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XANAX (alprazolam tablets USP)

Health Professional Information

SUMMARY PRODUCT INFORMATION

Route of Administration

Dosage Form / Strength

Clinically Relevant Nonmedicinal Ingredients

oral

tablet 0.25 mg, 0.5 mg and 1.0 mg

colloidal silicon dioxide, corn starch, docusate sodium-sodium benzoate, lactose monohydrate, magnesium stearate

0.5 mg tablet: also contains yellow aluminum lake

1 mg tablet: also contains blue aluminum lake and erythrosine aluminum lake

For a complete listing see Dosage Forms, Composition and Packaging section.

oral

triscored tablet 2 mg

colloidal silicon dioxide, corn starch, docusate sodium-sodium benzoate, lactose monohydrate, magnesium stearate

For a complete listing see Dosage Forms, Composition and Packaging section.

Indications And Clinical Use

Adults:

XANAX and XANAX TS (alprazolam) are 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
XANAX and XANAX TS are 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
XANAX and XANAX TS are 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 symptom:  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 XANAX and XANAX TS are recommended (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics; WARNINGS AND PRECAUTIONS, Special Populations - Geriatrics; and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Anxiety Disorders - Elderly and Debilitated Patients).

Pediatrics (< 18 years of age):

XANAX and XANAX TS are not recommended for use in patients under the age of 18 years (see WARNINGS AND PRECAUTIONS, Special Populations - Pediatrics).

Contraindications

XANAX and XANAX TS (alprazolam) are contraindicated in patients with known hypersensitivity to alprazolam or to any component of the product’s formulation, or other benzodiazepines. XANAX and XANAX TS are also contraindicated in patients with myasthenia gravis, severe hepatic insufficiency, severe respiratory insufficiency, sleep apnea syndrome, or acute narrow angle glaucoma. However, XANAX and XANAX TS may be used in patients with open angle glaucoma who are receiving appropriate treatment.

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

Warnings And Precautions

RISKS FROM CONCOMITANT USE WITH OPIOIDS

Concomitant use of XANAX and XANAX TS and opioids may result in profound sedation, respiratory depression, coma, and death (see WARNINGS AND PRECAUTIONS-Risks from concomitant use of opioids and benzodiazepines).

  • Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
  • Limit dosages and durations to the minimum required.
  • Follow patients for signs and symptoms of respiratory depression and sedation.

General

XANAX and XANAX TS (alprazolam) are not effective in patients with Personality Disorders. XANAX and XANAX TS are not recommended for the management of Mood or Psychotic Disorders.

Risks from concomitant use of opioids and benzodiazepines:

Concomitant use of benzodiazepines, including XANAX and XANAX TS, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.
If a decision is made to prescribe XANAX and XANAX TS concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of XANAX and XANAX TS than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking XANAX and XANAX TS, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation (see DRUG INTERACTIONS).
Advise both patients and caregivers about the risks of respiratory depression and sedation when XANAX and XANAX TS is used with opioids.
Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the opioid have been determined.

Dependence/Tolerance

Dependence Liability: Physical and psychological dependence may occur with benzodiazepines, including XANAX and XANAX TS. Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to 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 XANAX or XANAX TS. Patients with a history of alcohol or drug abuse are at higher risk for developing psychological dependence. Drug abuse is a known risk for alprazolam and other benzodiazepines, and patients should be monitored accordingly when receiving alprazolam. Alprazolam may be subject to diversion. There have been reports of overdose-related deaths when alprazolam is abused with other central nervous system (CNS) depressants including opioids, other benzodiazepines, and alcohol. These risks should be considered when prescribing or dispensing alprazolam. To reduce these risks the smallest appropriate quantity should be used and patients should be advised on the proper storage and disposal of unused drug.

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, Recommended Dose and Dosage Adjustment - Discontinuation). Even after relatively short-term use (eg, for several weeks) 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, as withdrawal symptoms, including seizures, have been reported. 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).

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.

Abrupt Discontinuations to be Avoided, Even With Short Duration of Treatment

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.

To discontinue treatment in patients taking XANAX and XANAX TS, the dosage should be reduced slowly in keeping with good medical practice. (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment - Discontinuation).

Risk of Withdrawal with 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 a hospital, etc.). Therefore, the dosage of XANAX should be reduced or discontinued gradually (See DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment - Discontinuation).

