ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. 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 (i.e., four weeks) placebo-controlled clinical studies with dosages up to 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 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 drug may relieve 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 (e.g., increased surveillance, decreased dosage or discontinuation of drug therapy) may be necessary because of the untoward clinical event.Table 1: Treatment-Emergent Adverse Events Reported in Placebo-Controlled Trials of Anxiety DisordersANXIETY DISORDERSTreatment-Emergent Symptom IncidenceEvents reported by 1% or more of alprazolam patients are included.Incidence of Intervention Because of SymptomAlprazolamPlaceboAlprazolamNumber of Patients565505565% of Patients Reporting:Central Nervous System Drowsiness41.021.615.1 Light-Headedness20.819.31.2 Depression13.918.12.4 Headache12.919.61.1 Confusion9.910.00.9 Insomnia8.918.41.3 Nervousness4.110.31.1 Syncope3.14.0None reported. Dizziness1.80.82.5 Akathisia1.61.2 Tiredness/Sleepiness1.8Gastrointestinal Dry Mouth14.713.30.7 Constipation10.411.40.9 Diarrhea10.110.31.2 Nausea/Vomiting9.612.81.7 Increased Salivation4.22.4Cardiovascular Tachycardia/Palpitations7.715.60.4 Hypotension4.72.2Sensory Blurred Vision6.26.20.4Musculoskeletal Rigidity4.25.3 Tremor4.08.80.4Cutaneous Dermatitis/Allergy3.83.10.6Other Nasal Congestion7.39.3 Weight Gain2.72.7 Weight Loss2.33.0In addition to the relatively common (i.e., 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.Table 2: Treatment-Emergent Adverse Events Reported in Placebo-Controlled Trials of Panic DisorderPANIC DISORDERTreatment-Emergent Symptom IncidenceEvents reported by 1% or more of alprazolam patients are included.Alprazolam PlaceboNumber of Patients1,3881,231% of Patients Reporting:Central Nervous System Drowsiness76.842.7 Fatigue and Tiredness48.642.3 Impaired Coordination40.117.9 Irritability33.130.1 Memory Impairment33.122.1 Light-Headedness/Dizziness29.836.9 Insomnia29.441.8 Headache29.235.6 Cognitive Disorder28.820.5 Dysarthria23.36.3 Anxiety16.624.9 Abnormal Involuntary Movement14.821.0 Decreased Libido14.48.0 Depression13.814.0 Confusional State10.48.2 Muscular Twitching7.911.8 Increased Libido7.74.1 Change in Libido (Not Specified)7.15.6 Weakness7.18.4 Muscle Tone Disorders6.37.5 Syncope3.84.8 Akathisia3.04.3 Agitation2.92.6 Disinhibition2.71.5 Paresthesias2.43.2 Talkativeness2.21.0 Vasomotor Disturbances2.02.6 Derealization1.91.2 Dream Abnormalities1.81.5 Fear1.41.0 Feeling Warm1.30.5Gastrointestinal Decreased Salivation32.834.2 Constipation26.215.4 Nausea/Vomiting22.031.8 Diarrhea20.622.8 Abdominal Distress18.321.5 Increased Salivation5.64.4Cardio-Respiratory Nasal Congestion17.416.5 Tachycardia15.426.8 Chest Pain10.618.1 Hyperventilation9.714.5 Upper Respiratory Infection4.33.7Sensory Blurred Vision21.021.4 Tinnitus6.610.4Musculoskeletal Muscular Cramps2.42.4 Muscle Stiffness2.23.3Cutaneous Sweating15.123.5 Rash10.88.1Other Increased Appetite32.722.8 Decreased Appetite27.824.1 Weight Gain27.217.9 Weight Loss22.616.5 Micturition Difficulties12.28.6 Menstrual Disorders10.48.7 Sexual Dysfunction7.43.7 Edema4.95.6 Incontinence1.50.6 Infection1.31.7In 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. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients (see PRECAUTIONS: General). Adverse Events Reported as Reasons for Discontinuation in Treatment of Panic Disorder in Placebo-Controlled Trials In larger database comprised of both controlled and uncontrolled studies in which 641 patients received alprazolam, discontinuation-emergent symptoms which occurred at rate of over 5% in patients treated with alprazolam and at greater rate than the placebo treated group were as follows:Table 3: Discontinuation-Emergent Symptom IncidencePercentage of 641 Alprazolam-Treated Panic Disorder Patients Reporting EventsBody System/EventNeurologicGastrointestinal Insomnia29.5 Nausea/Vomiting16.5 Light-Headedness19.3 Diarrhea13.6 Abnormal Involuntary Movement17.3 Decreased Salivation10.6 Headache17.0Metabolic-Nutritional Muscular Twitching6.9 Weight Loss13.3 Impaired Coordination6.6 Decreased Appetite12.8 Muscle Tone Disorders5.9Dermatological Weakness5.8 Sweating14.4PsychiatricCardiovascular Anxiety19.2 Tachycardia12.2 Fatigue and Tiredness18.4Special Senses Irritability10.5 Blurred Vision10.0 Cognitive Disorder10.3 Memory Impairment5.5 Depression5.1 Confusional State5.0From the studies cited, it has not been determined whether these symptoms are clearly related to the dose and duration of therapy with alprazolam in patients with panic disorder. 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 DOSAGE AND ADMINISTRATION). Some patients may benefit from an even slower dosage reduction. In controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with 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 reduction in symptoms associated with 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, 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 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, causal relationship to the use of alprazolam 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).

BOXED WARNING SECTION.

