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).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling:oRisks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)]oAbuse, Misuse, and Addiction [see Warnings and Precautions (5.2)]oDependence and Withdrawal Reactions [see Warnings and Precautions (5.3)]oEffects on Driving and Operating Machinery [see Warnings and Precautions (5.4)]oPatients with Depression [see Warnings and Precautions (5.6)]oNeonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.8)]oRisks in Patients with Impaired Respiratory Function [see Warnings and Precautions (5.9)]. oRisks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)]. oAbuse, Misuse, and Addiction [see Warnings and Precautions (5.2)]. oDependence and Withdrawal Reactions [see Warnings and Precautions (5.3)]. oEffects on Driving and Operating Machinery [see Warnings and Precautions (5.4)]. oPatients with Depression [see Warnings and Precautions (5.6)]. oNeonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.8)]. oRisks in Patients with Impaired Respiratory Function [see Warnings and Precautions (5.9)]. The most common adverse reactions reported in clinical trials for generalized anxiety disorder and panic disorder (incidence >= 5% and at least twice that of placebo) include: impaired coordination, hypotension, dysarthria, and increased libido. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data in the two tables below are estimates of adverse reaction incidence among adult patients who participated in:o4-week placebo-controlled clinical studies with alprazolam dosages up to mg per day for the acute treatment of generalized anxiety disorder (Table 1)oShort-term (up to 10 weeks) placebo-controlled clinical studies with alprazolam dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2).Table 1: Adverse Reactions Occurring in >=1% in Alprazolam-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials for Generalized AnxietyAlprazolamn=565Placebon=505Nervous system disorders Drowsiness41%22% Light-headedness21%19% Dizziness2%1% Akathisia2%1%Gastrointestinal disorders Dry mouth15%13% Increased salivation4%2%Cardiovascular disorders Hypotension5%2%Skin and subcutaneous tissue disorders Dermatitis/allergy4%3%In addition to the adverse reactions (i.e., greater than 1%) enumerated in the table above for patients with generalized anxiety disorder, the following adverse reactions have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention.Table 2: Adverse Reactions Occurring in >=1% in Alprazolam-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic DisorderAlprazolamn=1388Placebon=1231 Drowsiness77%43% Fatigue and Tiredness49%42% Impaired Coordination40%18% Irritability33%30% Memory Impairment33%22% Cognitive Disorder29%21% Decreased Libido14%8% Dysartharia23%6% Confusional state10%8% Increased libido8%4% Change in libido (not specified)7%6% Disinhibition3%2% Talkativeness2%1% Derealization2%1%Gastrointestinal disorders Constipation26%15% Increased salivation6%4%Skin and subcutaneous tissue disorders Rash11%8%Other Increased appetite33%23% Decreased appetite28%24% Weight gain27%18% Weight loss23%17% Micturition difficulties12%9% Menstrual disorders11%9% Sexual dysfunction7%4% Incontinence2%1%In addition to the reactions (i.e., greater than 1%) enumerated in the table above for patients with panic disorder, the following adverse reactions have been reported in association with the use of alprazolam: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice.Adverse Reactions Reported as Reasons for Discontinuation in Treatment of Panic Disorder in Placebo-Controlled Trials In 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 are shown in Table 3.Table 3: Discontinuation-Emergent Symptom Incidence Reported in >=5% of Alprazolam-treated Patients and Placebo-treated PatientsAlprazolam-treated Patientsn=641Nervous system disordersInsomnia29.5%Light-headedness19.3%Abnormal involuntary movement17.3%Headache17.0%Muscular twitching6.9%Impaired coordination6.6%Muscle tone disorders5.9%Weakness5.8%Psychiatric disordersAnxiety19.2%Fatigue and Tiredness18.4%Irritability10.5%Cognitive disorder10.3%Memory impairment5.5%Depression5.1%Confusional state5.0%Gastrointestinal disordersNausea/Vomiting16.5%Diarrhea13.6%Decreased salivation10.6%Metabolism and nutrition disordersWeight loss13.3%Decreased appetite12.8%Dermatological disordersSweating14.4%Cardiovascular disordersTachycardia12.2%Special SensesBlurred vision10.0% n=number of patients.There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam [see Warning and Precautions (5.2) and Drug Abuse and Dependence (9.3)].Paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations, and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous case reports of adverse behavioral effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, 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.. o4-week placebo-controlled clinical studies with alprazolam dosages up to mg per day for the acute treatment of generalized anxiety disorder (Table 1). oShort-term (up to 10 weeks) placebo-controlled clinical studies with alprazolam dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2).. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of alprazolam. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Endocrine disorders: HyperprolactinemiaGeneral disorders and administration site conditions: Edema peripheralHepatobiliary disorders: Hepatitis, hepatic failureInvestigations: Liver enzyme elevationsPsychiatric disorders: Hypomania, maniaReproductive system and breast disorders: Gynecomastia, galactorrheaSkin and subcutaneous tissue disorders: Photosensitivity reaction, angioedema, Stevens-Johnson syndrome.

