ily at mu receptors. when benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. prevention or management limit dosage and duration of concomitant use of alprazolam xr and opioids, and monitor patients closely for respiratory depression and sedation [see warnings and precautions (5.1) ]. examples morphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorpenol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol. cns depressants clinical implication the benzodiazepines, including alprazolam, produce additive cns depressant effects when coadministered with other cns depressants. prevention or management limit dosage and duration of alprazolam xr during concomitant use with cns depressants [see warnings and precautions (5.3) ] . examples psychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce cns depression. strong inhibitors of cyp3a (except ritonavir) clinical implication concomitant use of alprazolam xr with strong cyp3a inhibitors has a 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 management concomitant use of alprazolam xr with a strong cyp3a4 inhibitor (except ritonavir) is contraindicated [see contraindications (4) , warnings and precautions (5.5) ]. examples ketoconazole, itraconazole, clarithromycin moderate or weak inhibitors of cyp3a clinical implication concomitant use of alprazolam xr with cyp3a inhibitors may increase the concentrations of alprazolam xr, resulting in increased risk of adverse reactions [see clinical pharmacology (12.3) ]. prevention or management avoid use and consider appropriate dose reduction when alprazolam xr is coadministered with a moderate or weak cyp3a inhibitor [see warnings and precautions (5.5) ]. examples nefazodone, fluvoxamine, cimetidine, erythromycin cyp3a inducers clinical implication concomitant use of cyp3a inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam [see clinical pharmacology (12.3) ] . prevention or management caution is recommended during coadministration with alprazolam. examples carbamazepine, phenytoin ritonavir clinical implication interactions 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 – 14 days), cyp3a4 induction offsets this inhibition. alprazolam exposure was not meaningfully affected in the presence of ritonavir. prevention or management reduce alprazolam xr dose when a patient is initiated with ritonavir and alprazolam xr concomitantly, or when ritonavir is added to a regimen where alprazolam xr is stabilized. increase alprazolam xr dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam xr concomitantly. no dosage adjustment of alprazolam xr is necessary in patients receiving ritonavir for more than 10 to 14 days [see dosage and administration (2.5) ] . concomitant use of alprazolam xr with a strong cyp3a inhibitor, except ritonavir, is contraindicated [see contraindications (4) , warnings and precautions (5.5) ]. digoxin clinical implication increased digoxin concentrations have been reported when alprazolam was given, especially in geriatric patients (>65 years of age). prevention or management in patients on digoxin therapy, measure serum digoxin concentrations before initiating alprazolam xr. 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 a specific drug or specific test.

onstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. if a decision is made to prescribe alprazolam xr 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 a lower initial dose of alprazolam xr than indicated in the absence of an opioid and titrate based on clinical response. if an opioid is initiated in a patient already taking alprazolam xr, prescribe a lower initial dose of the opioid and titrate based upon clinical response. advise both patients and caregivers about the risks of respiratory depression and sedation when alprazolam xr is used with opioids. advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see drug interactions (7.1) ]. 5.2 abuse, misuse, and addiction the use of benzodiazepines, including alprazolam xr, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see drug abuse and dependence (9.2) ] . before prescribing alprazolam xr and throughout treatment, assess each patient's risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). use of alprazolam xr, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of alprazolam xr 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 a 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 a gradual taper to discontinue alprazolam xr 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 reactions the continued use of benzodiazepines, including alprazolam xr, may lead to clinically significant physical dependence. abrupt discontinuation or rapid dosage reduction of alprazolam xr 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 syndrome in some cases, benzodiazepine users have developed a 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 a direct consequence of physical dependence to alprazolam xr. these include a 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 ≤ 4 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 4 mg/day and for long periods (more than 12 weeks). however, in a controlled postmarketing discontinuation study of panic disorder patients who received alprazolam, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose. in contrast, patients treated with doses of alprazolam greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day. in a controlled clinical trial in which 63 patients were randomized to alprazolam and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease, and weight loss. other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound, or withdrawal. interdose symptoms early morning anxiety and emergence of anxiety symptoms between doses of alprazolam have been reported in patients with panic disorder taking prescribed maintenance doses. these symptoms may reflect the development of tolerance or a time interval between doses which is longer than the duration of clinical action of the administered dose. in either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels above those needed to prevent relapse, rebound, or withdrawal symptoms over the entire course of the interdosing interval. 5.4 effects on driving and operating machinery because of its cns depressant effects, patients receiving alprazolam xr should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. for the same reason, patients should be cautioned about the concomitant use of alcohol and other cns depressant drugs during treatment with alprazolam xr [see drug interactions (7.1) ] . 5.5 neonatal sedation and withdrawal syndrome use of alprazolam xr during the 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 a profound effect on the clearance of alprazolam. strong cyp3a inhibitors alprazolam xr is contraindicated in patients receiving strong inhibitors of cyp3a such as azole antifungal agents [see contraindications (4) ] . ketoconazole and itraconazole have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively. dosage adjustment is necessary when alprazolam xr and ritonavir are initiated concomitantly or when ritonavir is added to a stable dosage of alprazolam xr [see dosage and administration (2.5) , drug interactions (7.1) ]. drugs demonstrated to be cyp3a inhibitors on the basis of clinical studies involving alprazolam: nefazodone, fluvoxamine, and cimetidine [see drug interaction (7.1) , clinical pharmacology (12.3) ] . use caution and consider dose reduction of alprazolam xr, 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 alprazolam xr in patients with depression [see adverse reactions (6.1) ] . 5.9 risks in patients with impaired respiratory function there have been reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam. closely monitor patients with impaired respiratory function. if signs and symptoms of respiratory depression, hypoventilation, or apnea occur, discontinue alprazolam xr.

