INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. XANULLX is indicated for the:acute treatment of generalized anxiety disorder (GAD) in adults. treatment of panic disorder (PD), with or without agoraphobia in adults.. acute treatment of generalized anxiety disorder (GAD) in adults.. treatment of panic disorder (PD), with or without agoraphobia in adults.. XANULLX is benzodiazepine indicated for the:Acute treatment of generalized anxiety disorder in adults. (1)Treatment of panic disorder with or without agoraphobia in adults. (1). Acute treatment of generalized anxiety disorder in adults. (1). Treatment of panic disorder with or without agoraphobia in adults. (1).

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 Populations. Geriatric 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 Studies. In 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 XANULLX 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.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. XANULLX is supplied in the following strengths and package configurations:XANULLX TabletsPackage ConfigurationTablet Strength (mg)NDCPrintBottles of 1000.25 mgNDC 0009-0029-01white, oval, scored, imprinted XANULLX 0.25Reverse Numbered Unit dose (100)NDC 0009-0029-46Bottles of 500NDC 0009-0029-02Bottles of 1000NDC 0009-0029-14Bottles of 1000.5 mgNDC 0009-0055-01peach, oval, scored, imprinted XANULLX 0.5Reverse Numbered Unit dose (100)NDC 0009-0055-46Bottles of 500NDC 0009-0055-03Bottles of 1000NDC 0009-0055-15Bottles of 1001 mgNDC 0009-0090-01blue, oval, scored, imprinted XANULLX 1.0Bottles of 500NDC 0009-0090-04Bottles of 1000NDC 0009-0090-13Bottles of 1002 mgNDC 0009-0094-01white, oblong, multi-scored, imprinted XANULLX on one side and 2 on the reverse sideBottles of 500NDC 0009-0094-03. Store at controlled room temperature 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].

ABUSE SECTION.


9.2 Abuse. XANULLX 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:Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)] Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2)] Dependence and Withdrawal Reactions [see Warnings and Precautions (5.3)] Effects on Driving and Operating Machinery [see Warnings and Precautions (5.4)] Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.5)] Patients with Depression [see Warnings and Precautions (5.7)] Risks in Patients with Impaired Respiratory Function [see Warnings and Precautions (5.9)] Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)] Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2)] Dependence and Withdrawal Reactions [see Warnings and Precautions (5.3)] Effects on Driving and Operating Machinery [see Warnings and Precautions (5.4)] Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.5)] Patients with Depression [see Warnings and Precautions (5.7)] Risks 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 Pfizer Inc. at 1-800-438-1985 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:4-week placebo-controlled clinical studies with XANULLX dosages up to mg per day for the acute treatment of generalized anxiety disorder (Table 1)Short-term (up to 10 weeks) placebo-controlled clinical studies with XANULLX dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2).Table 1: Adverse Reactions Occurring in >=1% in XANULLX-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials for Generalized Anxiety XANULLX n=565 Placebo n=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 Occuring in >=1% in XANULLX-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic DisorderXANULLXn=1388Placebon=1231 Drowsiness77%43% Fatique 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 XANULLX: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice.. 4-week placebo-controlled clinical studies with XANULLX dosages up to mg per day for the acute treatment of generalized anxiety disorder (Table 1). Short-term (up to 10 weeks) placebo-controlled clinical studies with XANULLX dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2).. Adverse Reactions Reported as Reasons for Discontinuation in Treatment of Panic Disorder in Placebo-Controlled TrialsIn larger database comprised of both controlled and uncontrolled studies in which 641 patients received XANULLX, discontinuation-emergent symptoms which occurred at rate of over 5% in patients treated with XANULLX and at greater rate than the placebo-treated group are shown in Table 3.Table 3: Discontinuation-Emergent Symptom Incidence Reported in >=5% of XANULLX-treated Patients and Placebo-treated PatientsXANULLX-treated Patientsn=641n=number of patients.Nervous 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%There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of XANULLX [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.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of XANULLX. 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. Concomitant 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)].The use of benzodiazepines, including XANULLX, 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 XANULLX and throughout treatment, assess each patients risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2)].The continued use of benzodiazepines, including XANULLX, 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 XANULLX 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 XANULLX or reduce the dosage [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].. Concomitant 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)].. The use of benzodiazepines, including XANULLX, 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 XANULLX and throughout treatment, assess each patients risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2)].. The continued use of benzodiazepines, including XANULLX, 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 XANULLX 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 XANULLX 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 REACTIONSSee full prescribing information for complete boxed warning.Concomitant 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)The use of benzodiazepines, including XANULLX, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing XANULLX and throughout treatment, assess each patients risk for abuse, misuse, and addiction. (5.2)Abrupt discontinuation or rapid dosage reduction of XANULLX 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 XANULLX or reduce the dosage. (2.2, 5.3). Concomitant 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). The use of benzodiazepines, including XANULLX, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing XANULLX and throughout treatment, assess each patients risk for abuse, misuse, and addiction. (5.2). Abrupt discontinuation or rapid dosage reduction of XANULLX 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 XANULLX 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 DNULL 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 STUDIES SECTION.