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.

BOXED WARNING SECTION.

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation [see Warnings and Precautions (5.1), Drug Interactions (7.1)].oThe use of benzodiazepines, including alprazolam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing alprazolam and throughout treatment, assess each patients risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2)].oThe continued use of benzodiazepines, including alprazolam, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of alprazolam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue alprazolam or reduce the dosage [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].. oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation [see Warnings and Precautions (5.1), Drug Interactions (7.1)].. oThe use of benzodiazepines, including alprazolam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing alprazolam and throughout treatment, assess each patients risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2)].. oThe continued use of benzodiazepines, including alprazolam, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of alprazolam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue alprazolam or reduce the dosage [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].. WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS See full prescribing information for complete boxed warning.oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. (5.1, 7.1)oThe use of benzodiazepines, including alprazolam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing alprazolam and throughout treatment, assess each patients risk for abuse, misuse, and addiction. (5.2)oAbrupt discontinuation or rapid dosage reduction of alprazolam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue alprazolam or reduce the dosage. (2.2, 5.3). oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. (5.1, 7.1). oThe use of benzodiazepines, including alprazolam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing alprazolam and throughout treatment, assess each patients risk for abuse, misuse, and addiction. (5.2). oAbrupt discontinuation or rapid dosage reduction of alprazolam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue alprazolam or reduce the dosage. (2.2, 5.3).

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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 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.. 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Generalized Anxiety Disorder Alprazolam was compared to placebo in double-blind clinical studies (doses up to mg per 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.. 14.2 Panic Disorders The effectiveness of alprazolam in the treatment of panic disorder was studied in 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 mg to mg per day in of the studies, and the doses of alprazolam were fixed at mg and mg per day in the third study. In all 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 of the 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 improved on alprazolam during short-term treatment in of these trials was continued on an open basis up to months, without apparent loss of benefit.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS Alprazolam is contraindicated in patients:owith known hypersensitivity to alprazolam or other benzodiazepines. Angioedema has been reported [see Adverse Reactions (6.2)].otaking strong cytochrome P450 3A (CYP3A) inhibitors (e.g., ketoconazole, itraconazole), except ritonavir [see Dosage and Administration (2.6), Warnings and Precautions (5.5), Drug Interactions (7.1)]. owith known hypersensitivity to alprazolam or other benzodiazepines. Angioedema has been reported [see Adverse Reactions (6.2)].. otaking strong cytochrome P450 3A (CYP3A) inhibitors (e.g., ketoconazole, itraconazole), except ritonavir [see Dosage and Administration (2.6), Warnings and Precautions (5.5), Drug Interactions (7.1)]. oKnown hypersensitivity to alprazolam or other benzodiazepines. (4)oConcomitant use with strong cytochrome P450 3A (CYP3A) inhibitors, except ritonavir. (4, 5.5, 7.1). oKnown hypersensitivity to alprazolam or other benzodiazepines. (4). oConcomitant use with strong cytochrome P450 3A (CYP3A) inhibitors, except ritonavir. (4, 5.5, 7.1).

