ALPRAZOLAM- alprazolam  tablet 
Apotex Corp.

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ALPRAZOLAM TABLETS safely and effectively. See full prescribing information for ALPRAZOLAM TABLETS.

ALPRAZOLAM tablets, for oral use, CIV
Initial U.S. Approval: 1981

RECENT MAJOR CHANGES

Boxed Warning 2/2021

Dosage and Administration (2.3) 2/2021

Warnings and Precautions (5.2, 5.3) 2/2021

WARNINGS AND PRECAUTIONS

(1)

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS (1)

See full prescribing information for complete boxed warning. (1)

  • Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing 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. (5.1, 7.1)
  • The use of benzodiazepines, including alprazolam tablets, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing alprazolam tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction. (5.2)
  • Abrupt discontinuation or rapid dosage reduction of alprazolam tablets after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam tablets or reduce the dosage. (2.2, 5.3)

(1)

INDICATIONS AND USAGE

Alprazolam tablets area benzodiazepine indicated for the: (2)

  • Acute treatment of generalized anxiety disorder in adults. (1) (2)

  • Treatment of panic disorder with or without agoraphobia in adults. (1) (2)

DOSAGE AND ADMINISTRATION

  • Generalized Anxiety Disorder: (2.1)
    • Recommended starting oral dosage is 0.25 mg to 0.5 mg three times daily.
    • Dosage may be increased, at intervals of every 3 to 4 days, to a maximum recommended daily dose of 4 mg, given in divided doses.
    • Use the lowest possible effective dose and frequently assess the need for continued treatment.
  • Panic Disorder: Recommended starting oral dosage is 0.5 mg three times daily. The dosage may be increased at intervals of every 3 to 4 days in increments of no more than 1 mg per day. (2.2)
  • When tapering, decrease dosage by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction. (2.3, 5.2)
  • See the Full Prescribing Information for the recommended dosage in geriatric patients, patients with hepatic impairment, and with use with ritonavir. (2.4, 2.5, 2.6)

DOSAGE FORMS AND STRENGTHS

Tablets: 0.25 mg, 0.5 mg, 1 mg, and 2 mg (3) (4)

CONTRAINDICATIONS

  • Known hypersensitivity to alprazolam or other benzodiazepines. (4)
  • Concomitant use with strong cytochrome P450 3A (CYP3A) inhibitors, except ritonavir. (4, 5.5, 7.1)

WARNINGS AND PRECAUTIONS

  • Effects on Driving and Operating Machinery: Patients receiving alprazolam tablets should be cautioned against operating machinery or driving a motor vehicle, as well as avoiding concomitant use of alcohol and other central nervous system (CNS) depressant drugs. (5.4)
  • Neonatal Sedation and Withdrawal Syndrome (NOWS): Use of alprazolam tablets during pregnancy can result in neonatal sedation and neonatal withdrawal syndrome. (5.5, 8.1)
  • Patients with Depression: Exercise caution in patients with signs or symptoms of depression. Prescribe the least number of tablets feasible to avoid intentional overdosage. (5.7)

ADVERSE REACTIONS

The most common adverse reactions reported in clinical trials for generalized anxiety disorder and panic disorder (incidence >5% and at least twice that of placebo) include: impaired coordination, hypotension, dysarthria, and increased libido. (6.1) (7)

To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch (7)

DRUG INTERACTIONS

(8)

  • Use with Opioids: Increase the risk of respiratory depression. (7.1)Use with Other CNS Depressants: Produces additive CNS depressant effects. (7.1)
  • Use with Digoxin: Increase the risk of digoxin toxicity. (7.1)
  • Use with CYP3A Inhibitors (except ritonavir): Increase the risk of adverse reactions of alprazolam. (4, 5.6, 7.1)
  • Use with CYP3A Inducers: Increase the risk of reduced efficacy of alprazolam. (7.1)

USE IN SPECIFIC POPULATIONS

Lactation: Breastfeeding not recommended. (8.2) (9)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 4/2021

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Generalized Anxiety Disorder

2.2 Dosage in Panic Disorder

2.3 Discontinuation or Dosage Reduction of Alprazolam Tablets

2.4 Dosage Recommendations in Geriatric Patients

2.5 Dosage Recommendations in Patients with Hepatic Impairment

2.6 Dosage Modifications for Drug Interactions

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Risks from Concomitant Use with Opioids

5.2 Abuse, Misuse, and Addiction

5.3 Dependence and Withdrawal Reactions

5.4 Effects on Driving and Operating Machinery

5.5 Neonatal Sedation and Withdrawal Syndrome

5.6 Interaction with Drugs that Inhibit Metabolism via Cytochrome P450 3A

5.7 Patients with Depression

5.8 Mania

5.9 Risk in Patients with Impaired Respiratory Function

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Drugs Having Clinically Important Interactions with Alprazolam Tablets

7.2 Drug/Laboratory Test Interactions

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse

9.3 Dependence

10 OVERDOSAGE

10.1 Clinical Experience

10.2 Management of Overdose

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Generalized Anxiety Disorder

14.2 Panic Disorders

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS

  • Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for 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 [see Warnings and Precautions (5.1), Drug Interactions (7.1)].
  • The use of benzodiazepines, including alprazolam tablets, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing alprazolam tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2)].
  • The continued use of benzodiazepines, including alprazolam tablets, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of alprazolam tablets after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam tablets or reduce the dosage [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

1 INDICATIONS AND USAGE

Alprazolam tablets are indicated for the:

  • acute treatment of generalized anxiety disorder (GAD) in adults.
  • treatment of panic disorder (PD), with or without agoraphobia in adults.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Generalized Anxiety Disorder

The recommended starting oral dosage of alprazolam tablets for the acute treatment of patients with GAD is 0.25 mg to 0.5 mg administered three times daily. Depending upon the response, the dosage may be adjusted at intervals of every 3 to 4 days. The maximum recommended dosage is 4 mg daily (in divided doses).  