14 CLINICAL STUDIES. 14.1 Generalized Anxiety Disorder. XANULLX 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. XANULLX 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 Disorder. The effectiveness of XANULLX 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 XANULLX was mg to mg per day in of the studies, and the doses of XANULLX were fixed at mg and mg per day in the third study. In all studies, XANULLX 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, XANULLX 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 XANULLX during short-term treatment in of these trials was continued on an open basis up to months, without apparent loss of benefit.

CLINICAL TRIALS EXPERIENCE SECTION.


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:4-week placebo-controlled clinical studies with XANULLX dosages up to mg per day for the acute treatment of generalized anxiety disorder (Table 1)Short-term (up to 10 weeks) placebo-controlled clinical studies with XANULLX dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2).Table 1: Adverse Reactions Occurring in >=1% in XANULLX-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials for Generalized Anxiety XANULLX n=565 Placebo n=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 Occuring in >=1% in XANULLX-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic DisorderXANULLXn=1388Placebon=1231 Drowsiness77%43% Fatique 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 XANULLX: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice.. 4-week placebo-controlled clinical studies with XANULLX dosages up to mg per day for the acute treatment of generalized anxiety disorder (Table 1). Short-term (up to 10 weeks) placebo-controlled clinical studies with XANULLX dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2).. Adverse Reactions Reported as Reasons for Discontinuation in Treatment of Panic Disorder in Placebo-Controlled TrialsIn larger database comprised of both controlled and uncontrolled studies in which 641 patients received XANULLX, discontinuation-emergent symptoms which occurred at rate of over 5% in patients treated with XANULLX and at greater rate than the placebo-treated group are shown in Table 3.Table 3: Discontinuation-Emergent Symptom Incidence Reported in >=5% of XANULLX-treated Patients and Placebo-treated PatientsXANULLX-treated Patientsn=641n=number of patients.Nervous 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%There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of XANULLX [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.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. XANULLX is contraindicated in patients:with known hypersensitivity to alprazolam or other benzodiazepines. Angioedema has been reported [see Adverse Reactions (6.2)].taking 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)] with known hypersensitivity to alprazolam or other benzodiazepines. Angioedema has been reported [see Adverse Reactions (6.2)].. taking 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)] Known hypersensitivity to alprazolam or other benzodiazepines. (4)Concomitant use with strong cytochrome P450 3A (CYP3A) inhibitors, except ritonavir. (4, 5.5, 7.1). Known hypersensitivity to alprazolam or other benzodiazepines. (4). Concomitant use with strong cytochrome P450 3A (CYP3A) inhibitors, except ritonavir. (4, 5.5, 7.1).

CONTROLLED SUBSTANCE SECTION.


9.1 Controlled Substance. XANULLX contains alprazolam, which is Schedule IV controlled substance.

DEPENDENCE SECTION.


9.3 Dependence. XANULLX 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 XANULLX or reduce the dosage [see Dosage and Administration (2.3), Warnings and Precautions (5.3)].. Acute Withdrawal Signs and Symptoms Acute 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 XANULLX 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 XANULLX may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

DESCRIPTION SECTION.


