Alprazolam Extended Release

Name: Alprazolam Extended Release

Alprazolam Extended Release Description

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

The chemical name of alprazolam is 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-α] [1,4] benzodiazepine. The molecular formula is C17H13ClN4 which corresponds to a molecular weight of 308.76.

The structural formula is represented below:

Alprazolam, USP 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 extended-release tablet, for oral administration, contains 0.5 mg, 1 mg, 2 mg, or 3 mg of alprazolam. The inactive ingredients are lactose monohydrate, hypromellose, and magnesium stearate. In addition, the 1 mg tablets also contain D&C yellow #10 aluminum lake. The 2 mg tablets also contain FD&C Yellow #6 aluminum lake, and the 3 mg tablets also contain D&C Yellow #10 aluminum lake, and FD&C Blue #2 aluminum lake.

Product meets USP Dissolution Test 2.

Indications and Usage for Alprazolam Extended Release

Alprazolam extended-release tablets, USP are indicated for the treatment of panic disorder, with or without agoraphobia.

This claim is supported on the basis of two positive studies with alprazolam extended-release conducted in patients whose diagnoses corresponded closely to the DSM-III-R/IV criteria for panic disorder (see CLINICAL EFFICACY TRIALS).

Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.

The longer-term efficacy of alprazolam extended-release has not been systematically evaluated. Thus, the physician who elects to use this drug for periods longer than 8 weeks should periodically reassess the usefulness of the drug for the individual patient.

Contraindications

Alprazolam extended-release tablets are contraindicated in patients with known sensitivity to this drug or other benzodiazepines.

Alprazolam extended-release is contraindicated with ketoconazole and itraconazole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A) (see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS, Drug Interactions).

Adverse Reactions

The information included in the subsection on Adverse Events Observed in Short-Term, Placebo-Controlled Trials with alprazolam extended-release tablets is based on pooled data of five 6- and 8-week placebo-controlled clinical studies in panic disorder.

Adverse event reports were elicited either by general inquiry or by checklist, and were recorded by clinical investigators using terminology of their own choosing. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened during therapy following baseline evaluation. In the tables and tabulations that follow, standard MedDRA terminology (version 4.0) was used to classify reported adverse events.

Adverse Events Observed in Short-Term, Placebo-Controlled Trials of Alprazolam Extended-Release Tablets

Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials

Approximately 17% of the 531 patients who received alprazolam extended-release tablets in placebo-controlled clinical trials for panic disorder had at least one adverse event that led to discontinuation compared to 8% of 349 placebo-treated patients. The most common events leading to discontinuation and considered to be drug-related (i.e., leading to discontinuation in at least 1% of the patients treated with alprazolam extended-release tablets at a rate at least twice that of placebo) are shown in the following table.

Common Adverse Events Leading to Discontinuation of Treatment in Placebo-Controlled Trials
  System Organ Class/Adverse Event  Percentage of Patients Discontinuing Due to Adverse Events
   Alprazolam Extended-Release
(n=531)
 Placebo
(n=349)
 Nervous system disorders    
 Sedation  7.5  0.6
 Somnolence  3.2  0.3
 Dysarthria  2.1  0
 Coordination abnormal  1.9  0.3
 Memory impairment  1.5  0.3

 General disorders/administration site conditions
Fatigue

 
1.7

0.6

 Psychiatric disorders
Depression

 
2.5
 
1.2

Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated with Alprazolam Extended-Release Tablets

The prescriber should be aware that adverse event incidence cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with event incidence obtained from other clinical investigations involving different treatments, uses, and investigators. The cited values, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.

The following table shows the incidence of treatment-emergent adverse events that occurred during 6- to 8-week placebo-controlled trials in 1% or more of patients treated with alprazolam extended-release where the incidence in patients treated with alprazolam extended-release was greater than the incidence in placebo-treated patients. The most commonly observed adverse events in panic disorder patients treated with alprazolam extended-release (incidence of 5% or greater and at least twice the incidence in placebo patients) were: sedation, somnolence, memory impairment, dysarthria, coordination abnormal, ataxia, libido decreased (see table).