Status Epilepticus and its Treatment: The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of XANAX. In most cases, only a single seizure was reported; however, multiple seizures and status epilepticus were reported as well. 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.

Withdrawal and Rebound in Treating Panic Disorder: Because the management of Panic Disorder often requires the use of average daily doses of XANAX 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 XANAX compared to placebo-treated patients.

Relapse or return of illness was defined as a return of symptoms characteristic of Panic Disorder (primarily panic attacks) to levels approximately equal to those seen at baseline before active treatment was initiated. Rebound refers to a return of symptoms of Panic Disorder to a level substantially greater in frequency, or more severe in intensity, than seen at baseline. Withdrawal symptoms were identified as those which were generally not characteristic of Panic Disorder and which occurred for the first time more frequently during discontinuation than at baseline.

In a controlled clinical trial in which 63 patients were randomized to XANAX and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound or withdrawal.

In a larger database comprised of both controlled and uncontrolled studies in which 641 patients received XANAX, discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with XANAX and at a greater rate than the placebo-treated group were as follows:

 

Discontinuation-emergent symptom

Incidence

Body

System

Event

Percentage of XANAX-treated patients reporting event

N = 641

Neurologic

Insomnia

29.5

Lightheadedness

19.3

Abnormal involuntary movement

17.3

Headache

17.0

Muscular twitching

6.9

Impaired coordination

6.6

Muscle tone disorders

5.9

Weakness

5.8

Psychiatric

Anxiety

19.2

Fatigue and tiredness

18.4

Irritability

10.5

Cognitive disorder

10.3

Memory impairment

5.5

Depression

5.1

Confusional state

5.0

Gastrointestinal

Nausea/vomiting

16.5

Diarrhea

13.6

Decreased salivation

10.6

Metabolic-Nutritional

Weight Loss

13.3

Decreased apetite

12.8

Dermatological

Sweating

14.4

Cardiovascular

Tachycardia

12.2

Special Senses

Blurred vision

10.0

From the studies cited, it has not been determined whether these symptoms are clearly related to the dose and duration of therapy with XANAX 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 XANAX tapered completely off therapy compared to 89%-96% of placebo treated patients. The ability of patients to completely discontinue therapy with XANAX after long-term therapy has not been reliably determined.

Seizures attributable to XANAX were seen after drug discontinuance or dose reduction in 8 of 1980 patients with Panic Disorder or in patients participating in clinical trials where doses of XANAX greater than 4 mg 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 XANAX. The risk of seizure seems to be greatest 24‑72 hours after discontinuation. (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment - Discontinuation; ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).

Treating Interdose Symptoms in Panic Disorder

Interdose Symptoms: Early morning anxiety and emergence of anxiety symptoms between doses of XANAX have been reported in patients with Panic Disorder taking prescribed maintenance doses of XANAX. These symptoms may reflect the development of tolerance or a time interval between doses which is longer than the duration of clinical action of the administered dose. In either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels above those needed to prevent relapse, rebound or withdrawal symptoms over the entire course of the 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).

Psychiatric

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 XANAX and XANAX TS in treating patients with panic-related disorders. Prescriptions for XANAX and XANAX TS should be written for the smallest quantity of drug consistent with good patient management.

Mania: Episodes of hypomania and mania have been reported in association with the use of XANAX 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.

Hepatic

Hepatic Impairment: If treatment is necessary in patients with impaired hepatic 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 DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY).

Renal

Renal Impairment: If treatment is necessary in patients with 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 and DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY).

Special Populations

Pregnant Women: XANAX and XANAX TS are not recommended for use during pregnancy.

Teratogenic Effects: Benzodiazepines can potentially cause fetal harm when administered to pregnant women. 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,the administration of XANAX or XANAX TS 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. (see TOXICOLOGY)

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.

XANAX and XANAX TS have no established use in labour or delivery.

Nursing Women: 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 XANAX or XANAX TS.