11 DESCRIPTION. XANULLX 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 crystalline powder, which is soluble in methanol or ethanol but which has no appreciable solubility in water at physiological pH.Each XANULLX tablet, for oral administration, contains 0.25 mg, 0.5 mg, mg, or mg of alprazolam.Inactive ingredients: cellulose, corn starch, docusate sodium, lactose, magnesium stearate, silicon dioxide and sodium benzoate. In addition, the 0.5 mg tablet contains FD&C Yellow No. and the mg tablet contains FD&C Blue No. 2.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Generalized Anxiety Disorder: (2.1)Recommended starting oral dosage is 0.25 mg to 0.5 mg three times daily.Dosage may be increased, at intervals of every to days, to maximum recommended daily dose of mg, given in divided doses.Use the lowest possible effective dose and frequently assess the need for continued treatment.Panic 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)When 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)See 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). Generalized Anxiety Disorder: (2.1)Recommended starting oral dosage is 0.25 mg to 0.5 mg three times daily.Dosage may be increased, at intervals of every to days, to maximum recommended daily dose of mg, given in divided doses.Use the lowest possible effective dose and frequently assess the need for continued treatment.. Recommended starting oral dosage is 0.25 mg to 0.5 mg three times daily.. Dosage may be increased, at intervals of every to days, to maximum recommended daily dose of mg, given in divided doses.. Use the lowest possible effective dose and frequently assess the need for continued treatment.. Panic 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). When 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). See 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 XANULLX 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 XANULLX 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 XANULLX 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 XANULLX 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 XANULLX 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 XANULLX. To reduce the risk of withdrawal reactions, use gradual taper to discontinue XANULLX 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 XANULLX 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 XANULLX 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. XANULLX should be reduced to half of the recommended dosage when patient is started on ritonavir and XANULLX together, or when ritonavir administered to patient treated with XANULLX. Increase the XANULLX dosage to the target dose after 10 to 14 days of dosing ritonavir and XANULLX together. It is not necessary to reduce XANULLX dose in patients who have been taking ritonavir for more than 10 to 14 days.XANULLX 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. XANULLX tablets are available as:0.25 mg: white, oval, scored, imprinted XANULLX 0.250.5 mg: peach, oval, scored, imprinted XANULLX 0.51 mg: blue, oval, scored, imprinted XANULLX 1.02 mg: white, oblong, multi-scored, imprinted XANULLX on one side and 2 on the reverse side. 0.25 mg: white, oval, scored, imprinted XANULLX 0.25. 0.5 mg: peach, oval, scored, imprinted XANULLX 0.5. mg: blue, oval, scored, imprinted XANULLX 1.0. mg: white, oblong, multi-scored, imprinted XANULLX on one side and 2 on the reverse side. Tablets: 0.25 mg, 0.5 mg, mg, and mg (3).

DRUG ABUSE AND DEPENDENCE SECTION.


9 DRUG ABUSE AND DEPENDENCE. 9.1 Controlled Substance. XANULLX contains alprazolam, which is Schedule IV controlled substance.. 9.2 Abuse. XANULLX 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. XANULLX 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 XANULLX or reduce the dosage [see Dosage and Administration (2.3), Warnings and Precautions (5.3)].. Acute Withdrawal Signs and Symptoms Acute 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 XANULLX 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 XANULLX may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. Use with Opioids: Increase the risk of respiratory depression. (7.1)Use with Other CNS Depressants: Produces additive CNS depressant effects. (7.1)Use with Digoxin: Increase the risk of digoxin toxicity. (7.1)Use with CYP3A Inhibitors (except ritonavir): Increase the risk of adverse reactions of alprazolam. (4, 5.6, 7.1)Use with CYP3A Inducers: Increase the risk of reduced efficacy of alprazolam. (7.1). Use with Opioids: Increase the risk of respiratory depression. (7.1). Use with Other CNS Depressants: Produces additive CNS depressant effects. (7.1). Use with Digoxin: Increase the risk of digoxin toxicity. (7.1). Use with CYP3A Inhibitors (except ritonavir): Increase the risk of adverse reactions of alprazolam. (4, 5.6, 7.1). Use with CYP3A Inducers: Increase the risk of reduced efficacy of alprazolam. (7.1). 7.1 Drugs Having Clinically Important Interactions with XANULLX. Table includes clinically significant drug interactions with XANULLX [see Clinical Pharmacology (12.3)].Table 4: Clinically Significant Drug Interactions with XANULLXOpioidsClinical 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 XANULLX and opioids, and monitor patients closely for respiratory depression and sedation [see Warnings and Precautions (5.1)]. ExamplesMorphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorpenol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol.CNS DepressantsClinical implicationThe benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other CNS depressants.Prevention or managementLimit dosage and duration of XANULLX during concomitant use with CNS depressants [see Warnings and Precautions (5.3)].ExamplesPsychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression.Strong Inhibitors of CYP3A (except ritonavir)Clinical implicationConcomitant use of XANULLX 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 XANULLX with strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see Contraindications (4), Warnings and Precautions (5.5)]. ExamplesKetoconazole, itraconazole, clarithromycinModerate or Weak Inhibitors of CYP3AClinical implicationConcomitant use of XANULLX with CYP3A inhibitors may increase the concentrations of XANULLX, resulting in increased risk of adverse reactions of alprazolam [see Clinical Pharmacology (12.3)]. Prevention or managementAvoid use and consider appropriate dose reduction when XANULLX is coadministered with moderate or weak CYP3A inhibitor [see Warnings and Precautions (5.5)]. ExamplesNefazodone, fluvoxamine, cimetidine, erythromycinCYP3A InducersClinical implicationConcomitant use of CYP3A inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam [see Clinical Pharmacology (12.3)].Prevention or managementCaution is recommended during coadministration with XANULLX.ExamplesCarbamazepine, phenytoinRitonavirClinical implicationInteractions involving ritonavir and alprazolam are complex and time dependent. Short term administration of ritonavir increased alprazolam exposure due to CYP3A4 inhibition. Following long term treatment of ritonavir (>10 to 14 days), CYP3A4 induction offsets this inhibition.Alprazolam exposure was not meaningfully affected in the presence of ritonavir.Prevention or managementReduce XANULLX dosage when ritonavir and XANULLX are initiated concomitantly, or when ritonavir is added to regimen where XANULLX is stabilized.Increase XANULLX dosage to the target dosage after 10 to 14 days of dosing ritonavir and XANULLX concomitantly. No dosage adjustment of XANULLX is necessary in patients receiving ritonavir for more than 10 to14 days [see Dosage and Administration (2.6)].Concomitant use of XANULLX 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 XANULLX. 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. XANULLX-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 XANULLX is recommended in geriatric patients [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

