ALPRAZOLAM TABLETS, USP CIV 40-8786 Revised — January 2006, Rx only

/ALPRAZOLAM TABLETS, USP CIV 40-8786 Revised — January 2006, Rx only
ALPRAZOLAM TABLETS, USP CIV 40-8786 Revised — January 2006, Rx only2018-09-06T09:12:40+00:00

Prescription Drug Name:

ALPRAZOLAM TABLETS, USP CIV 40-8786 Revised — January 2006, Rx only

ID:

c89986aa-e7a2-46ed-9df5-784a1bd7e09d

Code:

34391-3

DESCRIPTION


id: cb0dc285-cce5-4320-9239-1204bb65fd4a
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3

Alprazolam 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-4 -s-triazolo [4,3-α] [1,4] benzodiazepine, and its structural formula is:
H

Structural formula

Alprazolam is a white to off-white crystalline powder, which is soluble in alcohol but which has no appreciable solubility in water at physiological pH. Each tablet, for oral administration, contains 0.25 mg, 0.5 mg, 1 mg, and 2 mg of alprazolam. The 2 mg tablets are multiscored, and may be divided in half to provide two 1 mg segments, or quarters to provide four 0.5 mg segments. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, docusate sodium, lactose (hydrous), magnesium stearate, microcrystalline cellulose, and sodium benzoate. The 0.5 mg tablet also contains FD&C yellow #6 aluminum lake (sunset yellow lake). The 1 mg tablet also contains FD&C blue #2 aluminum lake. The 2 mg tablet also contains D&C yellow #10 aluminum lake.

CLINICAL PHARMACOLOGY


id: c99d7cc9-a258-4d38-8dc7-5fbc06a36cdd
displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1

CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis. Following oral administration, alprazolam is readily absorbed. Peak concentrations in the plasma occur in one to two hours following administration. Plasma levels are proportionate to the dose given; over the dose range of 0.5 to 3 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults. The predominant metabolites are α -hydroxy-alprazolam and a benzophenone derived from alprazolam. The biological activity of α -hydroxy-alprazolam is approximately one-half that of alprazolam. The benzophenone metabolite is essentially inactive. Plasma levels of these metabolites are extremely low, thus precluding precise pharmacokinetic description. However, their half-lives appear to be of the same order of magnitude as that of alprazolam. Alprazolam and its metabolites are excreted primarily in the urine. The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined. However, this is not a property of benzodiazepines in general. Further, alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally. , alprazolam is bound (80 percent) to human serum protein.
In vitro
Changes in the absorption, distribution, metabolism and excretion of benzodiazepines have been reported in a variety of disease states including alcoholism, impaired hepatic function and impaired renal function. Changes have also been demonstrated in geriatric patients. A mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9.0 to 26.9 hours, n=16) compared to 11.0 hours (range: 6.3 to 15.8 hours, n=16) in healthy adult subjects. In patients with alcoholic liver disease the half-life of alprazolam ranged between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and 26.9 hours (mean=11.4 hours, n=17) in healthy subjects. In an obese group of subjects the half-life of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8 hours, n=12) as compared to between 6.3 and 15.8 hours (mean=10.6 hours, n=12) in healthy subjects. Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes transplacental passage and that it is excreted in human milk.

INDICATIONS AND USAGE


id: 6f32eb3f-512e-4d9f-b804-df81e3c613f2
displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