Treatment-Emergent Adverse Events: Incidence in Short-Term, Placebo-Controlled Clinical Trials with Alprazolam Extended-Release
 System Organ Class/Adverse Event  Percentage of Patients Reporting Adverse Event
   Alprazolam Extended-Release
(n=531)
 Placebo
(n=349)
 Nervous system disorders    
 Sedation  45.2  22.6
 Somnolence  23.0  6.0
 Memory impairment  15.4  6.9
 Dysarthria  10.9  2.6
 Coordination abnormal  9.4  0.9
 Mental Impairment   7.2  5.7
 Ataxia  7.2  3.2
 Disturbance in attention  3.2  0.6
 Balance impaired  3.2  0.6
 Paresthesia  2.4  1.7
 Dyskinesia  1.7  1.4
 Hypoesthesia  1.3  0.3
 Hypersomnia  1.3  0
 General disorders/administration site conditions    
 Fatigue  13.9  9.2
 Lethargy  1.7  0.6
 Infections and infestations    
 Influenza  2.4  2.3
 Upper respiratory tract infections  1.9  1.7
 Psychiatric disorders    
 Depression  12.1  9.2
 Libido decreased  6.0  2.3
 Disorientation  1.5  0
 Confusion  1.5  0.9
 Depressed mood  1.3  0.3
 Anxiety  1.1  0.6
 Metabolism and nutrition disorders    
 Appetite decreased  7.3  7.2
 Appetite increased  7.0  6.0
 Anorexia  1.5  0
 Gastrointestinal disorders    
 Dry mouth  10.2  9.7
 Constipation  8.1  4.3
 Nausea  6.0  3.2
 Pharyngolaryngeal pain  3.2  2.6
 Investigations    
 Weight increased  5.1  4.3
 Weight decreased  4.3  3.7
 Injury, poisoning, and procedural complications    
 Road traffic accident  1.5  0
 Reproductive system and breast disorders    
 Dysmenorrhea  3.6  2.9
 Sexual dysfunction  2.4  1.1
 Premenstrual syndrome  1.7  0.6
 Musculoskeletal and connective tissue disorders    
 Arthralgia  2.4  0.6
 Myalgia  1.5  1.1
 Pain in limb  1.1  0.3
 Vascular disorders    
 Hot flushes  1.5  1.4
 Respiratory, thoracic, and mediastinal disorders    
 Dyspnea  1.5  0.3
 Rhinitis allergic  1.1  0.6
 Skin and subcutaneous tissue disorders    
 Pruritis  1.1  0.9

Other Adverse Events Observed During the Premarketing Evaluation of Alprazolam Extended-Release Tablets

Following is a list of MedDRA terms that reflect treatment-emergent adverse events reported by 531 patients with panic disorder treated with alprazolam extended-release. All potentially important reported events are included except those already listed in the above table or elsewhere in labeling, those events for which a drug cause was remote, those event terms that were so general as to be uninformative, and those events that occurred at rates similar to background rates in the general population. It is important to emphasize that, although the events reported occurred during treatment with alprazolam extended-release, they were not necessarily caused by the drug. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on 1 or more occasions in at least 1/l00 patients; infrequent adverse events are those occurring in less than 1/100 patients but at least 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients.

Cardiac Disorders: Frequent: palpitation; Infrequent: sinus tachycardia

Ear and Labyrinth Disorders: Frequent: Vertigo; Infrequent: tinnitus, ear pain

Eye Disorders: Frequent: blurred vision; Infrequent: mydriasis, photophobia

Gastrointestinal Disorders: Frequent: diarrhea, vomiting, dyspepsia, abdominal pain; Infrequent: dysphagia, salivary hypersecretion

General Disorders and Administration Site Conditions: Frequent: malaise, weakness, chest pains; Infrequent: fall, pyrexia, thirst, feeling hot and cold, edema, feeling jittery, sluggishness, asthenia, feeling drunk, chest tightness, increased energy, feeling of relaxation, hangover, loss of control of legs, rigors

Musculoskeletal and Connective Tissue Disorders: Frequent: back pain, muscle cramps, muscle twitching

Nervous System Disorders: Frequent: headache, dizziness, tremor; Infrequent: amnesia, clumsiness, syncope, hypotonia, seizures, depressed level of consciousness, sleep apnea syndrome, sleep talking, stupor

Psychiatric System Disorders: Frequent: irritability, insomnia, nervousness, derealization, libido increased, restlessness, agitation, depersonalization, nightmare; Infrequent: abnormal dreams, apathy, aggression, anger, bradyphrenia, euphoric mood, logorrhea, mood swings, dysphonia, hallucination, homicidal ideation, mania, hypomania, impulse control, psychomotor retardation, suicidal ideation

Renal and Urinary Disorders: Frequent: difficulty in micturition; Infrequent: urinary frequency, urinary incontinence

Respiratory, Thoracic, and Mediastinal Disorders: Frequent: nasal congestion, hyperventilation; Infrequent: choking sensation, epistaxis, rhinorrhea

Skin and Subcutaneous Tissue Disorders: Frequent: sweating increased; Infrequent: clamminess, rash, urticaria

Vascular Disorders: Infrequent: hypotension

The categories of adverse events reported in the clinical development program for alprazolam tablets in the treatment of panic disorder differ somewhat from those reported for alprazolam extended-release tablets because the clinical trials with alprazolam tablets and alprazolam extended-release tablets used different standard medical nomenclature for reporting the adverse events. Nevertheless, the types of adverse events reported in the clinical trials with alprazolam tablets were generally the same as those reported in the clinical trials with alprazolam extended-release tablets.