HEPATIC IMPAIRMENT SUBSECTION.


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 XANULLX is recommended in patients with hepatic impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. Risks from Concomitant Use with OpioidsAdvise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when XANULLX 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 XANULLX, 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 XANULLX may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of XANULLX 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 XANULLX 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 XANULLX due to its CNS depressant effects. Also advise patients to avoid use of alcohol or other CNS depressants while taking XANULLX [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)].. PregnancyBenzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Advise mothers using XANULLX to monitor neonates for signs of sedation, respiratory depression, withdrawal symptoms, and feeding problems. Instruct patients to inform their healthcare provider if they are pregnant or intend to become pregnant during treatment with XANULLX [see Warnings and Precautions (5.4) Advise patients that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to XANULLX during pregnancy [see Use in Specific Populations (8.1)]. LactationAdvise women not to breastfeed during treatment with XANULLX [see Use in Specific Populations (8.2)].

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 and withdrawal symptoms in breastfed neonates and infants exposed to alprazolam. The effects of alprazolam on lactation are unknown.Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed neonates and infants, advise patients that breastfeeding is not recommended during treatment with XANULLX.

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 DNULL 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. 10.1Clinical Experience. Manifestations of alprazolam overdosage include somnolence, confusion, impaired coordination, diminished reflexes, and coma. Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with combination of single benzodiazepine, including alprazolam, and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality.. 10.2Management of Overdose. In case of an overdosage, consult Certified Poison Control Center at 1-800-222-1222 for latest recommendations.As in all cases of drug overdosage, respiration, pulse rate, and blood pressure should be monitored. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. As with the management of intentional overdosing with any drug, it should be borne in mind that multiple agents may have been ingested.Flumazenil may be useful in situations when an overdose with benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. Flumazenil is intended as an adjunct to, not as substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert should be consulted prior to use.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 0.25 mg Tablet Bottle Label. ALWAYS DISPENSE WITH MEDICATION GUIDENDC 0009-0029-01PfizerXanax(R) alprazolamtablets, USPCIV0.25 mg100 TabletsRx only. PRINCIPAL DISPLAY PANEL 0.25 mg Tablet Bottle Label.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. Safety and effectiveness of XANULLX 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 Populations. Geriatric 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 Studies. In 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 XANULLX 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.

POSTMARKETING EXPERIENCE SECTION.


6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of XANULLX. 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.

PREGNULLNCY SECTION.