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.

DESCRIPTION SECTION.

11 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: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.. alprazolam-structural-formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oGeneralized Anxiety Disorder: (2.1)oRecommended starting oral dosage is 0.25 mg to 0.5 mg three times daily.oDosage may be increased, at intervals of every to days, to maximum recommended daily dose of mg, given in divided doses.oUse the lowest possible effective dose and frequently assess the need for continued treatment.oPanic Disorder: Recommended starting oral dosage is 0.5 mg three times daily. The dosage may be increased at intervals of every to days in increments of no more than mg per day. (2.2)oWhen tapering, decrease dosage by no more than 0.5 mg every days. Some patients may require an even slower dosage reduction. (2.3, 5.2)oSee the Full Prescribing Information for the recommended dosage in geriatric patients, patients with hepatic impairment, and with use with ritonavir. (2.4, 2.5, 2.6). oGeneralized Anxiety Disorder: (2.1)oRecommended starting oral dosage is 0.25 mg to 0.5 mg three times daily.oDosage may be increased, at intervals of every to days, to maximum recommended daily dose of mg, given in divided doses.oUse the lowest possible effective dose and frequently assess the need for continued treatment.. oRecommended starting oral dosage is 0.25 mg to 0.5 mg three times daily.. oDosage may be increased, at intervals of every to days, to maximum recommended daily dose of mg, given in divided doses.. oUse the lowest possible effective dose and frequently assess the need for continued treatment.. oPanic Disorder: Recommended starting oral dosage is 0.5 mg three times daily. The dosage may be increased at intervals of every to days in increments of no more than mg per day. (2.2). oWhen tapering, decrease dosage by no more than 0.5 mg every days. Some patients may require an even slower dosage reduction. (2.3, 5.2). oSee the Full Prescribing Information for the recommended dosage in geriatric patients, patients with hepatic impairment, and with use with ritonavir. (2.4, 2.5, 2.6). 2.1 Dosage in Generalized Anxiety Disorder The recommended starting oral dosage of alprazolam for the acute treatment of patients with GAD is 0.25 mg to 0.5 mg administered three times daily. Depending upon the response, the dosage may be adjusted at intervals of every to days. The maximum recommended dosage is mg daily (in divided doses).Use the lowest possible effective dose and frequently assess the need for continued treatment [see Warnings and Precautions (5.2)].. 2.2 Dosage in Panic Disorder The recommended starting oral dosage of alprazolam for the treatment of PD is 0.5 mg three times daily. Depending on the response, the dosage may be increased at intervals of every to days in increments of no more than mg per day.Controlled trials of alprazolam in the treatment of panic disorder included dosages in the range of mg to 10 mg daily. The mean dosage was approximately mg to mg daily. Occasional patients required as much as 10 mg per day.For patients receiving doses greater than mg per 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 per day for months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit.The necessary duration of treatment for PD in patients responding to alprazolam is unknown. After period of extended freedom from panic 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 [see Dosage and Administration (2.3)].. 2.3 Discontinuation or Dosage Reduction of Alprazolam To reduce the risk of withdrawal reactions, use gradual taper to discontinue alprazolam or reduce the dosage. If patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly [see Warnings and Precautions (5.3), Drug Abuse and Dependence (9.3)].Reduced the dosage by no more than 0.5 mg every days. Some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.In controlled postmarketing discontinuation study of panic disorder patients which compared the 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.. 2.4 Dosage Recommendations in Geriatric Patients In geriatric patients, the recommended starting oral dosage of alprazolam is 0.25 mg, given or times daily. This may be gradually increased if needed and tolerated. Geriatric patients may be especially sensitive to the effects of benzodiazepines. If adverse reactions occur at the recommended starting dosage, the dosage may be reduced [see Use in Specific Populations (8.5), Clinical Pharmacology (12.3)].. 2.5 Dosage Recommendations in Patients with Hepatic Impairment In patients with hepatic impairment, the recommended starting oral dosage of alprazolam is 0.25 mg, given or times daily. This may be gradually increased if needed and tolerated. If adverse reactions occur at the recommended starting dose, the dosage may be reduced [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].. 2.6 Dosage Modifications for Drug Interactions Alprazolam should be reduced to half of the recommended dosage when patient is started on ritonavir and alprazolam together, or when ritonavir administered to patient treated with alprazolam. Increase the alprazolam dosage to the target dose after 10 to 14 days of dosing ritonavir and alprazolam together. It is not necessary to reduce alprazolam dose in patients who have been taking ritonavir for more than 10 to 14 days.Alprazolam is contraindicated with concomitant use of all strong CYP3A inhibitors, except ritonavir [see Contraindications (4), Warnings and Precautions (5.5)].