WARNING: RISK FROM CONCOMITANT USE WITH OPIOIDS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death [see WARNINGS, Drug Interactions]. oReserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.oLimit dosages and durations to the minimum required.oFollow patients for signs and symptoms of respiratory depression and sedation.. oReserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.. oLimit dosages and durations to the minimum required.. oFollow patients for signs and symptoms of respiratory depression and sedation.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. PharmacodynamicsCNS 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 dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis.PharmacokineticsAbsorptionFollowing oral administration, alprazolam is readily absorbed. Peak concentrations in the plasma occur in to hours following administration. Plasma levels are proportionate to the dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. Using 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. DistributionIn vitro, alprazolam is bound (80 percent) to human serum protein. Serum albumin accounts for the majority of the binding.Metabolism/EliminationAlprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and -hydroxyalprazolam. benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. The plasma concentrations of 4- hydroxyalprazolam and -hydroxyalprazolam relative to unchanged alprazolam concentration were always less than 4%. 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 -hydroxyalprazolam. Such low concentrations and the lesser potencies of 4-hydroxyalprazolam and -hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive. Alprazolam and its metabolites are excreted primarily in the urine.Special PopulationsChanges in the absorption, distribution, metabolism and excretion of benzodiazepines have been reported in variety of disease states including alcoholism, impaired hepatic function and impaired renal function. Changes have also been demonstrated in geriatric patients. 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.Race: Maximal concentrations and half-life of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians.Pediatrics: The pharmacokinetics of alprazolam in pediatric patients have not been studied.Gender: Gender has no effect on the pharmacokinetics of alprazolam.Cigarette Smoking: Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers.Drug-Drug InteractionsAlprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most of the interactions that have been documented with alprazolam are with drugs that inhibit or induce CYP3A4.Compounds that are potent inhibitors of CYP3A would be expected to increase plasma alprazolam concentrations. Drug products that have been studied in vivo, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.70 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions). CYP3A inducers would be expected to decrease alprazolam concentrations and this has been observed in vivo. The oral clearance of alprazolam (given in 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 h) following administration of 300 mg/day carbamazepine for 10 days (see PRECAUTIONS: Drug Interactions). However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000 to 1200 mg/day); the effect at usual carbamazepine doses is unknown.The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined. However, this is not property of benzodiazepines in general. Further, alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.

CLINICAL STUDIES SECTION.

CLINICAL STUDIES. Anxiety DisordersAlprazolam was compared to placebo in double blind clinical studies (doses up to mg/day) in patients with diagnosis of anxiety or anxiety with associated depressive symptomatology. Alprazolam was significantly better than placebo at each of the evaluation periods of these 4-week studies as judged by the following psychometric instruments: Physicians Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patients Global Impressions and Self-Rating Symptom Scale.Panic DisorderSupport for the effectiveness of alprazolam in the treatment of panic disorder came from three 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 was to mg/day in two of the studies, and the doses of alprazolam were fixed at and mg/day in the third study. In all three studies, alprazolam was superior to placebo on variable defined as the number of patients with zero panic attacks (range, 37 to 83% met this criterion), as well as on global improvement score. In two of the three studies, alprazolam was superior to placebo on variable defined as change from baseline on the number of panic attacks per week (range, 3.3 to 5.2), and also on phobia rating scale. subgroup of patients who were improved on alprazolam during short-term treatment in one of these trials was continued on an open basis up to months, without apparent loss of benefit.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Alprazolam Intensol TM oral solution is contraindicated in patients with known sensitivity to this drug or other benzodiazepines. Alprazolam Intensol TM oral solution is contraindicated with ketoconazole and itraconazole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A) (see WARNINGS and PRECAUTIONS: Drug Interactions).

DESCRIPTION SECTION.

DESCRIPTION. Alprazolam Intensol(TM) contains alprazolam which is 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-][1,4]benzodiazepine.The structural formula is represented below:Alprazolam is white to off-white crystalline powder, which is soluble in alcohol but which has no appreciable solubility in water at physiological pH.Each mL, for oral administration, contains mg of alprazolam USP and the following inactive ingredients: propylene glycol, succinic acid disodium salt and water.. chemstructure.jpg.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. 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 mg/day. In such cases, dosage should be increased cautiously to avoid adverse effects. Anxiety Disorders and Transient Symptoms of Anxiety Treatment for patients with anxiety should be initiated with dose of 0.25 to 0.5 mg given three times daily. The dose may be increased to achieve maximum therapeutic effect, at intervals of to days, to maximum daily dose of mg, given in divided doses. The lowest possible effective dose should be employed and the need for continued treatment reassessed frequently. The risk of dependence may increase with dose and duration of treatment. In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every days. Some patients may require an even slower dosage reduction. Panic Disorder The successful treatment of many panic disorder patients has required the use of alprazolam at doses greater than mg daily. In controlled trials conducted to establish the efficacy of alprazolam in panic disorder, doses in the range of to 10 mg daily were used. The mean dosage employed was approximately to mg daily. Among the approximately 1,700 patients participating in the panic disorder development program, about 300 received alprazolam in dosages of greater than mg/day, including approximately 100 patients who received maximum dosages of greater than mg/day. Occasional patients required as much as 10 mg day to achieve successful response.Dose Titration Treatment may be initiated with dose of 0.5 mg three times daily. Depending on the response, the dose may be increased at intervals of to days in increments of no more than mg per day. Slower titration to the dose levels greater than mg/day may be advisable to allow full expression of the pharmacodynamic effect of alprazolam. To lessen the possibility of interdose symptoms, the times of administration should be distributed as evenly as possible throughout the waking hours, that is, on three or four times per day schedule. Generally, therapy should be initiated at low dose to minimize the risk of adverse responses in patients especially sensitive to the drug. Dose should be advanced until an acceptable therapeutic response (i.e., substantial reduction in or total elimination of panic attacks) is achieved, intolerance occurs, or the maximum recommended dose is attained.Dose MaintenanceFor patients receiving doses greater than mg/day, periodic reassessment and consideration of dosage reduction is advised. In controlled postmarketing dose-response study, patients treated with doses of alprazolam greater than mg/day for months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit. Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided (see WARNINGS, PRECAUTIONS, DRUG ABUSE AND DEPENDENCE). The necessary duration of treatment for panic disorder patients responding to alprazolam is unknown. After period of extended freedom from attacks, 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.Dose ReductionBecause of the danger of withdrawal, abrupt discontinuation of treatment should be avoided (see WARNINGS, PRECAUTIONS, DRUG ABUSE AND DEPENDENCE).In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every three days. Some patients may require an even slower dosage reduction. In any case, reduction of dose must be undertaken under close supervision and must be gradual. If significant withdrawal symptoms develop, the previous dosing schedule should be reinstituted and, only after stabilization, should less rapid schedule of discontinuation be attempted. In controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with 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 reduction in symptoms associated with withdrawal syndrome. It is suggested that the dose be reduced by no more than 0.5 mg every days, with the understanding that some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.Dosing in Special Populations In elderly patients, in patients with advanced liver disease or in patients with debilitating disease, the usual starting dose is 0.25 mg, given two or three times daily. This may be gradually increased if needed and tolerated. The elderly may be especially sensitive to the effects of benzodiazepines. If side effects occur at the recommended starting dose, the dose may be lowered.