Use the lowest possible effective dose and frequently assess the need for continued treatment [see Warnings and Precautions (5.2)].

2.2 Dosage in Panic Disorder

The recommended starting oral dosage of alprazolam tablets for the treatment of PD is 0.5 mg three times daily. Depending on the response, the dosage may be increased at intervals of every 3 to 4 days in increments of no more than 1 mg per day.  

Controlled trials of alprazolam tablets in the treatment of panic disorder included dosages in the range of 1 mg to 10 mg daily. The mean dosage was approximately 5 mg to 6 mg daily. Occasional patients required as much as 10 mg per day.  

For patients receiving doses greater than 4 mg per day, periodic reassessment and consideration of dosage reduction is advised. In a controlled postmarketing dose-response study, patients treated with doses of alprazolam tablets greater than 4 mg per day for 3 months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit.  

The necessary duration of treatment for PD in patients responding to alprazolam tablets is unknown. After a period of extended freedom from panic attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena [see Dosage and Administration (2.3)].

2.3 Discontinuation or Dosage Reduction of Alprazolam Tablets

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam tablets or reduce the dosage. If  a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly [see Warnings and Precautions (5.3), Drug Abuse and Dependence (9.3)].  

Reduce the dosage by no more than 0.5 mg every 3 days. Some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.  

In a controlled postmarketing discontinuation study of panic disorder patients which compared the recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome.

2.4 Dosage Recommendations in Geriatric Patients

In geriatric patients, the recommended starting oral dosage of alprazolam tablets is 0.25 mg, given 2 or 3 times daily. This may be gradually increased if needed and tolerated. Geriatric patients may be especially sensitive to the effects of benzodiazepines. If adverse reactions occur at the recommended starting dosage, the dosage may be  reduced [see Use in Specific Populations (8.5), Clinical Pharmacology (12.3)].

2.5 Dosage Recommendations in Patients with Hepatic Impairment

In patients with hepatic impairment, the recommended starting oral dosage of alprazolam tablets is 0.25 mg, given 2 or 3 times daily. This may be gradually increased if needed and tolerated. If adverse reactions occur at the recommended starting dose, the dosage may be reduced [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.6 Dosage Modifications for Drug Interactions

Alprazolam tablets should be reduced to half of the recommended dosage when a patient is started on ritonavir and alprazolam tablets together, or when ritonavir administered to a patient treated with alprazolam tablets. Increase the alprazolam tablets dosage to the target dose after 10 to 14 days of dosing ritonavir and alprazolam tablets together. It is not necessary to  reduce alprazolam tablets dose in patients who have been taking ritonavir for more than 10 to 14 days.  

Alprazolam tablets are contraindicated with concomitant use of all strong CYP3A inhibitors, except ritonavir [see Contraindications (4), Warnings and Precautions (5.5)].

3 DOSAGE FORMS AND STRENGTHS

Alprazolam tablets, USP are available as:

  • 0.25 mg: white, oval shaped, scored tablets, imprinted “ALP” bisect “0.25" on one side and “APO” on the other side.
  • 0.5 mg: peach, oval shaped, scored tablets, imprinted “ALP” bisect “0.5" on one side and “APO” on the other side.
  • 1 mg: light blue, oval shaped, scored tablets, imprinted “ALP” bisect “1" on one side and “APO” on the other side.
  • 2 mg: white, rectangle shaped, scored tablets, imprinted “A” bisect “L” partial bisect “P” bisect “R” on one side and “A” bisect “P” partial bisect “O” bisect “2” on the other side.

4 CONTRAINDICATIONS

Alprazolam tablets are contraindicated in patients:

  • with known hypersensitivity to alprazolam or other benzodiazepines. Angioedema has been reported [see Adverse Reactions (6.2)].
  • taking strong cytochrome P450 3A (CYP3A) inhibitors (e.g., ketoconazole, itraconazole), except ritonavir [see Dosage and Administration (2.6), Warnings and Precautions (5.5), Drug Interactions (7.1)]

5 WARNINGS AND PRECAUTIONS

5.1 Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including alprazolam tablets, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs 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 opioids alone. If a decision is made to prescribe alprazolam tablets concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In  patients already receiving an opioid analgesic, prescribe a lower initial dose of alprazolam tablets than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking alprazolam tablets, prescribe a lower initial dose of the opioid and titrate based upon clinical response.  

Advise both patients and caregivers about the risks of respiratory depression and sedation when alprazolam tablets are used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Drug Interactions (7.1)].

5.2 Abuse, Misuse, and Addiction

The use of benzodiazepines, including alprazolam tablets, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see Drug Abuse and Dependence (9.2)].  

Before prescribing alprazolam tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of alprazolam tablets, particularly in patients at elevated risk,  necessitates counseling about the risks and proper use of alprazolam tablets along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

5.3 Dependence and Withdrawal Reactions

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam tablets or reduce the dosage (a  patient-specific plan should be used to taper the dose) [see Dosage and Administration (2.3)].  

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.  

Acute Withdrawal Reactions

The continued use of benzodiazepines, including alprazolam tablets, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of alprazolam tablets after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) [see Drug Abuse and Dependence (9.3)].  

Protracted Withdrawal Syndrome

In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Drug Abuse and Dependence (9.3)].  

Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to alprazolam tablets. These include a spectrum of withdrawal symptoms; the most important is seizure [see Drug Abuse and Dependence (9.3)]. Even after relatively short-term use at doses of < 4 mg/day, there is some risk of dependence. Spontaneous reporting system data suggest that the risk of dependence and its severity appear to be greater in patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks). However, in a controlled postmarketing discontinuation study of panic disorder patients who received alprazolam tablets, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients  to taper to zero dose.