Discontinuation-Emergent Adverse Events Occurring at an Incidence of 5% or More Among Patients Treated with Alprazolam Extended-Release Tablets.

The following table shows the incidence of discontinuation-emergent adverse events that occurred during short-term, placebo-controlled trials in 5% or more of patients treated with alprazolam extended-release where the incidence in patients treated with alprazolam extended-release was two times greater than the incidence in placebo-treated patients.

Discontinuation-Emergent Symptoms: Incidence in Short-Term, Placebo-Controlled Trials with Alprazolam Extended-Release
 System Organ Class/Adverse Event  Percentage of Patients Reporting Adverse Event
   Alprazolam Extended-Release  Placebo
   (n=422)  (n=261)
 Nervous system disorders    
 Tremor  28.2  10.7
 Headache  26.5  12.6
 Hypoesthesia  7.8  2.3
 Paresthesia  7.1  2.7
 Psychiatric disorders    
 Insomnia  24.2  9.6
 Nervousness  21.8  8.8
 Depression  10.9  5.0
 Derealization  8.0  3.8
 Anxiety  7.8  2.7
 Depersonalization  5.7  1.9
 Gastrointestinal disorders    
 Diarrhea  12.1  3.1
 Respiratory, thoracic and mediastinal disorders    
 Hyperventilation  8.5  2.7
 Metabolism and nutrition disorders    
 Appetite decreased  9.5  3.8
 Musculoskeletal and connective tissue disorders    
 Muscle twitching  7.4  2.7
 Vascular disorders    
 Hot flushes  5.9  2.7

There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam (see WARNINGS).

To discontinue treatment in patients taking alprazolam extended-release tablets, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam extended-release tablets be decreased by no more than 0.5 mg every three days (see DOSAGE AND ADMINISTRATION). Some patients may benefit from an even slower dosage reduction. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome.

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

Post Introduction Reports

Various adverse drug reactions have been reported in association with the use of alprazolam tablets since market introduction. The majority of these reactions were reported through the medical event voluntary reporting system. Because of the spontaneous nature of the reporting of medical events and the lack of controls, a causal relationship to the use of alprazolam tablets cannot be readily determined. Reported events include: gastrointestinal disorder, hypomania, mania, liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson syndrome, angioedema, peripheral edema, hyperprolactinemia, gynecomastia, and galactorrhea (see PRECAUTIONS).

To report SUSPECTED ADVERSE EVENTS, contact Actavis at 1-800-432-8534 or FDA at 1-800-FDA-1088 or http://www.fda.gov/ for voluntary reporting of adverse reactions.

How is Alprazolam Extended Release Supplied

Alprazolam extended-release tablets, USP are available as follows:

0.5 mg Each white to off white, round tablet imprinted with on one side and 83 on the other contains 0.5 mg of Alprazolam, USP. Tablets are supplied in bottles of 60 (NDC 0228-3083-06).

1 mg Each yellow, round tablet imprinted with on one side and 84 on the other contains 1 mg of Alprazolam, USP. Tablets are supplied in bottles of 60 (NDC 0228-3084-06).

2 mg Each peach, round tablet imprinted with on one side and 87 on the other contains 2 mg of Alprazolam, USP. Tablets are supplied in bottles of 60 (NDC 0228-3087-06).

3 mg Each light green, round tablet imprinted with on one side and 86 on the other contains 3 mg of Alprazolam, USP. Tablets are supplied in bottles of 60 (NDC 0228-3086-06).

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP.

ANIMAL STUDIES

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

Manufactured by:
Actavis Elizabeth LLC
Elizabeth, NJ 07207 USA

Distributed by:
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA

40-9181

Revised – May 2017

Package label.principal display panel

NDC 0228-3083-06

CIV

Alprazolam Extended-Release Tablets, USP   

0.5 mg

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

Actavis

60 Tablets

Rx Only

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