DRUG ABUSE AND DEPENDENCE SECTION.

DRUG ABUSE AND DEPENDENCE. 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 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. 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 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 mg/day (see WARNINGS).Patients, especially individuals with 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 dosage reduction be gradually tapered under close supervision (see WARNINGS and DOSAGE AND ADMINISTRATION). Psychological dependence is risk with all benzodiazepines, including alprazolam. The risk of psychological dependence may also be increased at doses greater than mg/day and with longer term use, and this risk is further increased in patients with 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.Controlled Substance Class Alprazolam is controlled substance under the Controlled Substance Act by the Drug Enforcement Administration and Alprazolam Intensol(TM) has been assigned to Schedule IV.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Alprazolam Intensol(TM) Oral Solution (Concentrate)1 mg per mL oral solution is supplied with calibrated dropper (graduations of 0.25 mL [0.25 mg], 0.5 mL [0.5 mg], 0.75 mL [0.75 mg], and mL [1 mg] on the dropper) and is clear, colorless solution. NDC 0054-3068-44: Bottle of 30 mL Store at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]PROTECT FROM LIGHT.Discard opened bottle after 90 days.Rx only.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Anxiety Disorders Alprazolam Intensol TM Oral Solution is 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 period of months or longer, during which the person has been bothered more days than not by these concerns. At least of the following 18 symptoms are often present in these patients: Motor Tension (trembling, twitching, or feeling shaky; muscle tension, aches, or soreness; restlessness; easy fatigability); Autonomic Hyperactivity (shortness of breath or smothering sensations; palpitations or accelerated heart rate; sweating, or cold clammy hands; dry mouth; dizziness or light-headedness; nausea, diarrhea, or other abdominal distress; flushes or chills; frequent urination; trouble swallowing or lump in throat); Vigilance and Scanning (feeling keyed up or on edge; exaggerated startle response; difficulty concentrating or mind going blank because of anxiety; trouble falling or staying asleep; irritability). These symptoms must not be secondary to another psychiatric disorder or caused by some organic factor.Anxiety associated with depression is responsive to Alprazolam Intensol TM Oral Solution.Panic Disorder Alprazolam Intensol TM Oral Solution is 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/IV criteria for panic disorder (see CLINICAL STUDIES).Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach 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. Demonstrations of the effectiveness of Alprazolam Intensol TM Oral Solution by systematic clinical study are limited to months duration for anxiety disorder and to 10 weeks duration for panic disorder; however, patients with panic disorder have been treated on an open basis for up to months without apparent loss of benefit. The physician should periodically reassess the usefulness of the drug for the individual patient.

OVERDOSAGE SECTION.

OVERDOSAGE. 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 combination of 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 LD50 in rats is 331 to 2,171 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.Animal experiments have suggested that forced diuresis or hemodialysis are probably of little value in treating overdosage.General Treatment of Overdose Overdosage reports with alprazolam 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. Flumazenil, 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 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 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 risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS should be consulted prior to use.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel . fpl-label-1mg-per-ml-os-05.jpg.

PRECAUTIONS SECTION.