Pediatrics (< 18 years of age): The safety and efficacy of XANAX and XANAX TS in patients under the age of 18 years have not been established. XANAX and XANAX TS are not recommended for use in patients under the age of 18 years. (see TOXICOLOGY)

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 DOSAGE AND ADMINISTRATION, Special Populations - Geriatrics and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Use in Patients with Concomitant Illness

It is recommended that the dosage be limited to the smallest effective dose to preclude the development of ataxia or oversedation which may be a particular problem in elderly or debilitated patients (see DOSAGE AND ADMINISTRATION). The usual precautions in treating patients with impaired renal, hepatic, or pulmonary function should be observed. There have been rare reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with XANAX Tablets. A decreased systemic alprazolam elimination rate (eg, increased plasma half-life) has been observed in both alcoholic liver disease patients and obese patients receiving XANAX Tablets (see CLINICAL PHARMACOLOGY).

Monitoring and Laboratory Tests

If XANAX or XANAX TS is administered for repeated cycles of therapy, periodic blood counts and liver function tests are advisable.

Information for Patients

To assure safe and effective use of XANAX and XANAX TS, the physician should provide the patient with the following guidance.

  1. Inform your physician about any alcohol consumption and medicine you are taking now, including medication you may buy without a prescription. Alcohol should generally not be used during treatment with benzodiazepines.
  2. Not recommended for use in pregnancy. Therefore, inform your physician if you are pregnant, if you are planning to have a child, or if you become pregnant while you are taking this medication.
  3. Inform your physician if you are nursing.
  4. Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery, etc.
  5. Do not increase the dose even if you think the medication "does not work anymore" without consulting your physician. Benzodiazepines, even when used as recommended, may produce emotional and/or physical dependence.
  6. Do not stop taking this medication abruptly or decrease the dose without consulting your physician, since withdrawal symptoms can occur.
  7. Some patients may find it very difficult to discontinue treatment with XANAX or XANAX TS due to severe emotional and physical dependence. Discontinuation symptoms, including possible seizures, may occur following discontinuation from any dose, but the risk may be increased with extended use at doses greater than 4 mg/day, especially if discontinuation is too abrupt. It is important that you seek advice from your physician to discontinue treatment in a careful and safe manner. Proper discontinuation will help to decrease the possibility of withdrawal reactions that can range from mild reactions to severe reactions such as seizure.

Adverse Reactions

Adverse Drug Reaction Overview

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

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

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

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

  • For the Anxiety Disorders Table: relatively short duration (i.e., four weeks) placebo-controlled clinical studies with dosages up to 4 mg/day of XANAX (for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety)
  • For the Panic Disorders Table: short-term (up to ten weeks) placebo-controlled clinical studies with dosages up to 10 mg/day of XANAX in patients with panic disorder, with or without agoraphobia.
ANXIETY DISORDERS

Treatment-emergent

symptom incidence

% of patients

reporting

Body System

Event

XANAX

N=565

Placebo

N=505

Central Nervous System

Drowsiness

41.0

21.6

Lightheadedness

20.8

19.3

Depression

13.9

18.1

Headache

12.9

19.6

Confusion

9.9

10.0

Insomnia

8.9

18.4

Nervousness

4.1

10.3

Syncope

3.1

4.0

Dizziness

1.8

0.8

Akathisia

1.6

1.2

Gastrointestinal

Dry mouth

14.7

13.3

Constipation

10.4

11.4

Diarrhea

10.1

10.3

Nausea/vomiting

9.6

12.8

Increased salivation

4.2

2.4

Cardiovascular

Tachycardia/

Palpitations

7.7

15.6

Hypotension

4.7

2.2

Sensory

Blurred vision

6.2

6.2

Musculoskeletal

Rigidity

4.2

5.3

Tremor

4.0

8.8

Cutaneous

Dermatitis/allergy

3.8

3.1

Other

Nasal congestion

7.3

9.3

Weight gain

2.7

2.7

Weight loss

2.3

3.0


PANIC DISORDERS

Treatment-emergent

symptom incidence

% of patients

reporting

Body System

Event

XANAX

N=1388

Placebo

N=1231

Central Nervous System

Drowsiness

76.8

42.7

Fatigue & Tiredness

48.6

42.3

Impaired Coordination

40.1

17.9

Irritability

33.1

30.1

Memory Impairment

33.1

22.1

Lightheadedness/Dizziness

29.8

36.9

Insomnia

29.4

41.8

Headache

29.2

35.6

Cognitive Disorder

28.8

20.5

Dysarthria

23.3

6.3

Anxiety

16.6

24.9

Abnormal Involuntary Movement

14.8

21.0

Decreased Libido

14.4

8.0

Depression

13.8

14.0

Confusional State

10.4

8.2

Muscular Twitching

7.9

11.8

Increased Libido

7.7

4.1

Change in Libido (Not Specified)

