ALPRAZOLAM EXTENDED-RELEASE TABLETS, USP

/ALPRAZOLAM EXTENDED-RELEASE TABLETS, USP
ALPRAZOLAM EXTENDED-RELEASE TABLETS, USP2018-09-06T09:12:40+00:00

Prescription Drug Name:

ALPRAZOLAM EXTENDED-RELEASE TABLETS, USP

ID:

a1d48fb0-adee-4f00-9ba1-64ae3765b34d

Code:

34391-3

DESCRIPTION


id: 3a67d903-7281-4364-abef-804173ad661f
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3

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-4Hs-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


id: c6f12554-93d4-4c59-85c1-bd790a5f8bb2
displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

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


id: 8b25acd7-2b14-4d8a-80d2-a3569c067bdf
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

Alprazolam extended-release tablets, USP are contraindicated in patients with known sensitivity to this drug or other benzodiazepines. Alprazolam extended-release may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in patients with acute narrow angle glaucoma. 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


id: 60747c9b-25ff-4461-86d8-4b8356d30d59
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

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 (ie, 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 conditionsFatigue  

1.7

 

0.6

 Psychiatric disordersDepression  
2.5
 
1.2
Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated with Alprazolam Extended-Release 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 disorder    
 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 disorder    
 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 l/l00 patients; infrequent adverse events are those occurring in less than l/100 patients but at least l/1000 patients; rare events are those occurring in fewer than l/1000 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. 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
 Musculosketal 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.

DRUG ABUSE AND DEPENDENCE


id: feb7d21a-7ce3-4be1-bacd-b8e807afa8ad
displayName: DRUG ABUSE AND DEPENDENCE SECTION
FDA Article Code: 42227-9

Physical and Psychological Dependence Withdrawal symptoms similar in character to those noted with sedative/hypnotics and alcohol have occurred following discontinuance of benzodiazepines, including alprazolam. The symptoms can range from mild dysphoria and insomnia to a major syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. Distinguishing between withdrawal emergent signs and symptoms and the recurrence of illness is often difficult in patients undergoing dose reduction. The long-term strategy for treatment of these phenomena will vary with their cause and the therapeutic goal. When necessary, immediate management of withdrawal symptoms requires re-institution of treatment at doses of alprazolam sufficient to suppress symptoms. There have been reports of failure of other benzodiazepines to fully suppress these withdrawal symptoms. These failures have been attributed to incomplete cross-tolerance but may also reflect the use of an inadequate dosing regimen of the substituted benzodiazepine or the effects of concomitant medications. While it is difficult to distinguish withdrawal and recurrence for certain patients, the time course and the nature of the symptoms may be helpful. A withdrawal syndrome typically includes the occurrence of new symptoms, tends to appear toward the end of taper or shortly after discontinuation, and will decrease with time. In recurring panic disorder, symptoms similar to those observed before treatment may recur either early or late, and they will persist. While the severity and incidence of withdrawal phenomena appear to be related to dose and duration of treatment, withdrawal symptoms, including seizures, have been reported after only brief therapy with alprazolam at doses within the recommended range for the treatment of anxiety (eg, 0.75 to 4 mg/day). Signs and symptoms of withdrawal are often more prominent after rapid decrease of dosage or abrupt discontinuance. The risk of withdrawal seizures may be increased at doses above 4 mg/day (see WARNINGS). Patients, especially individuals with a history of seizures or epilepsy, should not be abruptly discontinued from any CNS depressant agent, including alprazolam. It is recommended that all patients on alprazolam who require a dosage reduction be gradually tapered under close supervision (see WARNINGS and DOSAGE AND ADMINISTRATION). Psychological dependence is a risk with all benzodiazepines, including alprazolam. The risk of psychological dependence may also be increased at doses greater than 4 mg/day and with longer term use, and this risk is further increased in patients with a history of alcohol or drug abuse. Some patients have experienced considerable difficulty in tapering and discontinuing from alprazolam, especially those receiving higher doses for extended periods. Addiction-prone individuals should be under careful surveillance when receiving alprazolam. As with all anxiolytics, repeat prescriptions should be limited to those who are under medical supervision.

OVERDOSAGE


id: 5bf87061-a6d7-423c-9f84-c56faacf2a23
displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5

Clinical Experience Overdosage reports with alprazolam tablets are limited. 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. Animal experiments have suggested that forced diuresis or hemodialysis are probably of little value in treating overdosage.

DOSAGE AND ADMINISTRATION


id: 81423176-7243-4141-8404-1e44b5dc4a1c
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

Alprazolam extended-release tablets may be administered once daily, preferably in the morning. The tablets should be taken intact; they should not be chewed, crushed, or broken. The suggested total daily dose ranges between 3 to 6 mg/day. Dosage should be individualized for maximum beneficial effect. While the suggested total daily dosages given will meet the needs of most patients, there will be some patients who require doses greater than 6 mg/day. In such cases, dosage should be increased cautiously to avoid adverse effects.

HOW SUPPLIED


id: b9f2885b-8b71-4356-96b2-718c4c35bacf
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

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) with child-resistant closure, and 500 (NDC 0228-3083-50) without a child-resistant closure.
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) with child-resistant closure, and 500 (NDC 0228-3084-50) without a child-resistant closure.
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) with child-resistant closure, and 500 (NDC 0228-3087-50) without a child-resistant closure.
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) with child-resistant closure, and 500 (NDC 0228-3086-50) without a child-resistant closure.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°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 200 Elmora Avenue Elizabeth, NJ 07207 USA 40-9181 Revised – September 2012