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 ABUSE AND DEPENDENCE SECTION.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Alprazolam Intensol(TM) contains alprazolam, which is Schedule IV controlled substance.. 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).. 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.

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)].Examples:Morphine, 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)].Examples:Psychotropic 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)].Examples:Ketoconazole, 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)].Examples:Nefazodone, 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.Examples:Carbamazepine, 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)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Alprazolam Intensol(TM) Oral Solution (Concentrate)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) and is clear, colorless solution.NDC 0054-3068-44: Bottle of 30 mLStore 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.

1 INDICATIONS AND USAGE Alprazolam is indicated for the:oacute treatment of generalized anxiety disorder (GAD) in adults.otreatment of panic disorder (PD), with or without agoraphobia in adults.. oacute treatment of generalized anxiety disorder (GAD) in adults.. otreatment of panic disorder (PD), with or without agoraphobia in adults.. Alprazolam is benzodiazepine indicated for the:oAcute treatment of generalized anxiety disorder in adults. (1)oTreatment of panic disorder with or without agoraphobia in adults. (1). oAcute treatment of generalized anxiety disorder in adults. (1). oTreatment of panic disorder with or without agoraphobia in adults. (1).

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: 01/2023.

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.

OVERDOSAGE SECTION.

10 OVERDOSAGE Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, exctextent, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions 5.2)]. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received benzodiazepine for control of potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting the Poison Help Line (1-800-222-1222), or medical toxicologist for additional overdosage management recommendations.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0054-3068-44: 30 mL BOTTLE and ORAL SYRINGE Alprazolam Intensol(TM) Oral Solution (Concentrate), CIV1 mg per mLRx only. alprazolam-int-os-bl-1mg-per-1ml-30ml-c50000248-01-k05.

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.

SPL MEDGUIDE SECTION.