Alprazolam tablets are indicated for the management of anxiety disorder (a condition corresponding most closely to the APA Diagnostic and Statistical Manual (DSM-III-R) diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. Generalized anxiety disorder is characterized by unrealistic or excessive anxiety and worry (apprehensive expectation) about two or more life circumstances, for a period of six months or longer, during which the person has been bothered more days than not by these concerns. At least 6 of the following 18 symptoms are often present in these patients: (trembling, twitching, or feeling shaky; muscle tension, aches, or soreness; restlessness; easy fatigability); (shortness of breath or smothering sensations; palpitations or accelerated heart rate; sweating, or cold clammy hands; dry mouth; dizziness or light-headedness; nausea, diarrhea, or other abdominal distress; flushes or chills; frequent urination; trouble swallowing or ‘lump in throat’); (feeling keyed up or on edge; exaggerated startle response; difficulty concentrating or ‘mind going blank’ because of anxiety; trouble falling or staying asleep; irritability). These symptoms must not be secondary to another psychiatric disorder or caused by some organic factor.
Motor Tension
Autonomic Hyperactivity
Vigilance and Scanning
Anxiety associated with depression is responsive to alprazolam. Alprazolam tablets are also indicated for the treatment of panic disorder, with or without agoraphobia. Studies supporting this claim were conducted in patients whose diagnoses corresponded closely to the DSM-III-R criteria for panic disorder (see ). CLINICAL STUDIES Panic disorder is an illness characterized by recurrent panic attacks. The panic attacks, at least initially, are unexpected. Later in the course of this disturbance certain situations, eg, driving a car or being in a crowded place, may become associated with having a panic attack. These panic attacks are not triggered by situations in which the person is the focus of others’ attention (as in social phobia). The diagnosis requires four such attacks within a four week period, or one or more attacks followed by at least a month of persistent fear of having another attack. The panic attacks must be characterized by at least four of the following symptoms: dyspnea or smothering sensations; dizziness, unsteady feelings, or faintness; palpitations or tachycardia; trembling or shaking; sweating; choking; nausea or abdominal distress; depersonalization or derealization; paresthesias; hot flashes or chills; chest pain or discomfort; fear of dying; fear of going crazy or of doing something uncontrolled. At least some of the panic attack symptoms must develop suddenly, and the panic attack symptoms must not be attributed to some know organic factors. Panic disorder is frequently associated with some symptoms of agoraphobia. Demonstrations of the effectiveness of alprazolam by systematic clinical study are limited to four months duration for anxiety disorder and four to ten weeks duration for panic disorder; however, patients with panic disorder have been treated on an open basis for up to eight months without apparent loss of benefit. The physician should periodically reassess the usefulness of the drug for the individual patient.

CONTRAINDICATIONS


id: eb009d33-69f3-4f6d-a12b-ada120a6b76b
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

Alprazolam tablets are contraindicated in patients with known sensitivity to this drug or other benzodiazepines. Alprazolam 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 is contraindicated with ketoconazole and intraconazole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP 3A) (see and ). WARNINGS PRECAUTIONS-Drug Interactions

ADVERSE REACTIONS


id: e0b6645e-f12d-4599-b91c-bf447017cb64
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

Side effects to alprazolam, if they occur, are generally observed at the beginning of therapy and usually disappear upon continued medication. In the usual patient, the most frequent side effects are likely to be an extension of the pharmacological activity of alprazolam, eg, drowsiness or light-headedness. The data cited in the two tables below are estimates of untoward clinical event incidence among patients who participated under the following clinical conditions: relatively short duration (ie, four weeks) placebo-controlled clinical studies with dosages up to 4 mg/day of alprazolam (for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety) and short-term (up to ten weeks) placebo-controlled clinical studies with dosages up to 10 mg/day of alprazolam in patients with panic disorder, with or without agoraphobia. These data cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics, and other factors often differ from those in clinical trials. These figures cannot be compared with those obtained from other clinical studies involving related drug products and placebo as each group of drug trials are conducted under a different set of conditions. Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the relative contributions of drug and non-drug factors to the untoward event incidence in the population studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient but induce it in others. (For example, an anxiolytic drug may relieve dry mouth [a symptom of anxiety] in some subjects but induce it [an untoward event] in others.) Additionally, for anxiety disorders the cited figures can provide the prescriber with an indication as to the frequency with which physician intervention (eg, increased surveillance, decreased dosage or discontinuation of drug therapy) may be necessary because of the untoward clinical event.

