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Xanax (Alprazolam)
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Pharmacology
Alprazolam, a triazolo 1,4 benzodiazepine analog, binds with high affinity to the GABA benzodiazepine receptor complex. Considerable evidence suggest that the central pharmacologic/therapeutic actions of alprazolam are mediated via interaction with this receptor complex.
Pharmacokinetics: Orally administered alprazolam is readily absorbed in man. Plasma levels are proportional to the dose given; over the dose range of 0.5 to 3mg, peak levels of 8.0 to 37ng/mL were observed. The mean elimination half-life of alprazolam is about 11hours in healthy adults. With multiple doses, given 3times daily, steady state is reached within 7days. Alprazolam and its metabolites are excreted primarily in the urine. Degradation of alprazolam occurs mainly by oxidation yielding the primary metabolites a hydroxy-alprazolam and a benzophenone derivative. The a-hydroxy-metabolite is further transformed to demethylalprazolam. Both a-hydroxy-alprazolam and demethylalprazolam are active and appear to have half-lives similar to alprazolam but their plasma levels are low.
Table I summarizes some pharmacokinetic parameters in healthy adults and healthy elderly subjects (mean age 70years, range 62to 78years), as well as in obese subjects and in patients with impaired hepatic or renal function. Clearance was decreased and half-lives were increased in all special patient populations except in patients on hemodialysis. Time to peak plasma concentration was increased in patients with liver disease and CAPD.
Cimetidine: Cimetidine significantly impaired the clearance of alprazolam and prolonged its half-life. In healthy volunteers, a single 1mg dose of alprazolam was administered with and without concurrent administration of cimetidine (300mg) every 6hours. Cimetidine significantly reduced total metabolic clearance (1.05 versus 1.66mL/min/kg) and significantly prolonged elimination half-life (16.6hours versus 12.4hours). Similar results were observed during repeated administration of both drugs.
Oral contraceptives: The effect of oral contraceptives on the pharmacokinetics of a single 1mg dose of alprazolam was studied in healthy women. Alprazolam clearance was lower in subjects taking oral contraceptives (0.95mL/min/kg) than in the control group (1.21mL/min/kg) while its half-life was prolonged (12.4hours versus 9.6hours).
Anticoagulant: Alprazolam, 0.5mg, administered 3times a day for 14days, did not affect prothrombin times or plasma warfarin levels in male volunteers administered sodium warfarin orally.
Clinical Trial: In a placebo-controlled, 8-week trial, which included 526patients with diagnoses of panic disorder with or without agoraphobia, alprazolam in a dosage range of 1to 10mg/day (with a mean daily dosage of 5.7±2.27mg at the end of the treatment period) was found effective in blocking or attenuating panic attacks and reducing phobic avoidance.
Alprazolam, a triazolo 1,4 benzodiazepine analog, binds with high affinity to the GABA benzodiazepine receptor complex. Considerable evidence suggest that the central pharmacologic/therapeutic actions of alprazolam are mediated via interaction with this receptor complex.
Pharmacokinetics: Orally administered alprazolam is readily absorbed in man. Plasma levels are proportional to the dose given; over the dose range of 0.5 to 3mg, peak levels of 8.0 to 37ng/mL were observed. The mean elimination half-life of alprazolam is about 11hours in healthy adults. With multiple doses, given 3times daily, steady state is reached within 7days. Alprazolam and its metabolites are excreted primarily in the urine. Degradation of alprazolam occurs mainly by oxidation yielding the primary metabolites a hydroxy-alprazolam and a benzophenone derivative. The a-hydroxy-metabolite is further transformed to demethylalprazolam. Both a-hydroxy-alprazolam and demethylalprazolam are active and appear to have half-lives similar to alprazolam but their plasma levels are low.
Table I summarizes some pharmacokinetic parameters in healthy adults and healthy elderly subjects (mean age 70years, range 62to 78years), as well as in obese subjects and in patients with impaired hepatic or renal function. Clearance was decreased and half-lives were increased in all special patient populations except in patients on hemodialysis. Time to peak plasma concentration was increased in patients with liver disease and CAPD.
Cimetidine: Cimetidine significantly impaired the clearance of alprazolam and prolonged its half-life. In healthy volunteers, a single 1mg dose of alprazolam was administered with and without concurrent administration of cimetidine (300mg) every 6hours. Cimetidine significantly reduced total metabolic clearance (1.05 versus 1.66mL/min/kg) and significantly prolonged elimination half-life (16.6hours versus 12.4hours). Similar results were observed during repeated administration of both drugs.
Oral contraceptives: The effect of oral contraceptives on the pharmacokinetics of a single 1mg dose of alprazolam was studied in healthy women. Alprazolam clearance was lower in subjects taking oral contraceptives (0.95mL/min/kg) than in the control group (1.21mL/min/kg) while its half-life was prolonged (12.4hours versus 9.6hours).
Anticoagulant: Alprazolam, 0.5mg, administered 3times a day for 14days, did not affect prothrombin times or plasma warfarin levels in male volunteers administered sodium warfarin orally.
Clinical Trial: In a placebo-controlled, 8-week trial, which included 526patients with diagnoses of panic disorder with or without agoraphobia, alprazolam in a dosage range of 1to 10mg/day (with a mean daily dosage of 5.7±2.27mg at the end of the treatment period) was found effective in blocking or attenuating panic attacks and reducing phobic avoidance.
Indications
Alprazolam, A Triazolo 1,4 Benzodiazepine Analog, Binds With High Affinity To The GABA Benzodiazepine Receptor Complex. Considerable Evidence Suggest That The Central Pharmacologic/therapeutic Actions Of Alprazolam Are Mediated Via Interaction With This Receptor Complex.