PRECAUTIONS. GeneralSuicideAs with other psychotropic medications, the usual precautions with respect to administration of the drug and size of the prescription are indicated for severely depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients.ManiaEpisodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression.Uricosuric EffectAlprazolam has weak uricosuric effect. Although other medications with weak uricosuric effect have been reported to cause acute renal failure, there have been no reported instances of acute renal failure attributable to therapy with alprazolam.Use in Patients with Concomitant IllnessIt is recommended that the dosage be limited to the smallest effective dose to preclude the development of ataxia or oversedation which may be particular problem in elderly or debilitated patients (see DOSAGE AND ADMINISTRATION). The usual precautions in treating patients with impaired renal, hepatic or pulmonary function should be observed. There have been rare reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam. decreased systemic alprazolam elimination rate (e.g., increased plasma half-life) has been observed in both alcoholic liver disease patients and obese patients receiving alprazolam (see CLINICAL PHARMACOLOGY). Information for Patients For All Users of AlprazolamTo assure safe and effective use of benzodiazepines, all patients prescribed alprazolam should be provided with the following guidance.1.Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when alprazolam is used with opioids and not to use such drugs concomitantly unless supervised by health care provider.2.Advise patients not to drive or operate heavy machinery until the effects of concomitant use with opioids have been determined [see Drug Interactions].3.Inform your physician about any alcohol consumption and medicine you are taking now, including medication you may buy without prescription. Alcohol should generally not be used during treatment with benzodiazepines.4.Not recommended for use in pregnancy. Therefore, inform your physician if you are pregnant, if you are planning to have child, or if you become pregnant while you are taking this medication.5.Inform your physician if you are nursing. 6.Until you experience how this medication affects you, do not drive car or operate potentially dangerous machinery, etc. 7.Do not increase the dose even if you think the medication does not work anymore without consulting your physician. Benzodiazepines, even when used as recommended, may produce emotional and/or physical dependence.8.Do not stop taking this medication abruptly or decrease the dose without consulting your physician, since withdrawal symptoms can occur.Additional Advice for Panic Disorder PatientsThe use of alprazolam at doses greater than mg/day, often necessary to treat panic disorder, is accompanied by risks that you need to carefully consider. When used at doses greater than mg/day, which may or may not be required for your treatment, alprazolam has the potential to cause severe emotional and physical dependence in some patients and these patients may find it exceedingly difficult to terminate treatment. In two controlled trials of to weeks duration where the ability of patients to discontinue medication was measured, to 29% of patients treated with alprazolam did not completely taper off therapy. In controlled postmarketing discontinuation study of panic disorder patients, the patients treated with doses of alprazolam greater than mg/day had more difficulty tapering to zero dose than patients treated with less than mg/day. In all cases, it is important that your physician help you discontinue this medication in careful and safe manner to avoid overly extended use of alprazolam. In addition, the extended use at doses greater than mg/day appears to increase the incidence and severity of withdrawal reactions when alprazolam is discontinued. These are generally minor but seizure can occur, especially if you reduce the dose too rapidly or discontinue the medication abruptly. Seizure can be life-threatening.Laboratory TestsLaboratory tests are not ordinarily required in otherwise healthy patients. However, when treatment is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are advisable in keeping with good medical practice.DrugInteractionsUse with Opioids 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 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. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation.Use with Other CNS DepressantsIf alprazolam is to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines. The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression.Use with Imipramine and DesipramineThe 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 in doses up to mg/day. The clinical significance of these changes is unknown.Drugs that Inhibit Alprazolam Metabolism via Cytochrome P450 3AThe initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs which inhibit this metabolic pathway may have profound effect on the clearance of alprazolam (see CONTRAINDICATIONS and WARNINGS for additional drugs of this type).Drugs Demonstrated to be CYP3A Inhibitors of Possible Clinical Significance on the Basis of Clinical Studies Involving Alprazolam (Caution is Recommended During Coadministration with Alprazolam) Fluoxetine: Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased measured psychomotor performance.Propoxyphene: Coadministration of propoxyphene decreased the maximum plasma concentration of alprazolam by 6%, decreased clearance by 38%, and increased half-life by 58%. Oral Contraceptives: Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased half-life by 29%. Drugs and Other Substances Demonstrated to be CYP 3A Inhibitors on the Basis of Clinical Studies Involving Benzodiazepines Metabolized Similarly to Alprazolam or on the Basis of In Vitro Studies with Alprazolam or Other Benzodiazepines (Caution is Recommended During Coadministration with Alprazolam)Available data from clinical studies of benzodiazepines other than alprazolam suggest possible drug interaction with alprazolam for the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro studies of alprazolam suggest possible drug interaction with alprazolam for the following: sertraline and paroxetine. However, data from an in vivo drug interaction study involving single dose of alprazolam mg and steady state dose of sertraline (50 to 150 mg/day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Data from in vitro studies of benzodiazepines other than alprazolam suggest possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during the coadministration of any of these with alprazolam (see WARNINGS).Drugs Demonstrated to be Inducers of CYP3ACarbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels of alprazolam.Drug/Laboratory Test Interactions Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for specific drug or specific test.Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of carcinogenic potential was observed during 2-year bioassay studies of alprazolam in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum recommended daily human dose).Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which is 500 times the maximum recommended daily human dose of 10 mg/day. Alprazolam also was not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay. Alprazolam produced no impairment of fertility in rats at doses up to mg/kg/day, which is 25 times the maximum recommended daily human dose of 10 mg/day.Pregnancy Teratogenic Effects Pregnancy Category D: (See WARNINGS section).Nonteratogenic EffectsIt should be considered that the child born of mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.Labor and Delivery Alprazolam has no established use in labor or delivery.Nursing Mothers Benzodiazepines are known to be excreted in human milk. It should be assumed that alprazolam is as well. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. As general rule, nursing should not be undertaken by mothers who must use alprazolam.Pediatric Use Safety and effectiveness of alprazolam in individuals below 18 years of age have not been established.Geriatric Use The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug as compared with younger population receiving the same doses. The smallest effective dose of alprazolam should be used in the elderly to preclude the development of ataxia and oversedation (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).. 1.Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when alprazolam is used with opioids and not to use such drugs concomitantly unless supervised by health care provider.. 2.Advise patients not to drive or operate heavy machinery until the effects of concomitant use with opioids have been determined [see Drug Interactions].. 3.Inform your physician about any alcohol consumption and medicine you are taking now, including medication you may buy without prescription. Alcohol should generally not be used during treatment with benzodiazepines.. 4.Not recommended for use in pregnancy. Therefore, inform your physician if you are pregnant, if you are planning to have child, or if you become pregnant while you are taking this medication.. 5.Inform your physician if you are nursing. 6.Until you experience how this medication affects you, do not drive car or operate potentially dangerous machinery, etc. 7.Do not increase the dose even if you think the medication does not work anymore without consulting your physician. Benzodiazepines, even when used as recommended, may produce emotional and/or physical dependence.. 8.Do not stop taking this medication abruptly or decrease the dose without consulting your physician, since withdrawal symptoms can occur.

SPL MEDGUIDE SECTION.