In contrast, patients treated with doses of alprazolam tablets greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day.   In a controlled clinical trial in which 63 patients were randomized to alprazolam tablets 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.  

Interdose Symptoms

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

5.4 Effects on Driving and Operating Machinery

Because of its CNS depressant effects, patients receiving alprazolam tablets should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the concomitant use of alcohol and other CNS depressant drugs during treatment with alprazolam tablets [see Drug Interactions (7.1)].

5.5 Neonatal Sedation and Withdrawal Syndrome

Use of alprazolam tablets during later stages of pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and  feeding difficulties) in the neonate. Observe newborns for signs of sedation and neonatal withdrawal syndrome and manage accordingly [see Use in Specific Populations (8.1)].

5.6 Interaction with Drugs that Inhibit Metabolism via Cytochrome P450 3A

The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam.  

Strong CYP3A Inhibitors

Alprazolam tablets are contraindicated in patients receiving strong inhibitors of CYP3A (such as azole antifungal agents), except ritonavir [see Contraindications (4)]. Ketoconazole and itraconazole have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively.  

Dosage adjustment is necessary when alprazolam tablets and ritonavir are initiated concomitantly or when ritonavir is added to a stable dosage of alprazolam tablets [see Dosage and Administration (2.6), Drug Interactions (7.1)].  

Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam: nefazodone, fluvoxamine, and cimetidine [see Drug Interaction (7.1), Clinical Pharmacology (12.3)]. Use caution and consider dose reduction of alprazolam tablets, as appropriate, during co-administration with these drugs.  

5.7 Patients with Depression

Benzodiazepines may worsen depression. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered in patients with depression.

5.8 Mania

Episodes of hypomania and mania have been reported in association with the use of alprazolam tablets in patients with depression [see Adverse Reactions (6.2)].

5.9 Risk in Patients with Impaired Respiratory Function

There have been reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam tablets. Closely monitor patients with impaired respiratory function. If signs and symptoms of respiratory depression, hypoventilation, or apnea occur, discontinue alprazolam tablets.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

  • Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)]
  • Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2)]
  • Dependence and Withdrawal Reactions [see Warnings and Precautions (5.3)]
  • Effects on Driving and Operating Machinery [see Warnings and Precautions (5.4)]
  • Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.5)]
  • Patients with Depression [see Warnings and Precautions (5.7)]
  • Risks in Patients with Impaired Respiratory Function [see Warnings and Precautions (5.9)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.  

The data in the two tables below are estimates of adverse reaction incidence among adult patients who participated in:

  • 4-week placebo-controlled clinical studies with alprazolam tablets dosages up to 4 mg per day for the acute treatment of generalized anxiety disorder (Table 1)
  • Short-term (up to 10 weeks) placebo-controlled clinical studies with alprazolam tablets dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2).

Table 1: Adverse Reactions Occurring in ≥1% in Alprazolam Tablets-treated Patients and Greater than Placebo- treated Patients in Placebo-Controlled Trials for Generalized Anxiety

  Alprazolam Tabletsn=565Placebo n=505
Nervous system disorders    
Drowsiness 41% 22%
Light-headedness 21% 19%
Dizziness 2% 1%
Akathisia Gastrointestinal disorders 2% 1%
Dry mouth 15% 13%
Increased salivation 4% 2%
Cardiovascular disorders    
Hypotension Skin and subcutaneous tissue disorders 5% 2%
Dermatitis/allergy 4% 3%

In addition to the adverse reactions (i.e., greater than 1%) enumerated in the table above for patients with generalized anxiety disorder, the following adverse reactions have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention.  

Table 2: Adverse Reactions Occurring in ≥1% in Alprazolam Tablets-treated Patients and Greater than Placebo- treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic Disorder

  Alprazolam Tablets n=1388Placebo n=1231
Drowsiness 77% 43%
Fatique and Tiredness 49% 42%
Impaired Coordination 40% 18%
Irritability 33% 30%
Memory Impairment 33% 22%
Cognitive Disorder 29% 21%
Decreased Libido 14% 8%
Dysartharia 23% 6%
Confusional state 10% 8%
Increased libido 8% 4%
Change in libido (not specified) 7% 6%
Disinhibition 3% 2%
Talkativeness 2% 1%
Derealization 2% 1%
Gastrointestinal disorders Constipation Increased salivation   26% 6%   15% 4%
Skin and subcutaneous tissue disorders Rash   11%   8%
Other    
Increased appetite 33% 23%
Decreased appetite 28% 24%
Weight gain 27% 18%
Weight loss 23% 17%
Micturition difficulties 12% 9%
Menstrual disorders 11% 9%
Sexual dysfunction 7% 4%
Incontinence 2% 1%

In addition to the reactions (i.e., greater than 1%) enumerated in the table above for patients with panic disorder, the following adverse reactions have been reported in association with the use of alprazolam tablets: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice.  

Adverse Reactions Reported as Reasons for Discontinuation in Treatment of Panic Disorder in Placebo-Controlled Trials

In a larger database comprised of both controlled and uncontrolled studies in which 641 patients received alprazolam tablets, discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with   alprazolam tablets and at a greater rate than the placebo-treated group are shown in Table 3.

Table 3: Discontinuation-Emergent Symptom  Incidence Reported in ≥5% of Alprazolam Tablets treated Patients and > Placebo-treated Patients

  Alprazolam Tablets-treated Patientsn=641
Nervous system disorders  
Insomnia 29.5%
Light-headedness 19.3%
Abnormal involuntary movement 17.3%
Headache 17.%
Muscular twitching 6.9%
Impaired coordination 6.6%
Muscle tone disorders 5.9%
Weakness 5.8%
Psychiatric disorders  
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%
Gastrointestinal disorders  
Nausea/Vomiting 16.5%
Diarrhea 13.6%
Decreased salivation 10.6%
Metabolism and nutrition disorders  
Weight loss 13.3%
Decreased appetite 12.8%
Dermatological disorders   14.4%
Sweating
Cardiovascular disorders   12.2%
Tachycardia
Special Senses   10%
Blurred vision
n=number of patients.