8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to XANULLX during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Other Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications/.. Risk SummaryNeonates born to mothers using benzodiazepines during the later stages of pregnancy have been reported to experience symptoms of sedation and neonatal withdrawal [see Warnings and Precautions (5.4), Clinical Considerations)]. Overall available data from published observational studies of pregnant women exposed to alprazolam have not established drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). The estimated 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 Considerations. Fetal/Neonatal adverse reactionsBenzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to benzodiazepines during pregnancy and labor for signs of sedation, respiratory depression, withdrawal, and feeding problems and manage accordingly [see Warnings and Precautions (5.4)]. Data. Human 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. At this time, there is no clear evidence that alprazolam exposure in early pregnancy can cause major birth defects. Neonates exposed to benzodiazepines during the late third trimester of pregnancy or during labor have been reported to exhibit sedation and neonatal withdrawal symptoms.

RECENT MAJOR CHANGES SECTION.


Boxed Warning2/2021Dosage and Administration (2.3)2/2021Warnings and Precautions (5.2, 5.3)2/2021.

SPL MEDGUIDE SECTION.


MEDICATION GUIDEXANULLX (ZAN-aks)(alprazolam) tablets, C-IVThis Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 3/2021 What is the most important information should know about XANULLXXANULLX 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:shallow or slowed breathingbreathing stops (which may lead to the heart stopping)excessive sleepiness (sedation)Do not drive or operate heavy machinery until you know how taking XANULLX with opioids affects you.Risk of abuse, misuse, and addiction. There is risk of abuse, misuse, and addiction with benzodiazepines, including XANULLX, which can lead to overdose and serious side effects including coma and death. Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including XANULLX. 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. You can develop an addiction even if you take XANULLX as prescribed by your healthcare provider.Take XANULLX exactly as your healthcare provider prescribed.Do not share your XANULLX with other people.Keep XANULLX in safe place and away from children. Physical dependence and withdrawal reactions. XANULLX can cause physical dependence and withdrawal reactions.Do not suddenly stop taking XANULLX. Stopping XANULLX 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.Some 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.Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.Do not take more XANULLX than prescribed or take XANULLX for longer than prescribed.What is XANULLXXANULLX is prescription medicine used:to treat anxiety disordersfor the short-term relief of the symptoms of anxietyto treat panic disorder with or without fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia) XANULLX is federal controlled substance (C-IV) because it contains alprazolam that can be abused or lead to dependence. Keep XANULLX in safe place to prevent misuse and abuse. Selling or giving away XANULLX 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.It is not known if XANULLX is safe and effective in children.Elderly patients are especially susceptible to dose related adverse effects when taking XANULLX.It is not known if XANULLX is safe and effective when used to treat anxiety disorder for longer than months.It is not known if XANULLX is safe and effective when used to treat panic disorder for longer than 10 weeks.Do not take XANULLX if:you are allergic to alprazolam, other benzodiazepines, or any of the ingredients in XANULLX. See the end of this Medication Guide for complete list of ingredients in XANULLX.you are taking antifungal medicines including ketoconazole and itraconazoleBefore you take XANULLX, tell your healthcare provider about all of your medical conditions, including if you:have or have had depression, mood problems, or suicidal thoughts or behaviorhave liver or kidney problemshave lung disease or breathing problemsare pregnant or plan to become pregnant. XANULLX may harm your unborn baby. You and your healthcare provider should decide if you should take XANULLX while you are pregnant.are breastfeeding or plan to breastfeed. XANULLX passes into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take XANULLX. You should not breastfeed while taking XANULLX.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Taking XANULLX with certain other medicines can cause side effects or affect how well XANULLX or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.How should take XANULLXSee What is the most important information should know about XANULLXTake XANULLX exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much XANULLX to take and when to take it.If you take too much XANULLX, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of XANULLXXANULLX may cause serious side effects, including:See What is the most important information should know about XANULLXSeizures. Stopping XANULLX can cause seizures and seizures that will not stop (status epilepticus).Mania. XANULLX may cause an increase in activity and talking (hypomania and mania) in people who have depression.XANULLX 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 XANULLX affects you.Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking XANULLX without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, XANULLX may make your sleepiness or dizziness much worse. The most common side effects of XANULLX include:problems with coordinationhypotensiontrouble saying words clearly (dysarthria)changes in sex drive (libido)These are not all the possible side effects of XANULLX. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store XANULLXStore XANULLX at room temperature between 68F to 77F (20C to 25C)Keep XANULLX and all medicines out of the reach of children.General information about the safe and effective use of XANULLX.