days in increments of no more than 1 mg daily. the recommended dosage range is 3 mg to 6 mg once daily. controlled trials of alprazolam xr for the treatment of panic disorder included dosages in the range of 1 mg to 10 mg per day. most patients showed a response in the dosage range of 3 mg to 6 mg per day. occasional patients required as much as 10 mg per day. the longer-term efficacy of alprazolam xr has not been systematically evaluated. if alprazolam xr is used for periods longer than 8 weeks, the healthcare provider should periodically reassess the usefulness of the drug for the individual patient. after a period of extended freedom from panic attacks, a 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 (2.2) , warnings and precautions (5.2) ] . 2.2 discontinuation or dosage reduction of alprazolam xr to reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam xr or reduce the dosage. if a 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) ]. reduce the dosage by no more than 0.5 mg every three days. some patients may benefit from an even more gradual discontinuation. some patients may prove resistant to all discontinuation regimens. in a controlled postmarketing discontinuation study of panic disorder patients which compared the recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. 2.3 dosage recommendations in geriatric patients in geriatric patients, the recommended starting dosage of alprazolam xr is 0.5 mg once daily. this may be gradually increased if needed and tolerated. geriatric patients may be sensitive to the effects of benzodiazepines [see use in specific populations (8.5) , clinical pharmacology (12.3) ] . 2.4 dosage recommendations in patients with hepatic impairment in patients with hepatic impairment, the recommended starting dosage of alprazolam xr is 0.5 mg once daily. this may be gradually increased if needed and tolerated [see use in specific populations (8.6) , clinical pharmacology (12.3) ]. 2.5 dosage modifications for drug interactions alprazolam xr should be reduced to half of the recommended dosage when a patient is started on ritonavir and alprazolam xr together, or when ritonavir is added to a patient treated with alprazolam xr. increase alprazolam xr dosage to the target dose after 10 to 14 days of dosing ritonavir and alprazolam xr together. it is not necessary to reduce alprazolam xr dosage in patients who have been taking ritonavir for more than 10 to 14 days. alprazolam xr is contraindicated with concomitant use of all strong cyp3a inhibitors, except ritonavir [see contraindications (4) , warnings and precautions (5.5) , drug interactions (7.1) ] . 2.6 switching patients from alprazolam tablets to alprazolam xr tablets patients who are currently being treated with divided doses of alprazolam may be switched to alprazolam xr at the same total daily dose taken once daily. if the clinical response after switching is inadequate, titrate the dosage as outlined above.

