharmacokinetic drug interaction between erythromycin and triazolam. J Clin Psychopharmacol 1986;6:297-99.
36. 36. Pourbaix S, Desager JP, Hulhoven R, Smith RB, Harvengt C. Pharmacokinetic consequences of long term coadministration of cimetidine and triazolobenzodiazepines, alprazolam and triazolam, in healthy subjects. Int J Clin Pharmacol Ther Toxicol 1985;23:447-51.
37. 37.

    Rudzik AD, Hester JB, Tang AH, et al. Triazolobenzodiazepines, a new class of central nervous system-depressant compounds. In: Garattini S, Mussini E, Randall LO, eds. The Benzodiazepines.

    New York: Raven Press, 1973:284-97.

38. 38.

    Schmith VD, Piraino B, Smith RB Kroboth PD. Alprazolam in end-stage renal disease: I.

    Pharmacokinetics. J Clin Pharmacol 1991;31:571-79.

39. 39. Shioiri T, Kita N and Takahashi S. Two cases of alprazolam-induced hyperprolactinemia in patients with panic disorder. Int Clin Psychopharm 1996; 11:149-152.
40. 40. Stoehr GP, Kroboth PD, Juhl RP, et al. Effect of oral contraceptives on triazolam, temazepan, alprazolam and lorazepan kinetics. Clin Pharmacol Ther 1984;36:683-90.
41. 41. Varhe A, Olkkola KT, Neuvonen PJ. Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994;56:601-7.
42. 42. Von Moltke LL, Greenblatt DJ, et al. Inhibitors of alprazolam metabolism in vitro: effect of serotonin-reuptake-inhibitor antidepressants, ketoconazole and quinidine. Br J Clin Pharmac 1994;38:23-31.
43. 43.

    Warner MD, Peabody DA, Boutros NN, et al. Alprazolam and withdrawal seizures. J Nerv Ment Dis

    1990;178:208-9.

44. 44. Warot D, Bergougnan L, Lamiable D, et al. Troleandomycin-triazolam interaction in healthy volunteers: pharmacokinetic and psychometric evaluation. Eur J Clin Pharmacol 1987;32:389-93.
45. 45.

    Zemishlany Z, McQueeney R, Gabriel SM, Davidson M. Neuroendocrine and monoaminergic responses to acute administration of alprozolam in normal subjects. Neuropsychobiology 1990;

    23:124-128.

46. 46.

    Product Monograph of Xanax and Xanax TS, Submission Control No.168534, Date of Revision:

    November 27, 2013.