Medication Guide Alprazolam(al pra zoe lam)Intensol (TM) Oral Solution (Concentrate) CIVRx onlyWhat is the most important information should know about alprazolamoAlprazolam is benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. oAlprazolam can make you sleepy or dizzy, and can slow your thinking and motor skills.oDo not drive, operate heavy machinery, or do other dangerous activities until you know how alprazolam affects you. oDo not drink alcohol or take other drugs that may make you sleepy or dizzy while taking alprazolam without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, alprazolam may make your sleepiness or dizziness much worse. oDo not take more alprazolam than prescribed.What is alprazolam oAlprazolam is prescription medicine used: oto treat anxiety disorders ofor the short-term relief of the symptoms of anxiety oto treat panic disorder with or without fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia)oAlprazolam is federal controlled substance (C-IV) because it can be abused or lead to dependence. Keep alprazolam in safe place to prevent misuse and abuse. Selling or giving away alprazolam 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. oIt is not known if alprazolam is safe and effective in children. oElderly patients are especially susceptible to dose related adverse effects when taking alprazolam. oIt is not known if alprazolam is safe and effective when used to treat anxiety disorder for longer than months. oIt is not known if alprazolam is safe and effective when used to treat panic disorder for longer than 10 weeks.Do not take alprazolam if:oyou are allergic to alprazolam, other benzodiazepines, or any of the ingredients in Alprazolam Intensol(TM). See the end of this Medication Guide for complete list of ingredients in Alprazolam Intensol(TM).oyou are taking antifungal medicines including ketoconazole and itraconazole.Before you take alprazolam, tell your healthcare provider about all of your medical conditions, including if you:ohave or have had depression, mood problems, or suicidal thoughts or behavior ohave liver or kidney problems ohave lung disease or breathing problems oare pregnant or plan to become pregnant. Alprazolam may harm your unborn baby. You and your healthcare provider should decide if you should take alprazolam while you are pregnant. oare 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. You should not breastfeed while taking alprazolam. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking alprazolam with certain other medicines can cause side effects or affect how well alprazolam or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.How should take alprazolamoSee What is the most important information should know about alprazolamoTake alprazolam exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much alprazolam to take and when to take it. oIf you take too much alprazolam, call your healthcare provider or go to the nearest hospital emergency room right away.What should avoid while taking alprazolamoAlprazolam can cause you to be drowsy. Do not drive car or operate heavy machinery until you know how alprazolam affects you. oYou should not drink alcohol while taking alprazolam. Drinking alcohol can increase your chances of having serious side effects.What are the possible side effects of alprazolamAlprazolam may cause serious side effects, including: oSee What is the most important information should know about alprazolamoAbuse and dependence. Taking alprazolam can cause physical and psychological dependence. Physical and psychological dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical and psychological dependence and drug addiction. oWithdrawal symptoms. You may have withdrawal symptoms if you stop taking alprazolam suddenly. Withdrawal symptoms can be serious and include seizures. Mild withdrawal symptoms include depressed mood and trouble sleeping. Talk to your healthcare provider about slowly stopping alprazolam to avoid withdrawal symptoms. oSeizures. Stopping alprazolam can cause seizures and seizures that will not stop (status epilepticus).oMania. Alprazolam may cause an increase in activity and talking (hypomania and mania) in people who have depression. The most common side effects of alprazolam include drowsiness and light-headedness. These are not all the possible side effects of alprazolam. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store Alprazolam Intensol(TM)oStore alprazolam at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]oProtect from light.oDiscard open bottle after 90 days.oKeep alprazolam and all medicines out of the reach of children.General information about the safe and effective use of alprazolam.oMedicines are sometimes prescribed for purposes other than those listed in Medication Guide.oDo not use alprazolam for condition for which it was not prescribed.oDo not give alprazolam to other people, even if they have the same symptoms that you have. It may harm them.oYou can ask your pharmacist or healthcare provider for information about alprazolam that is written for health professionals.What are the ingredients in Alprazolam Intensol(TM)Active ingredient: alprazolam Inactive ingredients: propylene gycol, succinic acid disodium salt, and water.Distr. by: West-Ward Pharmaceuticals Corp.Eatontown, NJ 07724For more information, please call 1-800-962-8364.This Medication Guide has been approved by the U.S. Food and Drug Administration.4041495//05Revised March 2017. oAlprazolam is benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. oAlprazolam can make you sleepy or dizzy, and can slow your thinking and motor skills.oDo not drive, operate heavy machinery, or do other dangerous activities until you know how alprazolam affects you. oDo not drink alcohol or take other drugs that may make you sleepy or dizzy while taking alprazolam without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, alprazolam may make your sleepiness or dizziness much worse. oDo not drive, operate heavy machinery, or do other dangerous activities until you know how alprazolam affects you. oDo not drink alcohol or take other drugs that may make you sleepy or dizzy while taking alprazolam without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, alprazolam may make your sleepiness or dizziness much worse. oDo not take more alprazolam than prescribed.. oAlprazolam is prescription medicine used: oto treat anxiety disorders ofor the short-term relief of the symptoms of anxiety oto treat panic disorder with or without fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia). oto treat anxiety disorders ofor the short-term relief of the symptoms of anxiety oto treat panic disorder with or without fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia). oAlprazolam is federal controlled substance (C-IV) because it can be abused or lead to dependence. Keep alprazolam in safe place to prevent misuse and abuse. Selling or giving away alprazolam 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. oIt is not known if alprazolam is safe and effective in children. oElderly patients are especially susceptible to dose related adverse effects when taking alprazolam. oIt is not known if alprazolam is safe and effective when used to treat anxiety disorder for longer than months. oIt is not known if alprazolam is safe and effective when used to treat panic disorder for longer than 10 weeks.. oyou are allergic to alprazolam, other benzodiazepines, or any of the ingredients in Alprazolam Intensol(TM). See the end of this Medication Guide for complete list of ingredients in Alprazolam Intensol(TM).. oyou are taking antifungal medicines including ketoconazole and itraconazole.. ohave or have had depression, mood problems, or suicidal thoughts or behavior ohave liver or kidney problems ohave lung disease or breathing problems oare pregnant or plan to become pregnant. Alprazolam may harm your unborn baby. You and your healthcare provider should decide if you should take alprazolam while you are pregnant. oare 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. You should not breastfeed while taking alprazolam. oSee What is the most important information should know about alprazolam. oTake alprazolam exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much alprazolam to take and when to take it. oIf you take too much alprazolam, call your healthcare provider or go to the nearest hospital emergency room right away.. oAlprazolam can cause you to be drowsy. Do not drive car or operate heavy machinery until you know how alprazolam affects you. oYou should not drink alcohol while taking alprazolam. Drinking alcohol can increase your chances of having serious side effects.. oSee What is the most important information should know about alprazolam. oAbuse and dependence. Taking alprazolam can cause physical and psychological dependence. Physical and psychological dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical and psychological dependence and drug addiction. oWithdrawal symptoms. You may have withdrawal symptoms if you stop taking alprazolam suddenly. Withdrawal symptoms can be serious and include seizures. Mild withdrawal symptoms include depressed mood and trouble sleeping. Talk to your healthcare provider about slowly stopping alprazolam to avoid withdrawal symptoms. oSeizures. Stopping alprazolam can cause seizures and seizures that will not stop (status epilepticus).. oMania. Alprazolam may cause an increase in activity and talking (hypomania and mania) in people who have depression. oStore alprazolam at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]. oProtect from light.. oDiscard open bottle after 90 days.. oKeep alprazolam and all medicines out of the reach of children.. oMedicines are sometimes prescribed for purposes other than those listed in Medication Guide.. oDo not use alprazolam for condition for which it was not prescribed.. oDo not give alprazolam to other people, even if they have the same symptoms that you have. It may harm them.. oYou can ask your pharmacist or healthcare provider for information about alprazolam that is written for health professionals.

SPL UNCLASSIFIED SECTION.

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 years, tendency for dose related increase in the number of cataracts was observed in females and tendency for dose related increase in corneal vascularization was observed in males. These lesions did not appear until after 11 months of treatment.Distr. By: West-Ward Pharmaceuticals Corp.Eatontown, NJ 07724 4041495//05Revised March 2017.

WARNINGS SECTION.

