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 management limit dosage and duration of concomitant use of alprazolam tablets 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 tablets 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 tablets 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 tablets 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 tablets with cyp3a inhibitors may increase the concentrations of alprazolam tablets, resulting in increased risk of adverse reactions of alprazolam [see clinical pharmacology (12.3) ] . prevention or management avoid use and consider appropriate dose reduction when alprazolam tablets 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 tablets. 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 to 14 days), cyp3a4 induction offsets this inhibition. alprazolam exposure was not meaningfully affected in the presence of ritonavir. prevention or management reduce alprazolam tablets dosage when ritonavir and alprazolam are initiated concomitantly, or when ritonavir is added to a regimen where alprazolam is stabilized. increase alprazolam tablets dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam tablets concomitantly. no dosage adjustment of alprazolam tablets is necessary in patients receiving ritonavir for more than 10 to14 days [see dosage and administration (2.6) ] . concomitant use of alprazolam tablets 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 tablets. 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.

tudies have demonstrated 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 tablets 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 tablets 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 tablets, 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 tablets 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 tablets, 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 tablets and throughout treatment, assess each patient's risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). use of alprazolam tablets, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of alprazolam tablets 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 tablets 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 tablets, may lead to clinically significant physical dependence. abrupt discontinuation or rapid dosage reduction of alprazolam tablets 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 tablets. 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 tablets, 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 tablets 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 tablets 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 tablets 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 tablets 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 tablets [see drug interactions (7.1) ] . 5.5 neonatal sedation and withdrawal syndrome use of alprazolam tablets 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 a profound effect on the clearance of alprazolam. strong cyp3a inhibitors alprazolam tablets are contraindicated in patients receiving strong inhibitors of cyp3a (such as azole antifungal agents), except ritonavir [see contraindications (4) ] . ketoconazole and itraconazole have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively. dosage adjustment is necessary when alprazolam tablets and ritonavir are initiated concomitantly or when ritonavir is added to a stable dosage of alprazolam tablets [see dosage and administration (2.6) , drug interactions (7.1) ] . drugs demonstrated to be cyp3a inhibitors on the basis of clinical studies involving alprazolam: nefazodone, fluvoxamine, and cimetidine [see drug interaction (7.1) , clinical pharmacology (12.3) ] . use caution and consider dose reduction of alprazolam tablets, 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 tablets 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 alprazolam tablets. closely monitor patients with impaired respiratory function. if signs and symptoms of respiratory depression, hypoventilation, or apnea occur, discontinue alprazolam tablets.

nts 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 3 to 4 days. the maximum recommended dosage is 4 mg daily (in divided doses). use the lowest possible effective dose and frequently assess the need for continued treatment [see warnings and precautions (5.2) ] . 2.2 dosage in panic disorder the recommended starting oral dosage of alprazolam tablets 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 3 to 4 days in increments of no more than 1 mg per day. controlled trials of alprazolam tablets in the treatment of panic disorder included dosages in the range of 1 mg to 10 mg daily. the mean dosage was approximately 5 mg to 6 mg daily. occasional patients required as much as 10 mg per day. for patients receiving doses greater than 4 mg per day, periodic reassessment and consideration of dosage reduction is advised. in a controlled postmarketing dose-response study, patients treated with doses of alprazolam tablets greater than 4 mg per day for 3 months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit. the necessary duration of treatment for pd in patients responding to alprazolam tablets is unknown. 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 (2.3) ] . 2.3 discontinuation or dosage reduction of alprazolam tablets to reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam tablets 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 3 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. 2.4 dosage recommendations in geriatric patients in geriatric patients, the recommended starting oral dosage of alprazolam tablets is 0.25 mg, given 2 or 3 times daily. this may be gradually increased if needed and tolerated. geriatric patients may be especially sensitive to the effects of benzodiazepines. if adverse reactions occur at the recommended starting dosage, the dosage may be reduced [see use in specific populations (8.5) , clinical pharmacology (12.3) ] . 2.5 dosage recommendations in patients with hepatic impairment in patients with hepatic impairment, the recommended starting oral dosage of alprazolam tablets is 0.25 mg, given 2 or 3 times daily. this may be gradually increased if needed and tolerated. if adverse reactions occur at the recommended starting dose, the dosage may be reduced [see use in specific populations (8.6) , clinical pharmacology (12.3) ] . 2.6 dosage modifications for drug interactions alprazolam tablets should be reduced to half of the recommended dosage when a patient is started on ritonavir and alprazolam together, or when ritonavir is administered to a patient treated with alprazolam. increase the alprazolam tablets dosage to the target dose after 10 to 14 days of dosing ritonavir and alprazolam together. it is not necessary to reduce alprazolam tablets dose in patients who have been taking ritonavir for more than 10 to 14 days. alprazolam tablets are contraindicated with concomitant use of all strong cyp3a inhibitors, except ritonavir [see contraindications (4) , warnings and precautions (5.5) ] .