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 a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. the information included in the section on adverse reactions observed in short-term, placebo-controlled trials with alprazolam xr is based on pooled data of five 6- and 8-week placebo-controlled clinical studies in panic disorder. adverse reactions observed in short-term, placebo-controlled trials of alprazolam xr adverse reactions reported as reasons for discontinuation of treatment in placebo-controlled trials approximately 17% of the 531 patients who received alprazolam xr in placebo-controlled clinical trials for panic disorder had at least 1 adverse event that led to discontinuation compared to 8% of 349 placebotreated patients. the most common events leading to discontinuation and considered to be drug-related (i.e., leading to discontinuation in at least 1% of the patients treated with alprazolam xr at a rate at least twice that of placebo) are shown in table 1. table 1: adverse reactions leading to discontinuation in ≥1% of alprazolam xr-treated patients and at least twice the rate of placebo-treated patients in placebo-controlled trials percentage of patients discontinuing due to adverse reactions alprazolam xr (n=531) placebo (n=349) n=number of patients nervous system disorders sedation 7.5 0.6 somnolence 3.2 0.3 dysarthria 2.1 0 coordination abnormal 1.9 0.3 memory impairment 1.5 0.3 general disorders/administration site conditions fatigue 1.7 0.6 psychiatric disorders depression 2.5 1.2 adverse reactions occurring at an incidence of 1% or more among patients treated with alprazolam xr table 2 shows the incidence of adverse reactions that occurred during 6- and 8-week placebo-controlled trials in 1% or more of patients treated with alprazolam xr where the incidence in patients treated with alprazolam xr was greater than the incidence in placebo-treated patients. the most commonly observed adverse reactions in panic disorder patients treated with alprazolam xr (incidence of 5% or greater and at least twice the incidence in placebo patients) were: sedation, somnolence, memory impairment, dysarthria, coordination abnormal, ataxia, libido decreased. table 2: adverse reactions occuring in ≥ 1% in alprazolam-treated patients and greater than placebo-treated patients in 6 and 8 week placebo-controlled trials panic disorder alprazolam xr (n=531) placebo (n=349) nervous system disorders sedation 45% 23% somnolence 23% 6% memory impairment 15% 7% dysarthria 11% 3% coordination abnormal 9% 1% mental impairment 7% 6% ataxia 7% 3% disturbance in attention 3% 1% balance impaired 3% 1% dyskinesia 2% 1% hypoesthesia 1% <1% hypersomnia 1% 0% general disorders/administration site conditions fatigue 14% 9% lethargy 2% 1% psychiatric disorders depression 12% 9% libido decreased 6% 2% disorientation 2% 0% confusion 2% 1% depressed mood 1% <1% metabolism and nutrition disorders appetite increased 7% 6% anorexia 2% 0% gastrointestinal disorders constipation 8% 4% nausea 6% 3% investigations weight increased 5 4 injury, poisoning, and procedural complications road traffic accident 2% 0% reproductive system and breast disorders dysmenorrhea 4% 3% sexual dysfunction 2% 1% musculoskeletal and connective tissue disorder arthralgia 2% 1% myalgia 2% 1% pain in limb 1% 0% respiratory, thoracic, and mediatinal disorders dyspnea 2% 0% other adverse reactions observed during the premarketing evaluation of alprazolam xr following is a list of other adverse reaction reported by 531 patients with panic disorder treated with alprazolam xr. adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent); those occurring in less than 1/100 patients but at least 1/1000 patients (infrequent); those occurring in fewer than 1/1000 patients (rare). cardiac disorders: frequent: palpitation; infrequent: sinus tachycardia ear and labyrinth disorders: frequent: vertigo; infrequent : tinnitus, ear pain eye disorders: frequent: blurred vision; infrequent: mydriasis, photophobia gastrointestinal disorders : frequent: diarrhea, vomiting, dyspepsia, abdominal pain; infrequent : dysphagia, salivary hypersecretion general disorders and administration site conditions : frequent : malaise, weakness, chest pains; infrequent: fall, pyrexia, thirst, feeling hot and cold, edema, feeling jittery, sluggishness, asthenia, feeling drunk, chest tightness, increased energy, feeling of relaxation, hangover, loss of control of legs, rigors musculoskeletal and connective tissue disorders : frequent : back pain, muscle cramps, muscle twitching nervous system disorders : frequent: headache, dizziness, tremor; infrequen t: amnesia, clumsiness, syncope, hypotonia, seizures, depressed level of consciousness, sleep apnea syndrome, sleep talking, stupor psychiatric system disorders : frequent : irritability, insomnia, nervousness, derealization, libido increased, restlessness, agitation, depersonalization, nightmare; infrequent: abnormal dreams, apathy, aggression, anger, bradyphrenia, euphoric mood, logorrhea, mood swings, dysphonia, hallucination, homicidal ideation, mania, hypomania, impulse control, psychomotor retardation, suicidal ideation renal and urinary disorders : frequent : difficulty in micturition; infrequent : urinary frequency, urinary incontinence respiratory, thoracic, and mediastinal disorders : frequent : nasal congestion, hyperventilation; infrequent: choking sensation, epistaxis, rhinorrhea skin and subcutaneous tissue disorders : frequent: sweating increased; infrequent: clamminess, rash, urticaria vascular disorders : infrequent: hypotension discontinuation-emergent adverse reactions occurring at an incidence of 5% or more among patients treated with alprazolam xr table 3 shows the incidence of discontinuation-emergent adverse reactions that occurred during short-term, placebo-controlled trials in 5% or more of patients treated with alprazolam xr where the incidence in patients treated with alprazolam xr was 2 times greater than the incidence in placebo-treated patients. table 3: discontinuation-emergent symptom incidence reported in ≥5% of alprazolam xr-treated patients and at least twice the rate of placebo-treated patients in short-term, placebo-controlled trials alprazolam xr n=422 (%) placebo n=261 (%) nervous system disorders tremor 28.2 10.7 headache 26.5 12.6 hypoesthesia 7.8 2.3 paraesthesia 7.1 2.7 psychiatric disorders insomnia 24.2 9.6 nervousness 21.8 8.8 depression 10.9 5.0 derealization 8.0 3.8 anxiety 7.8 2.7 depersonalization 5.7 1.9 gastrointestinal disorders diarrhea 12.1 3.1 respiratory, thoracic and mediastinal disorders hyperventilation 8.5 2.7 metabolism and nutrition disorders appetite decreased 9.5 3.8 musculosketal and connective tissue disorders muscle twitching 7.4 2.7 vascular disorders hot flushes 5.9 2.7 there have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam [see warning and precautions (5.2) , 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, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder. 6.2 postmarketing experience the following adverse reactions have been identified during post-approval use of alprazolam and/oralprazolam xr. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. endocrine disorders: hyperprolactinemia general disorders and administration site conditions: edema peripheral hepatobiliary disorders: hepatitis, hepatic failure, jaundice investigations: liver enzyme elevations psychiatric disorders: hypomania, mania reproductive system and breast disorders: gynecomastia, galactorrhea, menstruation irregular skin and subcutaneous tissue disorders: photosensitivity reaction, angioedema, stevens-johnson syndrome