WARNINGS. Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including alprazolam, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.Observational studies have demonstrated that concomitant use of opioids analgesics and benzodiazepines increases the risks of drug-related mortality compared to use of opioids alone. If decision is made to prescribe alprazolam 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 lower initial dose of alprazolam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in patient already taking alprazolam, prescribe 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 is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with opioids have been determined [see Drug Interactions]. Dependence and Withdrawal Reactions, Including Seizures Certain adverse clinical events, some life-threatening, are direct consequence of physical dependence to alprazolam. These include spectrum of withdrawal symptoms; the most important is seizure (see DRUG ABUSE AND DEPENDENCE). Even after relatively short-term use at the doses recommended for the treatment of transient anxiety and anxiety disorder (i.e., 0.75 to 4.0 mg per 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 mg/day and for long periods (more than 12 weeks). However, in controlled postmarketing discontinuation study of panic disorder patients, the duration of treatment (3 months compared to months) had no effect on the ability of patients to taper to zero dose. In contrast, patients treated with doses of alprazolam greater than mg/day had more difficulty tapering to zero dose than those treated with less than mg/day. The Importance of Dose and the Risks of Alprazolam as Treatment for Panic Disorder Because the management of panic disorder often requires the use of average daily doses of alprazolam above mg, the risk of dependence among panic disorder patients may be higher than that among those treated for less severe anxiety. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder showed high rate of rebound and withdrawal symptoms in patients treated with alprazolam compared to placebo-treated patients. Relapse or return of illness was defined as return of symptoms characteristic of panic disorder (primarily panic attacks) to levels approximately equal to those seen at baseline before active treatment was initiated. Rebound refers to return of symptoms of panic disorder to level substantially greater in frequency, or more severe in intensity than seen at baseline. Withdrawal symptoms were identified as those which were generally not characteristic of panic disorder and which occurred for the first time more frequently during discontinuation than at baseline.In controlled clinical trial in which 63 patients were randomized to alprazolam and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound, or withdrawal.In two controlled trials of to weeks duration where the ability of patients to discontinue medication was measured, 71% to 93% of patients treated with alprazolam tapered completely off therapy compared to 89% to 96% of placebo-treated patients. In controlled postmarketing discontinuation study of panic disorder patients, the duration of treatment (3 months compared to months) had no effect on the ability of patients to taper to zero dose. Seizures attributable to alprazolam were seen after drug discontinuance or dose reduction in of 1,980 patients with panic disorder or in patients participating in clinical trials where doses of alprazolam greater than mg/day for over months were permitted. Five of these cases clearly occurred during abrupt dose reduction, or discontinuation from daily doses of to 10 mg. Three cases occurred in situations where there was not clear relationship to abrupt dose reduction or discontinuation. In one instance, seizure occurred after discontinuation from single dose of mg after tapering at rate of mg every days from mg daily. In two other instances, the relationship to taper is indeterminate; in both of these cases the patients had been receiving doses of mg daily prior to seizure. The duration of use in the above cases ranged from to 22 weeks. There have been occasional voluntary reports of patients developing seizures while apparently tapering gradually from alprazolam. The risk of seizure seems to be greatest 24 to 72 hours after discontinuation (see DOSAGE AND ADMINISTRATION for recommended tapering and discontinuation schedule). Status Epilepticus and its Treatment The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of alprazolam. In most cases, only single seizure was reported; however, multiple seizures and status epilepticus were reported as well.Interdose Symptoms Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam have been reported in patients with panic disorder taking prescribed maintenance doses of alprazolam. These symptoms may reflect the development of tolerance or 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. In these situations, it is recommended that the same total daily dose be given divided as more frequent administrations (see DOSAGE AND ADMINISTRATION).Risk of Dose Reduction Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes purposeful tapering, but also inadvertent reduction of dose (e.g., the patient forgets, the patient is admitted to hospital). Therefore, the dosage of alprazolam should be reduced or discontinued gradually (see DOSAGE AND ADMINISTRATION). CNS Depression and Impaired Performance Because of its CNS depressant effects, patients receiving alprazolam should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving motor vehicle. For the same reason, patients should be cautioned about the simultaneous ingestion of alcohol and other CNS depressant drugs during treatment with alprazolam.Risk of Fetal Harm Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If alprazolam is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Because of experience with other members of the benzodiazepine class, alprazolam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to pregnant woman during the first trimester. Because use of these drugs is rarely matter of urgency, their use during the first trimester should almost always be avoided. The possibility that woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug.Alprazolam Interaction with Drugs that Inhibit Metabolism via Cytochrome P4503A The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have profound effect on the clearance of alprazolam. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A. With drugs inhibiting CYP3A to lesser but still significant degree, alprazolam should be used only with caution and consideration of appropriate dosage reduction. For some drugs, an interaction with alprazolam has been quantified with clinical data; for other drugs, interactions are predicted from in vitro data and/or experience with similar drugs in the same pharmacologic class.The following are examples of drugs known to inhibit the metabolism of alprazolam and/or related benzodiazepines, presumably through inhibition of CYP3A.Potent CYP3A InhibitorsAzole Antifungal Agents: Ketoconazole and itraconazole are potent CYP3A inhibitors and have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively. The coadministration of alprazolam with these agents is not recommended. Other azole-type antifungal agents should also be considered potent CYP3A inhibitors and the coadministration of alprazolam with them is not recommended (see CONTRAINDICATIONS).Drugs Demonstrated to be CYP3A Inhibitors on the Basis of Clinical Studies Involving Alprazolam (Caution and Consideration of Appropriate Alprazolam Dose Reduction are Recommended During Coadministration with the Following Drugs)Nefazodone: Coadministration of nefazodone increased alprazolam concentration two-fold.Fluvoxamine: Coadministration of fluvoxamine approximately doubled the maximum plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71%, and decreased measured psychomotor performance.Cimetidine: Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 86%, decreased clearance by 42%, and increased half-life by 16%.Other Drugs Possibly Affecting Alprazolam MetabolismOther drugs possibly affecting alprazolam metabolism by inhibition of CYP3A are discussed in the PRECAUTIONS section (see PRECAUTIONS: Drug Interactions).

ABUSE SECTION.

9.2 Abuse Alprazolam is benzodiazepine and CNS depressant with potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of drug by an individual in way other than prescribed by health care provider or for whom it was not prescribed. Drug addiction is cluster of behavioral, cognitive, and physiological phenomena that may include strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving 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).

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology When rats were treated with alprazolam at oral doses of 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 years, tendency for dose related increase in the number of cataracts was observed in females and tendency for dose related increase in corneal vascularization was observed in males. These lesions did not appear until after 11 months of treatment.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisNo 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.MutagenesisAlprazolam 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 FertilityAlprazolam produced no impairment of fertility in rats at doses up to mg/kg per day, which is approximately times the maximum recommended human dose of 10 mg per day based on mg/m2 body surface area.

CONTROLLED SUBSTANCE SECTION.

9.1 Controlled Substance Alprazolam Intensol(TM) contains alprazolam, which is Schedule IV controlled substance.

DEPENDENCE SECTION.