-3395 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 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 alprazolam tablets dosages up to 4 mg per day for the acute treatment of generalized anxiety disorder (table 1) short-term (up to 10 weeks) placebo-controlled clinical studies with alprazolam tablets dosages up to 10 mg per day for panic disorder, with or without agoraphobia (table 2). table 1: adverse reactions occurring in ≥1% in alprazolam tablets-treated patients and greater than placebo-treated patients in placebo-controlled trials for generalized anxiety alprazolam tablets n=565 placebo n=505 nervous system disorders drowsiness 41% 22% light-headedness 21% 19% dizziness 2% 1% akathisia 2% 1% gastrointestinal disorders dry mouth 15% 13% increased salivation 4% 2% cardiovascular disorders hypotension 5% 2% skin and subcutaneous tissue disorders dermatitis/allergy 4% 3% in addition to the adverse reactions (i.e., greater than 1%) enumerated in the table above for patients with generalized anxiety disorder, the following adverse reactions have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention. table 2: adverse reactions occurring in ≥1% in alprazolam tablets-treated patients and greater than placebo-treated patients in placebo-controlled trials (up to 10 weeks) for panic disorder alprazolam tablets n=1388 placebo n=1231 drowsiness 77% 43% fatigue and tiredness 49% 42% impaired coordination 40% 18% irritability 33% 30% memory impairment 33% 22% cognitive disorder 29% 21% decreased libido 14% 8% dysarthria 23% 6% confusional state 10% 8% increased libido 8% 4% change in libido (not specified) 7% 6% disinhibition 3% 2% talkativeness 2% 1% derealization 2% 1% gastrointestinal disorders constipation 26% 15% increased salivation 6% 4% skin and subcutaneous tissue disorders rash 11% 8% other increased appetite 33% 23% decreased appetite 28% 24% weight gain 27% 18% weight loss 23% 17% micturition difficulties 12% 9% menstrual disorders 11% 9% sexual dysfunction 7% 4% incontinence 2% 1% in addition to the reactions (i.e., greater than 1%) enumerated in the table above for patients with panic disorder, the following adverse reactions have been reported in association with the use of alprazolam tablets: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice. adverse reactions reported as reasons for discontinuation in treatment of panic disorder in placebo-controlled trials in a larger database comprised of both controlled and uncontrolled studies in which 641 patients received alprazolam tablets, discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with alprazolam tablets and at a greater rate than the placebo-treated group are shown in table 3. table 3: discontinuation-emergent symptom incidence reported in ≥5% of alprazolam tablets-treated patients and > placebo-treated patients alprazolam tablets-treated patients n=641 n=number of patients. nervous system disorders insomnia 29.5% light-headedness 19.3% abnormal involuntary movement 17.3% headache 17.0% muscular twitching 6.9% impaired coordination 6.6% muscle tone disorders 5.9% weakness 5.8% psychiatric disorders anxiety 19.2% fatigue and tiredness 18.4% irritability 10.5% cognitive disorder 10.3% memory impairment 5.5% depression 5.1% confusional state 5.0% gastrointestinal disorders nausea/vomiting 16.5% diarrhea 13.6% decreased salivation 10.6% metabolism and nutrition disorders weight loss 13.3% decreased appetite 12.8% dermatological disorders sweating 14.4% cardiovascular disorders tachycardia 12.2% special senses blurred vision 10.0% there have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam tablets [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, 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 post-traumatic stress disorder. 6.2 postmarketing experience the following adverse reactions have been identified during postapproval use of alprazolam tablets. 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 investigations: liver enzyme elevations psychiatric disorders: hypomania, mania reproductive system and breast disorders: gynecomastia, galactorrhea skin and subcutaneous tissue disorders: photosensitivity reaction, angioedema, stevens-johnson syndrome

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 management limit dosage and duration of concomitant use of alprazolam tablets 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 tablets 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 tablets 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 tablets 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 tablets with cyp3a inhibitors may increase the concentrations of alprazolam tablets, resulting in increased risk of adverse reactions of alprazolam [see clinical pharmacology (12.3) ] . prevention or management avoid use and consider appropriate dose reduction when alprazolam tablets 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 tablets. 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 to 14 days), cyp3a4 induction offsets this inhibition. alprazolam exposure was not meaningfully affected in the presence of ritonavir. prevention or management reduce alprazolam tablets dosage when ritonavir and alprazolam are initiated concomitantly, or when ritonavir is added to a regimen where alprazolam is stabilized. increase alprazolam tablets dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam tablets concomitantly. no dosage adjustment of alprazolam tablets is necessary in patients receiving ritonavir for more than 10 to14 days [see dosage and administration (2.6) ] . concomitant use of alprazolam tablets 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 tablets. 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.

he estimated 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 tablets. 8.4 pediatric use safety and effectiveness of alprazolam tablets have not been established in pediatric patients. 8.5 geriatric use alprazolam-treated geriatric patients had higher plasma concentrations of alprazolam (due to reduced clearance) compared to younger adult patients receiving the same doses. therefore, dosage reduction of alprazolam tablets 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 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 tablets is recommended in patients with hepatic impairment [see dosage and administration (2.4) , clinical pharmacology (12.3) ] .

cated 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.

ydroxyalprazolam and α-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 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. 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 younger 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 mg to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. imipramine and desipramine: the steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam tablets 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 yet been determined.

razolam. 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. 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 younger 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 mg to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. imipramine and desipramine: the steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam tablets 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 yet been determined.

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.

all 3 studies, alprazolam tablets were superior to placebo on a variable defined as "the number of patients with zero panic attacks" (range, 37% to 83% met this criterion), as well as on a global improvement score. in 2 of the 3 studies, alprazolam tablets were superior to placebo on a variable defined as "change from baseline on the number of panic attacks per week" (range, 3.3 to 5.2), and also on a phobia rating scale. a subgroup of patients who improved on alprazolam tablets during short-term treatment in 1 of these trials was continued on an open basis up to 8 months, without apparent loss of benefit.

diction; 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 reactions inform patients that the continued use of alprazolam tablets may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of alprazolam tablets 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 tablets 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 tablets due to its cns depressant effects. also advise patients to avoid use of alcohol or other cns depressants while taking alprazolam tablets [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 tablets 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 tablets [see warnings and precautions (5.4) ] . advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to alprazolam tablets during pregnancy [see use in specific populations (8.1) ] . lactation advise women not to breastfeed during treatment with alprazolam tablets [see use in specific populations (8.2) ] .