There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam tablets [see Warning and Precautions (5.2) and Drug Abuse and Dependence (9.3)].  

Paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations, and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous case reports of adverse behavioral effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of alprazolam tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably  estimate their frequency or establish a causal relationship to drug exposure.  

Endocrine disorders: Hyperprolactinemia

General disorders and administration site conditions: Edema peripheral

Hepatobiliary disorders: Hepatitis, hepatic failure Investigations: Liver enzyme elevations 

Psychiatric disorders: Hypomania, mania Reproductive system and breast disorders: Gynecomastia, galactorrhea Skin and subcutaneous tissue disorders: Photosensitivity reaction, angioedema, Stevens-Johnson syndrome

7 DRUG INTERACTIONS

7.1 Drugs Having Clinically Important Interactions with Alprazolam Tablets

Table 4 includes clinically significant drug interactions with alprazolam tablets [see Clinical Pharmacology (12.3)].  

Table 4: Clinically Significant Drug Interactions with Alprazolam Tablets

Opioids
Clinical implication The concomitant use of benzodiazepines and opioids increases the risk of  respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at gamma- aminobutyric acid (GABAA) sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.
Prevention or management Limit dosage and duration of concomitant use of alprazolam tablets and opioids, and  monitor patients closely for respiratory depression and sedation [see Warnings and Precautions (5.1)].
Examples Morphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorpenol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol.
CNS Depressants
Clinical implication The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other CNS depressants.
Prevention or management Limit dosage and duration of alprazolam tablets during concomitant use with CNS  depressants [see Warnings and Precautions (5.3)].
Examples Psychotropic medications, anticonvulsants, antihistaminics, ethanol, and  other drugs which themselves produce CNS depression.
Strong Inhibitors of CYP3A (except ritonavir)
Clinical implication Concomitant use of alprazolam tablets with strong CYP3A inhibitors has a profound effect on the clearance of alprazolam, resulting in increased concentrations  of alprazolam and increased risk of adverse reactions [see Clinical Pharmacology (12.3)].
Prevention or management Concomitant use of alprazolam tablets with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see Contraindications (4), Warnings and Precautions (5.5)].
Examples Ketoconazole, itraconazole, clarithromycin
Moderate or Weak Inhibitors of CYP3A
Clinical implication Concomitant use of alprazolam tablets with CYP3A inhibitors may increase the concentrations of alprazolam tablets, resulting in increased risk of adverse reactions  of alprazolam [see Clinical Pharmacology (12.3)].
Prevention or management Avoid use and consider appropriate dose reduction when alprazolam tablets is coadministered with a moderate or weak CYP3A inhibitor [see Warnings  and Precautions (5.5)].
Examples Nefazodone, fluvoxamine, cimetidine, erythromycin
CYP3A Inducers
Clinical implication Concomitant use of CYP3A inducers can increase alprazolam metabolism  and therefore can decease plasma levels of alprazolam [see Clinical Pharmacology (12.3)].
Prevention or management Caution is recommended during coadministration with alprazolam tablets.
Examples Carbamazepine, phenytoin
Ritonavir  
Clinical implication Interactions involving ritonavir and alprazolam are complex and time dependent. Short term administration of ritonavir increased alprazolam exposure due to CYP3A4 inhibition. Following long term treatment of ritonavir (>10 to 14 days), CYP3A4 induction offsets this inhibition. Alprazolam exposure was not meaningfully affected in the presence of ritonavir.  
Prevention or management Reduce alprazolam tablets dosage when ritonavir and alprazolam tablets are initiated concomitantly, or when ritonavir is added to a regimen where alprazolam tablets is stabilized.   Increase alprazolam tablets dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam tablets concomitantly. No dosage adjustment of alprazolam tablets is necessary in patients receiving ritonavir for more than 10 to14 days [see Dosage and Administration (2.6)].   Concomitant use of alprazolam tablets with a strong CYP3A inhibitor, except ritonavir, is contraindicated [see Contraindications (4), Warnings and Precautions (5.5)].
Digoxin  
Clinical implication Increased digoxin concentrations have been reported when alprazolam was given, especially in geriatric patients (>65 years of age).
Prevention or management In patients on digoxin therapy, measure serum digoxin concentrations before initiating alprazolam tablets. Continue monitoring digoxin serum concentration and toxicity frequently. Reduce the digoxin dose if necessary.

7.2 Drug/Laboratory Test Interactions

Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Neonates born to mothers using benzodiazepines during the later stages of pregnancy have been reported to experience symptoms of sedation and neonatal withdrawal [see Warnings and Precautions (5.4), Clinical Considerations)]. Overall available data from published observational studies of pregnant women exposed to alprazolam have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).  

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal adverse reactions

Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to benzodiazepines during pregnancy and labor for signs of sedation, respiratory depression, withdrawal, and feeding problems and manage accordingly [see Warnings and Precautions (5.4)].  

Data

Human Data

Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco, and other medications, have not confirmed these findings. At this time, there is no clear evidence that alprazolam exposure in early pregnancy can cause major birth defects. Neonates exposed to benzodiazepines during the late third trimester of pregnancy or during labor have been reported to exhibit sedation and neonatal withdrawal symptoms.

8.2 Lactation

Risk Summary

Limited data from published literature reports the presence of alprazolam in human breast milk. There are reports of sedation and withdrawal symptoms in breastfed neonates and infants exposed to alprazolam. The effects of alprazolam on lactation are unknown.  

Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed neonates and infants, advise patients that breastfeeding is not recommended during treatment with alprazolam tablets.