9.3 Dependence Alprazolam may produce physical dependence from continued therapy. Physical dependence is state that develops as result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dose reduction of drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, 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 gradual taper to discontinue alprazolam or reduce the dosage [see Dosage and Administration (2.3), Warnings and Precautions (5.3)].Acute Withdrawal Signs and SymptomsAcute 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 SyndromeProtracted 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 to weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.ToleranceTolerance to alprazolam may develop from continued therapy. Tolerance is physiological state characterized by reduced response to drug after repeated administration (i.e., higher dose of drug is required to produce the same effect that was once obtained at lower dose). Tolerance to the therapeutic effect of alprazolam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Alprazolam Intensol(TM) is available as:1 mg per mL oral solution is supplied with calibrated oral syringe (graduations of 0.25 mL [0.25 mg], 0.5 mL [0.5 mg], 0.75 mL [0.75 mg], and mL [1 mg] on the oral syringe).. Oral solution: 0.25 mL [0.25 mg], 0.5 mL [0.5 mg], 0.75 mL [0.75 mg], and mL [1 mg] (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oUse with Opioids: Increase the risk of respiratory depression. (7.1)oUse with Other CNS Depressants: Produces additive CNS depressant effects. (7.1)oUse with Digoxin: Increase the risk of digoxin toxicity. (7.1)oUse with CYP3A Inhibitors (except ritonavir): Increase the risk of adverse reactions of alprazolam. (4, 5.5, 7.1)oUse with CYP3A Inducers: Increase the risk of reduced efficacy of alprazolam. (7.1). oUse with Opioids: Increase the risk of respiratory depression. (7.1). oUse with Other CNS Depressants: Produces additive CNS depressant effects. (7.1). oUse with Digoxin: Increase the risk of digoxin toxicity. (7.1). oUse with CYP3A Inhibitors (except ritonavir): Increase the risk of adverse reactions of alprazolam. (4, 5.5, 7.1). oUse with CYP3A Inducers: Increase the risk of reduced efficacy of alprazolam. (7.1). 7.1 Drugs Having Clinically Important Interactions with Alprazolam Table includes clinically significant drug interactions with alprazolam [see Clinical Pharmacology (12.3)].Table 4: Clinically Significant Drug Interactions with AlprazolamOpioidsClinical implicationThe 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 managementLimit dosage and duration of concomitant use of alprazolam and opioids, and monitor patients closely for respiratory depression and sedation [see Warnings and Precautions (5.1)].ExamplesMorphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorpenol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol.CNS DepressantsClinical implicationThe benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other CNS depressants.Prevention or managementLimit dosage and duration of alprazolam during concomitant use with CNS depressants [see Warnings and Precautions (5.3)].ExamplesPsychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression.Strong Inhibitors of CYP3A (except ritonavir)Clinical implicationConcomitant use of alprazolam with strong CYP3A inhibitors has 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 managementConcomitant use of alprazolam with strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see Contraindications (4), Warnings and Precautions (5.5)].ExamplesKetoconazole, itraconazole, clarithromycinModerate or Weak Inhibitors of CYP3AClinical implicationConcomitant use of alprazolam with CYP3A inhibitors may increase the concentrations of alprazolam, resulting in increased risk of adverse reactions of alprazolam [see Clinical Pharmacology (12.3)].Prevention or managementAvoid use and consider appropriate dose reduction when alprazolam is coadministered with moderate or weak CYP3A inhibitor [see Warnings and Precautions (5.5)].ExamplesNefazodone, fluvoxamine, cimetidine, erythromycinCYP3A InducersClinical implicationConcomitant use of CYP3A inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam [see Clinical Pharmacology (12.3)].Prevention or managementCaution is recommended during coadministration with alprazolam.ExamplesCarbamazepine, phenytoinRitonavirClinical implicationInteractions 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 managementReduce alprazolam dosage when ritonavir and alprazolam are initiated concomitantly, or when ritonavir is added to regimen where alprazolam is stabilized.Increase alprazolam dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam concomitantly. No dosage adjustment of alprazolam is necessary in patients receiving ritonavir for more than 10 to14 days [see Dosage and Administration (2.6)].Concomitant use of alprazolam with strong CYP3A inhibitor, except ritonavir, is contraindicated [see Contraindications (4), Warnings and Precautions (5.5)].DigoxinClinical implicationIncreased digoxin concentrations have been reported when alprazolam was given, especially in geriatric patients (>65 years of age).Prevention or managementIn patients on digoxin therapy, measure serum digoxin concentrations before initiating alprazolam. 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 specific drug or specific test.

GERIATRIC USE SECTION.

8.5 Geriatric Use Alprazolam-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 is recommended in geriatric patients [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).Risks from Concomitant Use with OpioidsAdvise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when alprazolam is used with opioids and not to use such drugs concomitantly unless supervised by 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 AddictionInform patients that the use of alprazolam, 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 ReactionsInform patients that the continued use of alprazolam may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of alprazolam may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Instruct patients that discontinuation or dosage reduction of alprazolam may require slow taper [see Warnings and Precautions (5.3), Drug Abuse and Dependence (9.3)].Effects on Driving and Operating MachineryAdvise patients not to drive motor vehicle or operate heavy machinery while taking alprazolam due to its CNS depressant effects. Also advise patients to avoid use of alcohol or other CNS depressants while taking alprazolam [see Warnings and Precautions (5.3)].Patients with DepressionAdvise patients, their families, and caregivers to look for signs of suicidality or worsening depression, and to inform the patients healthcare provider immediately [see Warnings and Precautions (5.6)].Concomitant MedicationsAdvise patients to inform their healthcare provider of all medicines they take, including prescription and nonprescription medications, vitamins and herbal supplements [see Drug Interactions (7)].PregnancyAdvise pregnant females that use of alprazolam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)]. Instruct patients to inform their healthcare provider if they are pregnant. Advise patients that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to alprazolam during pregnancy [see Use in Specific Populations (8.1)]. LactationAdvise patients that breastfeeding is not recommended during treatment with alprazolam [see Use in Specific Populations (8.2)].Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922C50000247/02Revised: January 2023.

LACTATION SECTION.

8.2 Lactation Risk SummaryLimited data from published literature reports the presence of alprazolam in human breast milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. The effects of alprazolam on lactation are unknown.Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed infants, advise patients that breastfeeding is not recommended during treatment with alprazolam.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Alprazolam is 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisNo 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.MutagenesisAlprazolam 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 FertilityAlprazolam produced no impairment of fertility in rats at doses up to mg/kg per day, which is approximately 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 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 years, tendency for dose related increase in the number of cataracts was observed in females and tendency for dose related increase in corneal vascularization was observed in males. These lesions did not appear until after 11 months of treatment.