ily at mu receptors. when benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. prevention or management limit dosage and duration of concomitant use of alprazolam xr and opioids, and monitor patients closely for respiratory depression and sedation [see warnings and precautions (5.1) ]. examples morphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorpenol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol. cns depressants clinical implication the benzodiazepines, including alprazolam, produce additive cns depressant effects when coadministered with other cns depressants. prevention or management limit dosage and duration of alprazolam xr during concomitant use with cns depressants [see warnings and precautions (5.3) ] . examples psychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce cns depression. strong inhibitors of cyp3a (except ritonavir) clinical implication concomitant use of alprazolam xr with strong cyp3a inhibitors has a 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 management concomitant use of alprazolam xr with a strong cyp3a4 inhibitor (except ritonavir) is contraindicated [see contraindications (4) , warnings and precautions (5.5) ]. examples ketoconazole, itraconazole, clarithromycin moderate or weak inhibitors of cyp3a clinical implication concomitant use of alprazolam xr with cyp3a inhibitors may increase the concentrations of alprazolam xr, resulting in increased risk of adverse reactions [see clinical pharmacology (12.3) ]. prevention or management avoid use and consider appropriate dose reduction when alprazolam xr is coadministered with a moderate or weak cyp3a inhibitor [see warnings and precautions (5.5) ]. examples nefazodone, fluvoxamine, cimetidine, erythromycin cyp3a inducers clinical implication concomitant use of cyp3a inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam [see clinical pharmacology (12.3) ] . prevention or management caution is recommended during coadministration with alprazolam. examples carbamazepine, phenytoin ritonavir clinical implication interactions 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 – 14 days), cyp3a4 induction offsets this inhibition. alprazolam exposure was not meaningfully affected in the presence of ritonavir. prevention or management reduce alprazolam xr dose when a patient is initiated with ritonavir and alprazolam xr concomitantly, or when ritonavir is added to a regimen where alprazolam xr is stabilized. increase alprazolam xr dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam xr concomitantly. no dosage adjustment of alprazolam xr is necessary in patients receiving ritonavir for more than 10 to 14 days [see dosage and administration (2.5) ] . concomitant use of alprazolam xr with a strong cyp3a inhibitor, except ritonavir, is contraindicated [see contraindications (4) , warnings and precautions (5.5) ]. digoxin clinical implication increased digoxin concentrations have been reported when alprazolam was given, especially in geriatric patients (>65 years of age). prevention or management in patients on digoxin therapy, measure serum digoxin concentrations before initiating alprazolam xr. 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 a specific drug or specific test.