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide.Do not use XANULLX for condition for which it was not prescribed.Do not give XANULLX to other people, even if they have the same symptoms that you have. It may harm them.You can ask your pharmacist or healthcare provider for information about XANULLX that is written for health professionals.What are the ingredients in XANULLXActive ingredient: alprazolam Inactive ingredients: Cellulose, corn starch, docusate sodium, lactose, magnesium stearate, silicon dioxide and sodium benzoate. In addition, the 0.5 mg tablet contains FD&C Yellow No. and the mg tablet contains FD&C Blue No. 2.XANULLX(R) is registered trademark of Pharmacia Upjohn Company LLC.For more information, go to www.pfizer.com or call 1-800-438-1985.LAB 0825-3.0. XANULLX 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:shallow or slowed breathingbreathing stops (which may lead to the heart stopping)excessive sleepiness (sedation)Do not drive or operate heavy machinery until you know how taking XANULLX with opioids affects you.. shallow or slowed breathing. breathing stops (which may lead to the heart stopping). excessive sleepiness (sedation). Risk of abuse, misuse, and addiction. There is risk of abuse, misuse, and addiction with benzodiazepines, including XANULLX, which can lead to overdose and serious side effects including coma and death. Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including XANULLX. 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. You can develop an addiction even if you take XANULLX as prescribed by your healthcare provider.Take XANULLX exactly as your healthcare provider prescribed.Do not share your XANULLX with other people.Keep XANULLX in safe place and away from children. Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including XANULLX. 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. You can develop an addiction even if you take XANULLX as prescribed by your healthcare provider.. Take XANULLX exactly as your healthcare provider prescribed.. Do not share your XANULLX with other people.. Keep XANULLX in safe place and away from children.. Physical dependence and withdrawal reactions. XANULLX can cause physical dependence and withdrawal reactions.Do not suddenly stop taking XANULLX. Stopping XANULLX 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.Some 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.Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.. Do not suddenly stop taking XANULLX. Stopping XANULLX 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.. Some 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.. Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.. Do not take more XANULLX than prescribed or take XANULLX for longer than prescribed.. XANULLX is prescription medicine used:to treat anxiety disordersfor the short-term relief of the symptoms of anxietyto treat panic disorder with or without fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia) to treat anxiety disorders. for the short-term relief of the symptoms of anxiety. to treat panic disorder with or without fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia). XANULLX is federal controlled substance (C-IV) because it contains alprazolam that can be abused or lead to dependence. Keep XANULLX in safe place to prevent misuse and abuse. Selling or giving away XANULLX 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.. It is not known if XANULLX is safe and effective in children.. Elderly patients are especially susceptible to dose related adverse effects when taking XANULLX.. It is not known if XANULLX is safe and effective when used to treat anxiety disorder for longer than months.. It is not known if XANULLX is safe and effective when used to treat panic disorder for longer than 10 weeks.. you are allergic to alprazolam, other benzodiazepines, or any of the ingredients in XANULLX. See the end of this Medication Guide for complete list of ingredients in XANULLX.. you are taking antifungal medicines including ketoconazole and itraconazole. have or have had depression, mood problems, or suicidal thoughts or behavior. have liver or kidney problems. have lung disease or breathing problems. are pregnant or plan to become pregnant. XANULLX may harm your unborn baby. You and your healthcare provider should decide if you should take XANULLX while you are pregnant.. are breastfeeding or plan to breastfeed. XANULLX passes into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take XANULLX. You should not breastfeed while taking XANULLX.. See What is the most important information should know about XANULLX. Take XANULLX exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much XANULLX to take and when to take it.. If you take too much XANULLX, call your healthcare provider or go to the nearest hospital emergency room right away.. See What is the most important information should know about XANULLX. Seizures. Stopping XANULLX can cause seizures and seizures that will not stop (status epilepticus).. Mania. XANULLX may cause an increase in activity and talking (hypomania and mania) in people who have depression.XANULLX 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 XANULLX affects you.Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking XANULLX without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, XANULLX may make your sleepiness or dizziness much worse. XANULLX 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 XANULLX affects you.. Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking XANULLX without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, XANULLX may make your sleepiness or dizziness much worse.. problems with coordination. hypotension. trouble saying words clearly (dysarthria). changes in sex drive (libido). Store XANULLX at room temperature between 68F to 77F (20C to 25C). Keep XANULLX and all medicines out of the reach of children.. Medicines are sometimes prescribed for purposes other than those listed in Medication Guide.. Do not use XANULLX for condition for which it was not prescribed.. Do not give XANULLX to other people, even if they have the same symptoms that you have. It may harm them.. You can ask your pharmacist or healthcare provider for information about XANULLX that is written for health professionals.. Logo.