8.4 Pediatric Use

Safety and effectiveness of alprazolam tablets have not been established in pediatric patients.

8.5 Geriatric Use

Alprazolam tablets-treated geriatric patients had higher plasma concentrations of alprazolam (due to reduced clearance)   compared to younger adult patients receiving the same doses. Therefore, dosage reduction of alprazolam tablets is recommended in geriatric patients [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

Patients with alcoholic liver disease exhibit a longer elimination half-life (19.7 hours), compared to healthy subjects (11.4 hours). This may be caused by decreased clearance of alprazolam in patients with alcoholic liver disease. Dosage reduction of alprazolam tablets is recommended in patients with hepatic impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Alprazolam tablets contains alprazolam, which is a Schedule IV controlled substance.

9.2 Abuse

Alprazolam tablets is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction.  

Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2)].  

The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.  

The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

9.3 Dependence

Alprazolam tablets may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3)].

  To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam tablets or reduce the dosage [see Dosage and Administration (2.3), Warnings and Precautions (5.3)].  

Acute Withdrawal Signs and Symptoms

Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality.

Protracted Withdrawal Syndrome

Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.  

Tolerance

Tolerance to alprazolam tablets may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of alprazolam tablets may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

10 OVERDOSAGE

10.1 Clinical Experience

Manifestations of alprazolam overdosage include somnolence, confusion, impaired coordination, diminished reflexes, and coma. Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including alprazolam, and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality.

10.2 Management of Overdose

In case of an overdosage, consult a Certified Poison Control Center at 1-800-222-1222 for latest recommendations.  

As in all cases of drug overdosage, respiration, pulse rate, and blood pressure should be monitored. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. As with the management of intentional overdosing with any drug, it should be borne in mind that multiple agents may have been ingested.  

Flumazenil may be useful in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert should be consulted prior to use.

11 DESCRIPTION

Alprazolam tablets, USP contains alprazolam which is a triazolo analog of the 1,4 benzodiazepine class of central nervous system-active compounds.  

The chemical name of alprazolam is 8-Chloro-1-methyl-6-phenyl-4H-[1,2,4] triazolo [4,3-(alpha)] [1,4] benzodiazepine.  

The structural formula is:

structure.jpg

Alprazolam is a white crystalline powder, which is soluble in methanol or ethanol but which has no appreciable solubility in water at physiological pH.  

Each alprazolam tablet, USP for oral administration, contains 0.25 mg, 0.5 mg, 1 mg, or 2 mg of alprazolam.  

Alprazolam tablets, USP 2 mg, are multi-scored and may be divided as shown below:

figure1.jpg

Inactive ingredients: colloidal silicon dioxide, magnesium stearate, mannitol and microcrystalline cellulose. In addition, the 0.5 mg tablet contains FD&C Yellow No. 6 Aluminum Lake and the 1 mg tablet contains FD&C Blue No. 2 Aluminum Lake.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Alprazolam is a 1,4 benzodiazepine. Alprazolam exerts its effect for the acute treatment of generalized anxiety disorder and panic disorder through binding to the benzodiazepine site of gamma-aminobutyric acid-A (GABAA) receptors in the brain and enhances GABA-mediated synaptic inhibition.

12.3 Pharmacokinetics

Plasma levels of alprazolam increase proportionally to the dose over the range of 0.5 to 3 mg.  

Absorption

Following oral administration, peak plasma concentration of alprazolam (Cmax) occurs in 1 to 2 hours post dose.  

Distribution

Alprazolam is 80% bound to human serum protein, and albumin accounts for the majority of the binding.  

Elimination

The mean plasma elimination half-life (T1/2) of alprazolam is approximately 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults.  

Metabolism

Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to 2 major active metabolites in the plasma: 4-hydroxyalprazolam and a-hydroxyalprazolam. The plasma circulation levels of the two active metabolites are less than 4% of the parent. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and a-hydroxyalprazolam. The low concentrations and low potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam indicate that they unlikely contribute much to the effects of alprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam.  

Excretion

Alprazolam and its metabolites are excreted primarily in the urine.  

Specific Populations

Geriatric Patients

The mean T1/2 of alprazolam was 16.3 hours (range: 9 to 26.9 hours) in healthy elderly subjects compared to 11 hours (range: 6.3 to -15.8 hours, n=16) in healthy younger adult subjects.

Obese Patients

The mean T1/2 of alprazolam was 21.8 hours (range: 9.9 to 40.4 hours) in a group of obese subjects.

Patients with Hepatic Impairment

The mean T1/2 of alprazolam was 19.7 hours (range: 5.8 to 65.3 hours) in patients with alcoholic liver disease.  

Racial or Ethnic Groups Maximal concentrations and T1/2 of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians.  

Smoking

Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers.

Drug Interaction Studies

In Vivo Studies

Most of the interactions that have been documented with alprazolam are with drugs that modulate CYP3A4 activity.  

Compounds that are inhibitors or inducers of CYP3A would be expected to increase or decrease plasma alprazolam concentrations, respectively. Drug products that have been studied in vivo, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.66 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold [see Contraindications (4), Warnings and Precautions (5.5), Drug Interactions (7.2)]. Other studied drugs include:  

Cimetidine: Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 82%, decreased clearance by 42%, and increased T1/2 by 16%.

Fluoxetine: Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased T1/2 by 17%, and decreased measured psychomotor performance.  

Oral Contraceptives: Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased T1/2 by 29%.

Carbamazepine: The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.90±0.21 mL/min/kg to 2.13±0.54 mL/min/kg and the elimination T1/2 was shortened (from 17.1±4.9 to 7.7±1.7 hour) following administration of 300 mg per day carbamazepine for 10 days [see Drug Interactions (7.2)]. However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000-1200 mg per day); the effect at usual carbamazepine doses is unknown.