ated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a 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 reactions benzodiazepines 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 data published data from observational studies on the use of benzodiazepines during pregnancy do not report a 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 summary limited 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 alprazolam xr. 8.4 pediatric use safety and effectiveness of alprazolam xr have not been established in pediatric patients. 8.5 geriatric use alprazolam xr-treated geriatric patients had higher plasma concentrations of alprazolam (due to reduced clearance) compared to younger adults receiving the same doses. therefore, dosage reduction of alprazolam xr is recommended in geriatric patients [see dosage and administration (2.3) and clinical pharmacology (12.3) ] . 8.6 hepatic impairment patients with alcoholic liver disease exhibit a longer elimination half-life (19.7 hours), compared to healthy subjects (11.4 hours). this may be caused by decreased clearance of alprazolam in patients with alcoholic liver disease. dosage reduction of alprazolam xr is recommended in patients with hepatic impairment [see dosage and administration (2.4) , clinical pharmacology (12.3) ] .

pulation is unknown. all pregnancies have a 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 reactions benzodiazepines 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 data published data from observational studies on the use of benzodiazepines during pregnancy do not report a 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.

100%. the bioavailability and pharmacokinetics of alprazolam following administration of alprazolam xr are similar to that for alprazolam, with the exception of a slower rate of absorption. effect of food a high-fat meal given up to 2 hours before dosing with alprazolam xr increased the mean c max by about 25%. the effect of this meal on t max depended on the timing of the meal, with a reduction in t max by about 1/3 for subjects eating immediately before dosing and an increase in t max by about 1/3 for subjects eating 1 hour or more after dosing. the extent of exposure (auc) and elimination half-life (t ½ ) were not affected by eating. distribution the apparent volume of distribution of alprazolam is similar for alprazolam xr and alprazolam. alprazolam is 80% bound to human serum protein, and albumin accounts for the majority of the binding. elimination the mean plasma elimination half-life of alprazolam following administration of alprazolam xr ranges from 10.7 to 15.8 hours in healthy adults. metabolism alprazolam is extensively metabolized in humans, primarily by cytochrome p450 3a4 (cyp3a4), to two major active metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. the plasma circulation levels of the two active metabolites after both alprazolam xr and alprazolam are less than 10% and 4% of the parent, respectively. 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 α-hydroxyalprazolam. the low concentrations and low potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam indicate that they unlikely contribute much to the effects of alprazolam. a benzophenone derived from alprazolam is also found in humans. their half-lives appear to be similar to that of alprazolam. the pharmacokinetic parameters at steady-state for the two hydroxylated metabolites of alprazolam (4-hydroxyalprazolam and α-hydroxyalprazolam) were similar for alprazolam and alprazolam xr, indicating that the metabolism of alprazolam is not affected by absorption rate. excretion alprazolam and its metabolites are excreted primarily in the urine. specific populations geriatric patients the mean t 1/2 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 adult subjects. obese patients the mean t 1/2 of alprazolam was 21.8 hours (range: 9.9 to 40.4 hours) in a group of obese subjects. patients with hepatic impairment the mean t 1/2 of alprazolam was 19.7 hours (range: 5.8 to 65.3 hours) in patients with alcoholic liver disease. racial or ethnic groups maximal concentrations and t 1/2 of alprazolam are approximately 15% and 25% higher in asians compared to caucasians. smoking alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers. drug interaction studies in vivo studies most 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 t 1/2 by 16%. fluoxetine: coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased t 1/2 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 t 1/2 by 29%. carbamazepine: the oral clearance of alprazolam (given in a 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 t 1/2 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 c max of alprazolam. the elimination t 1/2 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 c max was reduced by 12% and 16%, respectively, in the presence of ritonavir. the elimination t 1/2 of alprazolam was not significantly changed [see warnings and precautions (5.5) ] . sertraline: a single dose of alprazolam 1 mg and steady state dose of sertraline (50 to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. imipramine and desipramine: the steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam in doses up to 4 mg per day. warfarin: alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally. in vitro studies data from in vitro studies of alprazolam suggest a possible drug interaction of alprazolam with paroxetine. the ability of alprazolam to induce human hepatic enzyme systems has not been determined.