7.1

5.6

Weakness

7.1

8.4

Muscle Tone Disorders

6.3

7.5

Syncope

3.8

4.8

Akathisia

3.0

4.3

Agitation

2.9

2.6

Disinhibition

2.7

1.5

Paresthesia

2.4

3.2

Talkativeness

2.2

1.0

Vasomotor Disturbances

2.0

2.6

Derealization

1.9

1.2

Dream Abnormalities

1.8

1.5

Fear

1.4

1.0

Feeling Warm

1.3

0.5

Gastrointestinal

Decreased Salivation

32.8

34.2

Constipation

26.2

15.4

Nausea/vomiting

22.0

31.8

Diarrhea

20.6

22.8

Abdominal Distress

18.3

21.5

Increased Salivation

5.6

4.4

Cardio-Respiratory

Nasal Congestion

17.4

16.5

Tachycardia

15.4

26.8

Chest Pain

10.6

18.1

Hyperventilation

9.7

14.5

Upper Respiratory Infection

4.3

3.7

Sensory

Blurred vision

21.0

21.4

Tinnitus

6.6

10.4

Musculoskeletal

Muscular Cramps

2.4

2.4

Muscle Stiffness

2.2

3.3

Cutaneous

Sweating

15.1

23.5

Rash

10.8

8.1

Other

Increased Appetite

32.7

22.8

Decreased Appetite

27.8

24.1

Weight Gain

27.2

17.9

Weight Loss

22.6

16.5

Micturition Difficulties

12.2

8.6

Menstrual Disorders

10.4

8.7

Sexual Dysfunction

7.4

3.7

Edema

4.9

5.6

Incontinence

1.5

0.6

Infection

1.3

1.7

Less Common Clinical Trial Adverse Drug Reactions (<1%)

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 hepatic function, elevated hepatic enzymes, elevated bilirubin, jaundice, pruritus, diplopia and hyperprolactinemia. Increased intraocular pressure has been rarely reported.

Post-Market Adverse Drug Reactions

Various adverse events have been reported in association with the use of XANAX 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 XANAX cannot be readily determined. Events include: drug abuse, drug dependence, drug withdrawal syndrome, 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.

In some of the spontaneous case reports of adverse behavioural 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 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.

Withdrawal seizures have been reported for patients taking XANAX alone.

Drug Interactions

Drug-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 XANAX or XANAX TS (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 XANAX or XANAX TS.

Opioids

Due to additive CNS depressant effect, the concomitant use of benzodiazepines, including XANAX and XANAX TS, and opioids increases the risk of profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations of concomitant use of benzodiazepines and opioids to the minimum required. Follow patients closely for respiratory depression and sedation (see WARNINGS AND PRECAUTIONS -Risks from concomitant use of opioids and benzodiazepines).

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

If XANAX is co-administered with nefazodone, a reduction in the XANAX 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 XANAX 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 of age). Patients who receive alprazolam and digoxin should therefore be monitored for signs and symptoms related to digoxin toxicity.

Drug-Food Interactions

Alcohol should not be ingested during treatment with XANAX or XANAX TS (see also CNS‑Acting Drugs, above)

Drug-Lifestyle Interactions

Driving and Hazardous Activities: Because of its central nervous system depressant effect, patients receiving XANAX or XANAX TS 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 XANAX or XANAX TS.

Alcohol and other CNS-depressant drugs: Alcohol or central nervous system depressant drugs should not be ingested during treatment with XANAX or XANAX TS.

Dosage And Administration

Dosing Considerations

Dosage should be individualized for maximal benefit. The risk of dependence may increase with dose and duration of treatment, therefore, the lowest possible effective dose and duration should be used and the need for continued treatment reassessed frequently. 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.

Both XANAX and XANAX TS are immediate-release formulations. XANAX TS is scored in three places (“tri-scored”) and can be broken into 4 equal parts of 0.5 mg each.