Ritonavir: Interactions involving HIV protease inhibitors (e.g., ritonavir) and alprazolam are complex and time dependent. Short-term low doses of ritonavir (4 doses of 200 mg) increased mean AUC of alprazolam by about 2.5-fold, and did not significantly affect Cmax of alprazolam. The elimination T1/2 was prolonged (30 hours versus 13 hours). However, upon extended exposure to ritonavir (500 mg, twice daily for 10 days), CYP3A induction offset this inhibition. Alprazolam AUC and Cmax was reduced by 12% and 16%, respectively, in the presence of ritonavir. The elimination T1/2 of alprazolam was not significantly changed [see Warnings and Precautions (5.5)].

Sertraline: A single dose of alprazolam 1 mg and steady state dose of sertraline (50 mg to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam.  

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 per day.  

Warfarin: Alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.  

In Vitro Studies

Data from in vitro studies of alprazolam suggest a possible drug interaction of alprazolam with paroxetine. The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No evidence of carcinogenic potential was observed in rats or mice administered alprazolam for 2-years at doses up to 30 and 10 mg/kg day respectively. These doses are 29 times and 4.8 times the maximum recommended human dose of 10 mg/day based on mg/m2 body surface area, respectively.   Mutagenesis

Alprazolam was negative in the in vitro Ames bacterial reverse mutation assay and DNA Damage/Alkaline Elution Assay and in vivo rat micronucleus genetic toxicology assays.  

Impairment of Fertility

Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg per day, which is approximately 5 times the maximum recommended human dose of 10 mg per day based on mg/m2 body surface area.

13.2 Animal Toxicology and/or Pharmacology

When rats were treated with alprazolam at oral doses of 3 mg, 10 mg, and 30 mg/kg day (3 to 29 times the maximum recommended human dose based on mg/m2 body surface area) for 2 years, a tendency for a dose related increase in the number of cataracts was observed in females and a tendency for a dose related increase in corneal vascularization was observed in males. These lesions did not appear until after 11 months of treatment.

14 CLINICAL STUDIES

14.1 Generalized Anxiety Disorder

Alprazolam tablets was compared to placebo in double-blind clinical studies (doses up to 4 mg per day) in patients with a diagnosis of anxiety or anxiety with associated depressive symptomatology. alprazolam tablets was significantly better than placebo at each of the evaluation periods of these 4-week studies as judged by the following psychometric  instruments: Physician’s Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient’s Global Impressions, and Self-Rating Symptom Scale.

14.2 Panic Disorders

The effectiveness of alprazolam tablets in the treatment of panic disorder was studied in 3 short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely corresponding to DSM-III-R criteria for panic disorder.  

The average dose of alprazolam tablets was 5 mg to 6 mg per day in 2 of the studies, and the doses of alprazolam tablets were fixed at 2 mg and 6 mg per day in the third study. In all 3 studies, alprazolam tablets was superior to placebo on a variable defined as “the number of patients with zero panic attacks” (range, 37% to 83% met this criterion), as well as on a global improvement score. In 2 of the 3 studies, alprazolam tablets was superior to placebo on a variable defined as “change from baseline on the number of panic attacks per week” (range, 3.3 to 5.2), and also on a phobia rating scale. A subgroup of patients who improved on alprazolam tablets during short-term treatment in 1 of these  trials was continued on an open basis up to 8 months, without apparent loss of benefit.

16 HOW SUPPLIED/STORAGE AND HANDLING

Alprazolam Tablets, USP is supplied in the following strengths and package configurations:

Alprazolam Tablets
Package ConfigurationTablet Strength (mg)   NDC   Print
Bottles of 30 Bottles of 60 Bottles of 100 Bottles of 500 Bottles of 1000 0.25 mg NDC 60505-1331-3 NDC 60505-1331-6 NDC 60505-1331-1 NDC 60505-1331-5 NDC 60505-1331-8 White, oval shaped, scored tablets, imprinted “ALP” bisect “0.25" on one side and “APO” on the other side.
Bottles of 30 Bottles of 60 Bottles of 100 Bottles of 500 Bottles of 1000 0.5 mg NDC 60505-1332-3 NDC 60505-1332-6 NDC 60505-1332-1 NDC 60505-1332-5 NDC 60505-1332-8 Peach, oval shaped, scored tablets, imprinted “ALP” bisect “0.5" on one side and “APO” on the other side.
Bottles of 30 Bottles of 60 Bottles of 100 Bottles of 500 Bottles of 1000 1 mg NDC 60505-1333-3 NDC 60505-1333-6 NDC 60505-1333-1 NDC 60505-1333-5 NDC 60505-1333-8 Light blue, oval shaped, scored tablets, imprinted “ALP” bisect “1" on one side and “APO” on the other side.
Bottles of 30 Bottles of 60 Bottles of 100 Bottles of 500 Bottles of 1000 2 mg NDC 60505-1334-3 NDC 60505-1334-6 NDC 60505-1334-1 NDC 60505-1334-5 NDC 60505-1334-8 White, rectangle shaped, scored tablets, imprinted “A” bisect “L” partial bisect “P” bisect “R” on one side and “A” bisect “P” partial bisect “O” bisect “2” on the other side.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container [see USP].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).  

Risks from Concomitant Use with Opioids

Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when alprazolam tablets is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Warnings and Precautions (5.1), Drug Interactions (7.1)].  

Abuse, Misuse, and Addiction

Inform patients that the use of alprazolam tablets, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions (5.2), Drug Abuse and Dependence (9.2)].  

Withdrawal Reactions

Inform patients that the continued use of alprazolam tablets may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of alprazolam tablets may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months.  Instruct patients that discontinuation or dosage reduction of alprazolam tablets may require a slow taper [see Warnings and Precautions (5.3), Drug Abuse and Dependence (9.3)].  