MEDICATION GUIDE Alprazolam(al pra zoe lam)Intensol(TM) Oral Solution (Concentrate) CIVWhat is the most important information should know about alprazolamoAlprazolam is benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death.Get emergency help right away if any of the following happens: oshallow or slowed breathingobreathing stops (which may lead to the heart stopping)oexcessive sleepiness (sedation) Do not drive or operate heavy machinery until you know how taking alprazolam with opioids affects you.oRisk of abuse, misuse, and addiction. There is risk of abuse, misuse, and addiction with benzodiazepines, including alprazolam, which can lead to overdose and serious side effects including coma and death.oSerious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including alprazolam. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. oYou can develop an addiction even if you take alprazolam as prescribed by your healthcare provider.oTake alprazolam exactly as your healthcare provider prescribed.oDo not share your alprazolam with other people.oKeep alprazolam in safe place and away from children. oPhysical dependence and withdrawal reactions. Alprazolam can cause physical dependence and withdrawal reactions.oDo not suddenly stop taking alprazolam. Stopping alprazolam suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. oSome people who suddenly stop benzodiazepines, have symptoms that can last for several weeks to more than 12 months, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.oPhysical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. oDo not take more alprazolam than prescribed or take alprazolam for longer than prescribed.What is alprazolamoAlprazolam is prescription medicine used:oto treat anxiety disordersofor the short-term relief of the symptoms of anxietyoto 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 contains alprazolam that 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 behaviorohave liver or kidney problemsohave lung disease or breathing problemsoare pregnant or plan to become pregnant. oTaking alprazolam late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems).oTell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with alprazolam.oThere is pregnancy registry for women who take alprazolam during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with alprazolam, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/pregnancyregistry/.oAre breastfeeding or plan to breastfeed. Alprazolam passes into your breast milk. oTalk to your healthcare provider about the best way to feed your baby if you take alprazolam.oBreastfeeding is not recommended during treatment with 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 are the possible side effects of alprazolamAlprazolam may cause serious side effects, including:oSee What is the most important information should know about alprazolamoSeizures. 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.oAlprazolam can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how alprazolam 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. The most common side effects of alprazolam include:oproblems with coordinationohypotensionotrouble saying words clearly (dysarthria)ochanges in sex drive (libido)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 room temperature between 68F to 77F (20C to 25C).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: alprazolamInactive ingredients: propylene glycol, succinic acid disodium salt, and water.Distributed by:Hikma Pharmaceuticals USA Inc.Berkeley Heights, NJ 07922For more information, go to www.hikma.com or call 1-800-962-8364.This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 1/2023C50000247/02Revised: January 2023. oAlprazolam is benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death.. oshallow or slowed breathingobreathing stops (which may lead to the heart stopping)oexcessive sleepiness (sedation). oshallow or slowed breathing. obreathing stops (which may lead to the heart stopping). oexcessive sleepiness (sedation). Do not drive or operate heavy machinery until you know how taking alprazolam with opioids affects you.. oRisk of abuse, misuse, and addiction. There is risk of abuse, misuse, and addiction with benzodiazepines, including alprazolam, which can lead to overdose and serious side effects including coma and death.oSerious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including alprazolam. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. oYou can develop an addiction even if you take alprazolam as prescribed by your healthcare provider.oTake alprazolam exactly as your healthcare provider prescribed.oDo not share your alprazolam with other people.oKeep alprazolam in safe place and away from children. oSerious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including alprazolam. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. oYou can develop an addiction even if you take alprazolam as prescribed by your healthcare provider.. oTake alprazolam exactly as your healthcare provider prescribed.. oDo not share your alprazolam with other people.. oKeep alprazolam in safe place and away from children.. oPhysical dependence and withdrawal reactions. Alprazolam can cause physical dependence and withdrawal reactions.oDo not suddenly stop taking alprazolam. Stopping alprazolam suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. oSome people who suddenly stop benzodiazepines, have symptoms that can last for several weeks to more than 12 months, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.oPhysical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. oDo not suddenly stop taking alprazolam. Stopping alprazolam suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. oSome people who suddenly stop benzodiazepines, have symptoms that can last for several weeks to more than 12 months, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.. oPhysical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.. oDo not take more alprazolam than prescribed or take alprazolam for longer than prescribed.. oAlprazolam is prescription medicine used:oto treat anxiety disordersofor the short-term relief of the symptoms of anxietyoto 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 contains alprazolam that 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. oTaking alprazolam late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems).. oTell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with alprazolam.. oThere is pregnancy registry for women who take alprazolam during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with alprazolam, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/pregnancyregistry/.. oAre breastfeeding or plan to breastfeed. Alprazolam passes into your breast milk. oTalk to your healthcare provider about the best way to feed your baby if you take alprazolam.. oBreastfeeding is not recommended during treatment with 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.. oSee What is the most important information should know about alprazolam. 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.oAlprazolam can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how alprazolam 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. oAlprazolam can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how alprazolam 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.. oproblems with coordination. ohypotension. otrouble saying words clearly (dysarthria). ochanges in sex drive (libido). oStore alprazolam at room temperature between 68F to 77F (20C to 25C).. 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.

2.1 Dosage in Generalized Anxiety Disorder The recommended starting oral dosage of alprazolam for the acute treatment of patients with GAD is 0.25 mg to 0.5 mg administered three times daily. Depending upon the response, the dosage may be adjusted at intervals of every to days. The maximum recommended dosage is mg daily (in divided doses).Use the lowest possible effective dose and frequently assess the need for continued treatment [see Warnings and Precautions (5.2)].

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.