ANXIETY DISORDERS
  Treatment-Emergent Symptom Incidence†    
Incidence of Intervention


Because of Symptom

 *None reported
  †Events reported by 1% or more of alprazolam patients are included
   

Alprazolam
 

Placebo
   

Alprazolam
 Number of Patients  565  505    565
 % of Patients Reporting:        
 CENTRAL NERVOUS SYSTEM        
 Drowsiness  41.0  21.6    15.1
 Light-headedness  20.8  19.3    1.2
 Depression  13.9  18.1    2.4
 Headache  12.9  19.6    1.1
 Confusion  9.9  10.0    0.9
 Insomnia  8.9  18.4    1.3
 Nervousness  4.1  10.3    1.1
 Syncope  3.1  4.0    *
 Dizziness  1.8  0.8    2.5
 Akathisia  1.6  1.2    *
 Tiredness/Sleepiness  *  *    1.8
 GASTROINTESTINAL        
 Dry Mouth  14.7  13.3    0.7
 Constipation  10.4  11.4    0.9
 Diarrhea  10.1  10.3    1.2
 Nausea/Vomiting  9.6  12.8    1.7
 Increased Salivation  4.2  2.4    *
 CARDIOVASCULAR        
 Tachycardia/Palpitations  7.7  15.6    0.4
 Hypotension  4.7  2.2    *
 SENSORY        
 Blurred Vision  6.2  6.2    0.4
 MUSCULOSKELETAL        
 Rigidity  4.2  5.3    *
 Tremor  4.0  8.8    0.4
 CUTANEOUS        
 Dermatitis/Allergy  3.8  3.1    0.6
 OTHER        
 Nasal Congestion  7.3  9.3    *
 Weight Gain  2.7  2.7    *
 Weight Loss  2.3  3.0    *
In addition to the relatively common (ie, greater than 1%) untoward events enumerated in the table above, the following adverse events 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.
PANIC DISORDER
    Treatment-Emergent


Symptom Incidence*

 
*Events reported by 1% or more of alprazolam patients are included.
     Alprazolam  Placebo
 Number of Patients    1388  1231
 % of Patients Reporting:      
 
Central Nervous System
     
 Drowsiness    76.8  42.7
 Fatigue and Tiredness    48.6  42.3
 Impaired Coordination    40.1  17.9
 Irritability    33.1  30.1
 Memory Impairment    33.1  22.1
 Light-headedness/Dizziness    29.8  36.9
 Insomnia    29.4  41.8
 Headache    29.2  35.6
 Cognitive Disorder    28.8  20.5
 Dysarthria    23.3  6.3
 Anxiety    16.6  24.9
 Abnormal Involuntary Movement     14.8

  21.0

 Decreased Libido    14.4  8.0
 Depression    13.8  14.0
 Confusional State    10.4  8.2
 Muscular Twitching    7.9  11.8
 Increased Libido    7.7  4.1
 Change in Libido (Not Specified)

    7.1

  5.6

 Weakness    7.1  8.4
 Muscle Tone Disorders    6.3  7.5
 Syncope    3.8  4.8
 Akathisia    3.0  4.3
 Agitation    2.9  2.6
 Disinhibition    2.7  1.5
 Paresthesia    2.4  3.2
 Talkativeness    2.2  1.0
 Vasomotor Disturbances    2.0  2.6
 Derealization    1.9  1.2
 Dream Abnormalities    1.8  1.5
 Fear    1.4  1.0
 Feeling Warm    1.3  0.5
 
Gastrointestinal
     
 Decreased Salivation    32.8  34.2
 Constipation    26.2  15.4
 Nausea/Vomiting    22.0  31.8
 Diarrhea    20.6  22.8
 Abdominal Distress    18.3  21.5
 Increased Salivation    5.6  4.4
 
Cardio-Respiratory
     
 Nasal Congestion    17.4  16.5
 Tachycardia    15.4  26.8
 Chest Pain    10.6  18.1
 Hyperventilation    9.7  14.5
 Upper Respiratory Infection    4.3  3.7
 