Effects on Driving and Operating Machinery

Advise patients not to drive a motor vehicle or operate heavy machinery while taking alprazolam tablets due to its CNS depressant effects. Also advise patients to avoid use of alcohol or other CNS depressants while taking alprazolam tablets [see Warnings and Precautions (5.3)].  

Patients with Depression

Advise patients, their families, and caregivers to look for signs of suicidality or worsening depression, and to inform the patient’s healthcare provider immediately [see Warnings and Precautions (5.6)].  

Concomitant Medications

Advise patients to inform their healthcare provider of all medicines they take, including prescription and nonprescription medications, vitamins and herbal supplements [see Drug Interactions (7)].  

Pregnancy

Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Advise mothers using alprazolam tablets to monitor neonates for signs of sedation, respiratory depression, withdrawal symptoms, and feeding problems. Instruct patients to inform their healthcare provider if they are pregnant or intend to become pregnant during treatment with alprazolam tablets [see Warnings and Precautions (5.4). Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to alprazolam tablets during pregnancy [see Use in Specific Populations (8.1)].    

Lactation

Advise women not to breastfeed during treatment with alprazolam tablets [see Use in Specific Populations (8.2)].  

This product’s labeling may have been updated. For the most recent prescribing information, please visit  www.apotex.com.

ALPRAZOLAM TABLETS, USP

0.25 mg, 0.50 mg, 1 mg and 2 mg

Manufactured by
Apotex Inc. Toronto, Ontario
Canada M9L 1T9
Manufactured for
Apotex Corp.
Weston, Florida
33326

Revised: April 2021

Rev. 4

MEDICATION GUIDE

Alprazolam Tablets, USP C-IV

(al pra' zoe lam)

What is the most important information I should know about alprazolam tablets?

  • Alprazolam tablets is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. Get emergency help right away if any of the following happens:
    • shallow or slowed breathing
    • breathing stops (which may lead to the heart stopping)
    • excessive sleepiness (sedation)

Do not drive or operate heavy machinery until you know how taking alprazolam tablets with opioids affects you.

  • Risk of abuse, misuse, and addiction. There is a risk of abuse, misuse, and addiction with benzodiazepines, including alprazolam tablets, which can lead to overdose and serious side effects including coma and death.
    • Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including alprazolam tablets. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects.
    • You can develop an addiction even if you take alprazolam tablets as prescribed by your healthcare provider.
    • Take alprazolam tablets exactly as your healthcare provider prescribed.
    • Do not share your alprazolam tablets with other people.
    • Keep alprazolam tablets in a safe place and away from children.
  • Physical dependence and withdrawal reactions. Alprazolam tablets can cause physical dependence and withdrawal reactions.
    • Do not suddenly stop taking alprazolam tablets. Stopping alprazolam tablets suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms.
    • Some people who suddenly stop benzodiazepines, have symptoms that can last for several weeks to more than 12 months, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.
    • Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.
  • Do not take more alprazolam tablets than prescribed or take alprazolam tablets for longer than prescribed.

What is alprazolam tablets?

  • Alprazolam tablets is a prescription medicine used:
    • to treat anxiety disorders
    • for the short-term relief of the symptoms of anxiety
    • to treat panic disorder with or without a fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia)
  • Alprazolam tablets is a federal controlled substance (C-IV) because it contains alprazolam that can be abused or lead to dependence. Keep alprazolam tablets in a safe place to prevent misuse and abuse. Selling or giving away alprazolam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs.
  • It is not known if alprazolam tablets is safe and effective in children.
  • Elderly patients are especially susceptible to dose related adverse effects when taking alprazolam tablets.
  • It is not known if alprazolam tablets is safe and effective when used to treat anxiety disorder for longer than 4 months.
  • It is not known if alprazolam tablets is safe and effective when used to treat panic disorder for longer than 10 weeks.

Do not take alprazolam tablets if:

  • you are allergic to alprazolam, other benzodiazepines, or any of the ingredients in alprazolam tablets. See the end of this Medication Guide for a complete list of ingredients in alprazolam tablets.

you are taking antifungal medicines including ketoconazole and itraconazole

Before you take alprazolam tablets, tell your healthcare provider about all of your medical conditions, including if you:

  • have or have had depression, mood problems, or suicidal thoughts or behavior
  • have liver or kidney problems
  • have lung disease or breathing problems
  • are pregnant or plan to become pregnant. Alprazolam tablets may harm your unborn baby. You and your  healthcare provider should decide if you should take alprazolam tablets while you are pregnant.
  • are breastfeeding or plan to breastfeed. Alprazolam passes into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if  you take alprazolam tablets. You should not breastfeed while taking alprazolam tablets.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking alprazolam tablets with certain other medicines can cause side effects or affect how well alprazolam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.

How should I take alprazolam tablets?

  • See “What is the most important information I should know about alprazolam tablets?”
  • Take alprazolam tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much alprazolam tablets to take and when to take it.
  • If you take too much alprazolam tablets, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of alprazolam tablets

Alprazolam tablets may cause serious side effects, including:

  • See “What is the most important information I should know about alprazolam tablets?”
  • Seizures. Stopping alprazolam tablets can cause seizures and seizures that will not stop (status epilepticus).
  • Mania. Alprazolam tablets may cause an increase in activity and talking (hypomania and mania) in people who have depression.
    • Alprazolam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how alprazolam tablets affects you.
    • Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking alprazolam tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, alprazolam tablets may make your sleepiness or dizziness much worse.

The most common side effects of alprazolam tablets include:

  • problems with coordination
  • hypotension
  • trouble saying words clearly (dysarthria)
  • changes in sex drive (libido)

These are not all the possible side effects of alprazolam tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store alprazolam tablets?

  • Store alprazolam tablets at room temperature between 68°F to 77°F (20°C to 25°C)
  • Keep alprazolam tablets and all medicines out of the reach of children.