SPL UNCLASSIFIED SECTION.


2.1 Dosage in Generalized Anxiety Disorder. The recommended starting oral dosage of XANULLX 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)].

STORAGE AND HANDLING SECTION.


Store at controlled room temperature 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].

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 XANULLX during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Other Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications/.. Risk SummaryNeonates born to mothers using benzodiazepines during the later stages of pregnancy have been reported to experience symptoms of sedation and neonatal withdrawal [see Warnings and Precautions (5.4), Clinical Considerations)]. Overall available data from published observational studies of pregnant women exposed to alprazolam have not established drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). The estimated 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 Considerations. Fetal/Neonatal adverse reactionsBenzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to benzodiazepines during pregnancy and labor for signs of sedation, respiratory depression, withdrawal, and feeding problems and manage accordingly [see Warnings and Precautions (5.4)]. Data. Human 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. At this time, there is no clear evidence that alprazolam exposure in early pregnancy can cause major birth defects. Neonates exposed to benzodiazepines during the late third trimester of pregnancy or during labor have been reported to exhibit sedation and neonatal withdrawal symptoms.. 8.2 Lactation. Risk SummaryLimited data from published literature reports the presence of alprazolam in human breast milk. There are reports of sedation and withdrawal symptoms in breastfed neonates and infants exposed to alprazolam. The effects of alprazolam on lactation are unknown.Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed neonates and infants, advise patients that breastfeeding is not recommended during treatment with XANULLX.. 8.4 Pediatric Use. Safety and effectiveness of XANULLX have not been established in pediatric patients.. 8.5 Geriatric Use. XANULLX-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 XANULLX 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 XANULLX 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. Effects on Driving and Operating Machinery: Patients receiving XANULLX 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)Neonatal Sedation and Withdrawal Syndrome (NOWS): Use of XANULLX during pregnancy can result in neonatal sedation and neonatal withdrawal syndrome. (5.5, 8.1)Patients with Depression: Exercise caution in patients with signs or symptoms of depression. Prescribe the least number of tablets feasible to avoid intentional overdosage. (5.7). Effects on Driving and Operating Machinery: Patients receiving XANULLX 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). Neonatal Sedation and Withdrawal Syndrome (NOWS): Use of XANULLX during pregnancy can result in neonatal sedation and neonatal withdrawal syndrome. (5.5, 8.1). Patients with Depression: Exercise caution in patients with signs or symptoms of depression. Prescribe the least number of tablets feasible to avoid intentional overdosage. (5.7). 5.1 Risks from Concomitant Use with Opioids. Concomitant use of benzodiazepines, including XANULLX, 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 XANULLX 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 XANULLX than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in patient already taking XANULLX, 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 XANULLX 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 XANULLX, 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 XANULLX and throughout treatment, assess each patients risk for abuse, misuse, and addiction (e.g., using standardized screening tool). Use of XANULLX, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of XANULLX 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 XANULLX 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 XANULLX, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of XANULLX 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 XANULLX. 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 XANULLX, 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 XANULLX 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 XANULLX 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 XANULLX 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 XANULLX 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 XANULLX [see Drug Interactions (7.1)].. 5.5 Neonatal Sedation and Withdrawal Syndrome. Use of XANULLX during later stages of pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate. Observe newborns for signs of sedation and neonatal withdrawal syndrome and manage accordingly [see Use in Specific Populations (8.1)].. 5.6 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 InhibitorsXANULLX 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 XANULLX and ritonavir are initiated concomitantly or when ritonavir is added to stable dosage of XANULLX [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 XANULLX, as appropriate, during co-administration with these drugs.. 5.7 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.. 5.8 Mania. Episodes of hypomania and mania have been reported in association with the use of XANULLX in patients with depression [see Adverse Reactions (6.2)].. 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 XANULLX. Closely monitor patients with impaired respiratory function. If signs and symptoms of respiratory depression, hypoventilation, or apnea occur, discontinue XANULLX.