Recommended Dose and Dosage Adjustment

Anxiety Disorders

Adults:
The initial adult dosage of XANAX (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, especially 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 Impairment: 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, presumed to reflect insufficient plasma levels, may be lessened by using the same dose, but a schedule that provides for administration 3 or 4 times per day.

In controlled trials conducted to establish the efficacy of XANAX 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 XANAX 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.

Because the management of Panic Disorder often requires the use of average daily doses of XANAX above 3 mg, the risk of rebound and withdrawal symptoms may be higher than in patients treated for anxiety. (See also WARNINGS AND PRECAUTIONS, Withdrawal and Rebound in Treating Panic Disorder)

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 XANAX and XANAX TS, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of XANAX or XANAX TS 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. The ability of patients to completely discontinue therapy with XANAX after long-term therapy has not been reliably determined. (see also WARNINGS AND PRECAUTIONS, Dependence/Tolerance)

Overdosage

Symptoms

Overdose of XANAX or XANAX TS  (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.

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

Action And Clinical Pharmacology

Mechanism of Action

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 / 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 αhydroxy-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.

Special Populations and Conditions

The table below 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
 

Alprazolam pharmacokinetics in special patient populations following the administration of single oral doses.

Values are means with the ranges in parentheses.

Patient Population

Parameter

Adults

Elderly

Obese

Alcoholic

Liver Disease

End Stage Renal Disease

Hemodialysis

CAPDa

No.

16

16

12

17

7

5

Dose (mg)

1.0

1.0

1.0

1.0

0.5

0.5

Cmax (ng/ml)

17.9

(8.5-29.5)

22.9

(12.4-36.3)

not

reported

17.3

(8.6-26.0)

8.1

(5.9-14.4)

8.6

(6.8-10.5)

Tmax (hr)

1.6

(0.25-6.0)

0.9

(0.5-2.0)

not

reported

3.3

(0.5-8.0)

1.1

(0.5-2.0)

3.0

(0.5-6.0)

C1 (ml/min/kg)

1.33

(0.90-2.23)

0.86

(0.40-1.84)

0.59

(not available)

0.56

(0.17-1.46)

not reported

not reported

t½ (hr)

11.0

(6.3-15.8)

16.3

(9.0-26.9)

21.8

(9.9-40.5)

19.7

(5.8-65.3)

11.2

(7.1-19.1)

19.2

(8.8-33.8)

Unbound fraction in plasma (%)

29.0

(25.0-32.8)

29.8

(25.0-35.4)

30.3

(26.4-35.4)

23.2

(16.9-32.8)

27.6

(22.7-30.7)

30.9

(28.0-34.2)

Storage And Stability

XANAX and XANAX TS (alprazolam) should be stored at controlled room temperature (15 - 30ºC).

Dosage Forms, Composition And Packaging

XANAX (alprazolam) is available in 0.25 mg (white, single score, embossed with “UPJOHN 29"), 0.5 mg (light orange, single score, embossed with "UPJOHN 55") and 1 mg (lavender, single score, embossed with "UPJOHN 90") tablets in bottles of 100 and 1000.

XANAX TS is available in white 2 mg triscored tablets (3 scores), with the number "U94" on one side and can be broken into 4 equal parts of 0.5 mg each, in bottles of 100 tablets.

 

Each 0.25 mg tablet of XANAX contains 0.25 mg alprazolam and includes the following inactive ingredients: colloidal silicon dioxide, corn starch, docusate sodium-sodium benzoate, lactose monohydrate and magnesium stearate.

Each 0.5 mg tablet of XANAX contains 0.5 mg alprazolam and includes the following inactive ingredients: colloidal silicon dioxide, corn starch, docusate sodium-sodium benzoate, lactose monohydrate, magnesium stearate and yellow aluminum lake.

Each 1 mg tablet of XANAX contains 1 mg alprazolam and includes the following inactive ingredients: blue aluminum lake, colloidal silicon dioxide, corn starch, docusate sodium-sodium benzoate, erythrosine aluminum lake, lactose monohydrate and magnesium stearate.

Each 2 mg tablet of XANAX TS contains 2 mg alprazolam and includes the following inactive ingredients: colloidal silicon dioxide, corn starch, docusate sodium-sodium benzoate, lactose monohydrate and magnesium stearate.

 

Control #: 223422
4 April 2019

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