General information about the safe and effective use of alprazolam tablets.

  • Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
  • Do not use alprazolam tablets for a condition for which it was not prescribed.
  • Do not give alprazolam tablets to other people, even if they have the same symptoms that you have. It may harm them.
  • You can ask your pharmacist or healthcare provider for information about alprazolam tablets that is written for health professionals.

What are the ingredients in alprazolam tablets? 

Active ingredient: alprazolam

Inactive ingredients: Colloidal silicon dioxide, magnesium stearate, mannitol and microcrystalline cellulose. In addition, the 0.5 mg tablet contains FD&C Yellow No. 6 Aluminum Lake and the 1 mg tablet contains FD&C Blue No. 2 Aluminum Lake.  

This Medication Guide has been approved by the U.S. Food and Drug Administration.

APOTEX INC.
ALPRAZOLAM TABLETS, USP
0.25 mg, 0.50 mg, 1 mg and 2 mg

Manufactured byManufactured for
Apotex Inc.Apotex Corp.
Toronto, OntarioWeston, Florida
Canada M9L 1T933326

Revised: April 2021

Rev. 4

PRINCIPAL DISPLAY PANEL - 0.25 mg BOTTLE LABEL

APOTEX CORP NDC 60505-1331-3

Alprazolam Tablets USP

0.25 mg

Rx

30 Tablets

0.25mg30tablets

PRINCIPAL DISPLAY PANEL - 0.5 mg BOTTLE LABEL

APOTEX CORP NDC 60505-1332-3

Alprazolam Tablets USP

0.5 mg

Rx

30 Tablets

0.5mg30tablets

PRINCIPAL DISPLAY PANEL - 1 mg BOTTLE LABEL

APOTEX CORP NDC 60505-1333-3

Alprazolam Tablets USP

1 mg

Rx

30 Tablets

1mg30tablets

PRINCIPAL DISPLAY PANEL SECTION - 2 mg BOTTLE LABEL

APOTEX CORP NDC 60505-1334-3

Alprazolam Tablets USP

2 mg

Rx

30 Tablets

2mg30tablets

ALPRAZOLAM 
alprazolam tablet
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:60505-1331
Route of AdministrationORALDEA ScheduleCIV    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
ALPRAZOLAM (UNII: YU55MQ3IZY) (alprazolam - UNII:YU55MQ3IZY) ALPRAZOLAM0.25 mg
Inactive Ingredients
Ingredient NameStrength
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
MANNITOL (UNII: 3OWL53L36A)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
Product Characteristics
ColorWHITEScore2 pieces
ShapeOVALSize9mm
FlavorImprint Code ALP;0;25;APO
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:60505-1331-330 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
2NDC:60505-1331-660 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
3NDC:60505-1331-1100 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
4NDC:60505-1331-5500 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
5NDC:60505-1331-81000 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA07774101/19/200701/20/2007
ALPRAZOLAM 
alprazolam tablet
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:60505-1332
Route of AdministrationORALDEA ScheduleCIV    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
ALPRAZOLAM (UNII: YU55MQ3IZY) (alprazolam - UNII:YU55MQ3IZY) ALPRAZOLAM0.5 mg
Inactive Ingredients
Ingredient NameStrength
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
MANNITOL (UNII: 3OWL53L36A)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
FD&C YELLOW NO. 6 (UNII: H77VEI93A8)  
Product Characteristics
ColorORANGE (peach) Score2 pieces
ShapeOVALSize9mm
FlavorImprint Code ALP;0;5;APO
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:60505-1332-330 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
2NDC:60505-1332-660 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
3NDC:60505-1332-1100 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
4NDC:60505-1332-5500 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
5NDC:60505-1332-81000 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA07774101/19/200701/20/2007
ALPRAZOLAM 
alprazolam tablet
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:60505-1333
Route of AdministrationORALDEA ScheduleCIV    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
ALPRAZOLAM (UNII: YU55MQ3IZY) (alprazolam - UNII:YU55MQ3IZY) ALPRAZOLAM1 mg
Inactive Ingredients
Ingredient NameStrength
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
MANNITOL (UNII: 3OWL53L36A)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
FD&C Blue No. 2 (UNII: L06K8R7DQK)  
Product Characteristics
ColorBLUE (light blue) Score2 pieces
ShapeOVALSize9mm
FlavorImprint Code ALP;1;APO
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:60505-1333-330 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
2NDC:60505-1333-660 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
3NDC:60505-1333-1100 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
4NDC:60505-1333-5500 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
5NDC:60505-1333-81000 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA07774101/19/200701/20/2007
ALPRAZOLAM 
alprazolam tablet
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:60505-1334
Route of AdministrationORALDEA ScheduleCIV    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
alprazolam (UNII: YU55MQ3IZY) (alprazolam - UNII:YU55MQ3IZY) alprazolam2 mg
Inactive Ingredients
Ingredient NameStrength
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
MANNITOL (UNII: 3OWL53L36A)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
Product Characteristics
ColorWHITEScore4 pieces
ShapeRECTANGLESize15mm
FlavorImprint Code A;L;P;R;A;P;O;2
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:60505-1334-330 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
2NDC:60505-1334-660 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
3NDC:60505-1334-1100 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
4NDC:60505-1334-5500 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
5NDC:60505-1334-81000 in 1 BOTTLE; Type 0: Not a Combination Product01/19/200701/20/2007
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA07774101/19/200701/20/2007
Labeler - Apotex Corp. (845263701)
Registrant - Apotex Inc (209429182)
Establishment
NameAddressID/FEIBusiness Operations
Apotex Inc209429182manufacture(60505-1331, 60505-1332, 60505-1334, 60505-1333) , analysis(60505-1331, 60505-1332, 60505-1334, 60505-1333)

Revised: 4/2021
 
Apotex Corp.