bout 25%. the effect of this meal on t max depended on the timing of the meal, with a reduction in t max by about 1/3 for subjects eating immediately before dosing and an increase in t max by about 1/3 for subjects eating 1 hour or more after dosing. the extent of exposure (auc) and elimination half-life (t ½ ) were not affected by eating. distribution the apparent volume of distribution of alprazolam is similar for alprazolam xr and alprazolam. alprazolam is 80% bound to human serum protein, and albumin accounts for the majority of the binding. elimination the mean plasma elimination half-life of alprazolam following administration of alprazolam xr ranges from 10.7 to 15.8 hours in healthy adults. metabolism alprazolam is extensively metabolized in humans, primarily by cytochrome p450 3a4 (cyp3a4), to two major active metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. the plasma circulation levels of the two active metabolites after both alprazolam xr and alprazolam are less than 10% and 4% of the parent, respectively. 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 α-hydroxyalprazolam. the low concentrations and low potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam indicate that they unlikely contribute much to the effects of alprazolam. a benzophenone derived from alprazolam is also found in humans. their half-lives appear to be similar to that of alprazolam. the pharmacokinetic parameters at steady-state for the two hydroxylated metabolites of alprazolam (4-hydroxyalprazolam and α-hydroxyalprazolam) were similar for alprazolam and alprazolam xr, indicating that the metabolism of alprazolam is not affected by absorption rate. excretion alprazolam and its metabolites are excreted primarily in the urine. specific populations geriatric patients the mean t 1/2 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 adult subjects. obese patients the mean t 1/2 of alprazolam was 21.8 hours (range: 9.9 to 40.4 hours) in a group of obese subjects. patients with hepatic impairment the mean t 1/2 of alprazolam was 19.7 hours (range: 5.8 to 65.3 hours) in patients with alcoholic liver disease. racial or ethnic groups maximal concentrations and t 1/2 of alprazolam are approximately 15% and 25% higher in asians compared to caucasians. smoking alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers. drug interaction studies in vivo studies most 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 t 1/2 by 16%. fluoxetine: coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased t 1/2 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 t 1/2 by 29%. carbamazepine: the oral clearance of alprazolam (given in a 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 t 1/2 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 c max of alprazolam. the elimination t 1/2 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 c max was reduced by 12% and 16%, respectively, in the presence of ritonavir. the elimination t 1/2 of alprazolam was not significantly changed [see warnings and precautions (5.5) ] . sertraline: a single dose of alprazolam 1 mg and steady state dose of sertraline (50 to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. imipramine and desipramine: the steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam in doses up to 4 mg per day. warfarin: alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally. in vitro studies data from in vitro studies of alprazolam suggest a possible drug interaction of alprazolam with paroxetine. the ability of alprazolam to induce human hepatic enzyme systems has not been determined.

g/m 2 body surface area) for 2 years, a tendency for a dose related increase in the number of cataracts was observed in females and a tendency for a dose related increase in corneal vascularization was observed in males. these lesions did not appear until after 11 months of treatment.

/ once per day that did not show a benefit for either dose of alprazolam xr. analyses of the relationship between treatment outcome and gender did not suggest any differential responsiveness on the basis of gender.

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 reactions inform patients that the continued use of alprazolam xr may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of alprazolam xr may precipitate acute withdrawal reactions, which can be life-threatening. inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. instruct patients that discontinuation or dosage reduction of alprazolam xr may require a slow taper [see warnings and precautions (5.3) , drug abuse and dependence (9.3) ] . effects on driving and operating machinery advise patients not to drive a motor vehicle or operate heavy machinery while taking alprazolam xr due to its cns depressant effects. also advise patients to avoid use of alcohol or other cns depressants while taking alprazolam xr [see warnings and precautions (5.3) ] . patients with depression advise patients, their families and caregivers to look for signs of suicidality or worsening depression, and to inform the patient's healthcare provider immediately [see warnings and precautions (5.6) ] . concomitant medications advise patients to inform their healthcare provider of all medicines they take, including prescription and nonprescription medications, vitamins and herbal supplements [see drug interactions (7) ] . pregnancy benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. advise mothers using alprazolam xr 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 alprazolam xr [see warnings and precautions (5.4) ] . advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to alprazolam xr during pregnancy [see use in specific populations (8.1) ]. lactation advise women not to breastfeed during treatment with alprazolam xr [see use in specific populations (8.2) ] .