Sensory
     
 Blurred Vision    21.0  21.4
 Tinnitus    6.6  10.4
 
Musculoskeletal
     
 Muscular Cramps    2.4  2.4
 Muscle Stiffness    2.2  3.3
 
Cutaneous
     
 Sweating    15.1  23.5
 Rash    10.8  8.1
 
Other
     
 Increased    32.7  22.8
 Decreased Appetite    27.8  24.1
 Weight Gain    27.2  17.9
 Weight Loss    22.6  16.5
 Micturition Difficulties    12.2  8.6
 Menstrual Disorders    10.4  8.7
 Sexual Dysfunction    7.4  3.7
 Edema    4.9  5.6
 Incontinence    1.5  0.6
 Infection    1.3  1.7
In addition to the relatively common (ie, greater than 1%) untoward events enumerated in the table above, the following adverse events have been reported in association with the use of alprazolam: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice. 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, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.5 mg every three days (see ). 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. DOSAGE AND ADMINISTRATION Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Therefore, the same precaution must be exercised when using doses of alprazolam greater than 4 mg/day in treating patients with panic disorders as is exercised with the use of any psychotropic drug in treating depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans. 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. Laboratory analyses were performed on all patients participating in the clinical program for alprazolam. The following incidences of abnormalities shown below were observed in patients receiving alprazolam and in patients in the corresponding placebo group. Few of these abnormalities were considered to be of physiological significance.
  Placebo
   
LOW
 
HIGH
 
LOW
 
HIGH
 *Less Than 1%
 HEMATOLOGY        
 Hematocrit  *  *  *  *
 Hemoglobin  *  *  *  *
 Total WBC Count  1.4  2.3  1.0  2.0
 Neutrophil Count  2.3  3.0  4.2  1.7
 Lymphocyte Count  5.5  7.4  5.4  9.5
 Monocyte Count  5.3  2.8  6.4  *
 Eosinophil Count  3.2  9.5  3.3  7.2
 Basophil Count  *  *  *  *
 URINALYSIS        
 Albumin  —  *  —  *
 Sugar  —  *  —  *
 RBC/HPF  —  3.4  —  5.0
 WBC/HPF  —  25.7  —  25.9
 BLOOD CHEMISTRY        
 Creatinine  2.2  1.9  3.5  1.0
 Bilirubin  *  1.6  *  *
 SGOT  *  3.2  1.0  1.8
 Alkaline Phosphatase  *  1.7  *  1.8
When treatment with alprazolam is protracted, periodic blood counts, urinalysis and blood chemistry analyses are advisable. Minor changes in EEG patterns, usually low-voltage fast activity have been observed in patients during therapy with alprazolam and are of no known significance. Various adverse drug reactions have been reported in association with the use of alprazolam since market introduction. The majority of these reactions were reported through the medical event voluntary reporting system. Because of the spontaneous nature of the reporting of medical events and the lack of controls, a causal relationship to the use of alprazolam cannot be readily determined. Reported events include: liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson syndrome, hyperprolactinemia, gynecomastia and galactorrhea.
Post Introduction Reports:

DRUG ABUSE AND DEPENDENCE


id: 504cb02b-6603-413d-adbc-8dfccec9b615
displayName: DRUG ABUSE AND DEPENDENCE SECTION
FDA Article Code: 42227-9

Withdrawal symptoms similar in character to those noted with sedative/hypnotics and alcohol have occurred following abrupt 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.
Physical And Psychological Dependence:
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 and ). WARNINGS 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: 63622dde-311b-4dd7-afe4-62a91a0e520b
displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5

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. The acute oral LD in rats is 331 to 2171 mg/kg. Other experiments in animals have indicated that cardiopulmonary collapse can occur following massive intravenous doses of alprazolam (over 195 mg/kg; 975 times the maximum recommended daily human dose of 10 mg/day). Animals could be resuscitated with positive mechanical ventilation and the intravenous infusion of norepinephrine bitartrate.
50
Animal experiments have suggested that forced diuresis or hemodialysis are probably of little value in treating overdosage. Overdosage reports with alprazolam tablets are limited. 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. If hypotension occurs, it may be combated by the use of vasopressors. Dialysis is of limited value. As with the management of intentional overdosing with any drug, it should be borne in mind that multiple agents may have been ingested.
General Treatment Of Overdose:
Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used 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 complete flumazenil package insert including , , and should be consulted prior to use.
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. CONTRAINDICATIONS WARNINGS PRECAUTIONS

DOSAGE AND ADMINISTRATION


id: 5ed7a959-6e97-41c1-a169-4e9dbfb2e38b
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who require doses greater than 4 mg/day. In such cases, dosage should be increased cautiously to avoid adverse effects.

Alprazolam 1mg (CIV) Tablet


id: 25fcc9db-406d-4cd5-bd37-a65f324e0194
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4