PEDIATRIC USE SECTION.

8.4 Pediatric Use Safety and effectiveness of alprazolam have not been established in pediatric patients.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Plasma levels of alprazolam increase proportionally to the dose over the range of 0.5 to 3.0 mg.AbsorptionFollowing oral administration, peak plasma concentration of alprazolam (Cmax) occurs in to hours post dose.DistributionAlprazolam is 80% bound to human serum protein, and albumin accounts for the majority of the binding.EliminationThe mean plasma elimination half-life (T1/2) of alprazolam is approximately 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults.MetabolismAlprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to major active metabolites in the plasma: 4-hydroxyalprazolam and -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 -hydroxyalprazolam. The low concentrations and low potencies of 4-hydroxyalprazolam and -hydroxyalprazolam indicate that they unlikely contribute much to the effects of alprazolam. benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam.ExcretionAlprazolam and its metabolites are excreted primarily in the urine.Specific PopulationsGeriatric PatientsThe mean T1/2 of alprazolam was 16.3 hours (range: 9.0 to 26.9 hours) in healthy elderly subjects compared to 11.0 hours (range: 6.3 to -15.8 hours, n=16) in healthy younger adult subjects.Obese PatientsThe mean T1/2 of alprazolam was 21.8 hours (range: 9.9 to 40.4 hours) in group of obese subjects.Patients with Hepatic ImpairmentThe 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 GroupsMaximal concentrations and T1/2 of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians.SmokingAlprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers.Drug Interaction StudiesIn Vivo StudiesMost 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 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: single dose of alprazolam 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 in doses up to mg per day.Warfarin: Alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.In Vitro StudiesData from in vitro studies of alprazolam suggest possible drug interaction of alprazolam with paroxetine. The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined.

PREGNANCY SECTION.

8.1 Pregnancy Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including alprazolam, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/.Risk SummaryNeonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.8) and Clinical Considerations]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report clear association with benzodiazepines and major birth defects (see Data).The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 ConsiderationsFetal/Neonatal adverse reactionsBenzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to alprazolam during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to alprazolam during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.8)].DataHuman DataPublished data from observational studies on the use of benzodiazepines during pregnancy do not report 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.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions (5.8) 1/2023.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended. (8.2). 8.1 Pregnancy Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including alprazolam, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/.Risk SummaryNeonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.8) and Clinical Considerations]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report clear association with benzodiazepines and major birth defects (see Data).The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 ConsiderationsFetal/Neonatal adverse reactionsBenzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to alprazolam during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to alprazolam during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.8)].DataHuman DataPublished data from observational studies on the use of benzodiazepines during pregnancy do not report 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.. 8.2 Lactation Risk SummaryLimited data from published literature reports the presence of alprazolam in human breast milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. The effects of alprazolam on lactation are unknown.Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed infants, advise patients that breastfeeding is not recommended during treatment with alprazolam.. 8.4 Pediatric Use Safety and effectiveness of alprazolam have not been established in pediatric patients.. 8.5 Geriatric Use Alprazolam-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 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 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 is recommended in patients with hepatic impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oEffects on Driving and Operating Machinery: Patients receiving alprazolam should be cautioned against operating machinery or driving motor vehicle, as well as avoiding concomitant use of alcohol and other central nervous system (CNS) depressant drugs. (5.4)oPatients with Depression: Exercise caution in patients with signs or symptoms of depression. Prescribe the least number of tablets feasible to avoid intentional overdosage. (5.6)oNeonatal Sedation and Withdrawal Syndrome: Alprazolam use during pregnancy can result in neonatal sedation and/or neonatal withdrawal. (5.8, 8.1). oEffects on Driving and Operating Machinery: Patients receiving alprazolam should be cautioned against operating machinery or driving motor vehicle, as well as avoiding concomitant use of alcohol and other central nervous system (CNS) depressant drugs. (5.4). oPatients with Depression: Exercise caution in patients with signs or symptoms of depression. Prescribe the least number of tablets feasible to avoid intentional overdosage. (5.6). oNeonatal Sedation and Withdrawal Syndrome: Alprazolam use during pregnancy can result in neonatal sedation and/or neonatal withdrawal. (5.8, 8.1). 5.1 Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including alprazolam, 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 decision is made to prescribe alprazolam 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 lower initial dose of alprazolam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in patient already taking alprazolam, prescribe 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 is 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, 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 and throughout treatment, assess each patients risk for abuse, misuse, and addiction (e.g., using standardized screening tool). Use of alprazolam, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of alprazolam 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 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 gradual taper to discontinue alprazolam 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 ReactionsThe continued use of benzodiazepines, including alprazolam, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of alprazolam 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 SyndromeIn some cases, benzodiazepine users have developed 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 direct consequence of physical dependence to alprazolam. These include 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 <= 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 mg/day and for long periods (more than 12 weeks). However, in controlled postmarketing discontinuation study of panic disorder patients who received alprazolam, the duration of treatment (3 months compared to months) had no effect on the ability of patients to taper to zero dose. In contrast, patients treated with doses of alprazolam greater than mg/day had more difficulty tapering to zero dose than those treated with less than mg/day.In controlled clinical trial in which 63 patients were randomized to alprazolam 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 SymptomsEarly morning anxiety and emergence of anxiety symptoms between doses of alprazolam have been reported in patients with panic disorder taking prescribed maintenance doses. These symptoms may reflect the development of tolerance or 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 should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving 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 [see Drug Interactions (7.1)].. 5.5 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 profound effect on the clearance of alprazolam. Strong CYP3A Inhibitors Alprazolam is 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 and ritonavir are initiated concomitantly or when ritonavir is added to stable dosage of alprazolam [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, as appropriate, during co-administration with these drugs. 5.6 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.. 5.7 Mania Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression [see Adverse Reactions (6.2)]. 5.8 Neonatal Sedation and Withdrawal Syndrome Use of alprazolam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate [see Use in Specific Populations (8.1)]. Monitor neonates exposed to alprazolam during pregnancy or labor for signs of sedation and monitor neonates exposed to alprazolam during pregnancy for signs of withdrawal; manage these neonates accordingly. 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. Closely monitor patients with impaired respiratory function. If signs and symptoms of respiratory depression, hypoventilation, or apnea occur, discontinue alprazolam.