Pharmacokinetics: Orally Administered Alprazolam Is Readily Absorbed In Man. Plasma Levels Are Proportional To The Dose Given; Over The Dose Range Of 0.5 To 3mg, Peak Levels Of 8.0 To 37ng/mL Were Observed. The Mean Elimination Half-life Of Alprazolam Is About 11hours In Healthy Adults. With Multiple Doses, Given 3times Daily, Steady State Is Reached Within 7days. Alprazolam And Its Metabolites Are Excreted Primarily In The Urine. Degradation Of Alprazolam Occurs Mainly By Oxidation Yielding The Primary Metabolites A Hydroxy-alprazolam And A Benzophenone Derivative. The A-hydroxy-metabolite Is Further Transformed To Demethylalprazolam. Both A-hydroxy-alprazolam And Demethylalprazolam Are Active And Appear To Have Half-lives Similar To Alprazolam But Their Plasma Levels Are Low.
Table I Summarizes Some Pharmacokinetic Parameters In Healthy Adults And Healthy Elderly Subjects (mean Age 70years, Range 62to 78years), As Well As In Obese Subjects And In Patients With Impaired Hepatic Or Renal Function. Clearance Was Decreased And Half-lives Were Increased In All Special Patient Populations Except In Patients On Hemodialysis. Time To Peak Plasma Concentration Was Increased In Patients With Liver Disease And CAPD.
Cimetidine: Cimetidine Significantly Impaired The Clearance Of Alprazolam And Prolonged Its Half-life. In Healthy Volunteers, A Single 1mg Dose Of Alprazolam Was Administered With And Without Concurrent Administration Of Cimetidine (300mg) Every 6hours. Cimetidine Significantly Reduced Total Metabolic Clearance (1.05 Versus 1.66mL/min/kg) And Significantly Prolonged Elimination Half-life (16.6hours Versus 12.4hours). Similar Results Were Observed During Repeated Administration Of Both Drugs.
Oral Contraceptives: The Effect Of Oral Contraceptives On The Pharmacokinetics Of A Single 1mg Dose Of Alprazolam Was Studied In Healthy Women. Alprazolam Clearance Was Lower In Subjects Taking Oral Contraceptives (0.95mL/min/kg) Than In The Control Group (1.21mL/min/kg) While Its Half-life Was Prolonged (12.4hours Versus 9.6hours).
Anticoagulant: Alprazolam, 0.5mg, Administered 3times A Day For 14days, Did Not Affect Prothrombin Times Or Plasma Warfarin Levels In Male Volunteers Administered Sodium Warfarin Orally.
Clinical Trial: In A Placebo-controlled, 8-week Trial, Which Included 526patients With Diagnoses Of Panic Disorder With Or Without Agoraphobia, Alprazolam In A Dosage Range Of 1to 10mg/day (with A Mean Daily Dosage Of 5.7±2.27mg At The End Of The Treatment Period) Was Found Effective In Blocking Or Attenuating Panic Attacks And Reducing Phobic Avoidance.
Alprazolam, A Triazolo 1,4 Benzodiazepine Analog, Binds With High Affinity To The GABA Benzodiazepine Receptor Complex. Considerable Evidence Suggest That The Central Pharmacologic/therapeutic Actions Of Alprazolam Are Mediated Via Interaction With This Receptor Complex.
Pharmacokinetics: Orally Administered Alprazolam Is Readily Absorbed In Man. Plasma Levels Are Proportional To The Dose Given; Over The Dose Range Of 0.5 To 3mg, Peak Levels Of 8.0 To 37ng/mL Were Observed. The Mean Elimination Half-life Of Alprazolam Is About 11hours In Healthy Adults. With Multiple Doses, Given 3times Daily, Steady State Is Reached Within 7days. Alprazolam And Its Metabolites Are Excreted Primarily In The Urine. Degradation Of Alprazolam Occurs Mainly By Oxidation Yielding The Primary Metabolites A Hydroxy-alprazolam And A Benzophenone Derivative. The A-hydroxy-metabolite Is Further Transformed To Demethylalprazolam. Both A-hydroxy-alprazolam And Demethylalprazolam Are Active And Appear To Have Half-lives Similar To Alprazolam But Their Plasma Levels Are Low.
Table I Summarizes Some Pharmacokinetic Parameters In Healthy Adults And Healthy Elderly Subjects (mean Age 70years, Range 62to 78years), As Well As In Obese Subjects And In Patients With Impaired Hepatic Or Renal Function. Clearance Was Decreased And Half-lives Were Increased In All Special Patient Populations Except In Patients On Hemodialysis. Time To Peak Plasma Concentration Was Increased In Patients With Liver Disease And CAPD.
Cimetidine: Cimetidine Significantly Impaired The Clearance Of Alprazolam And Prolonged Its Half-life. In Healthy Volunteers, A Single 1mg Dose Of Alprazolam Was Administered With And Without Concurrent Administration Of Cimetidine (300mg) Every 6hours. Cimetidine Significantly Reduced Total Metabolic Clearance (1.05 Versus 1.66mL/min/kg) And Significantly Prolonged Elimination Half-life (16.6hours Versus 12.4hours). Similar Results Were Observed During Repeated Administration Of Both Drugs.
Oral Contraceptives: The Effect Of Oral Contraceptives On The Pharmacokinetics Of A Single 1mg Dose Of Alprazolam Was Studied In Healthy Women. Alprazolam Clearance Was Lower In Subjects Taking Oral Contraceptives (0.95mL/min/kg) Than In The Control Group (1.21mL/min/kg) While Its Half-life Was Prolonged (12.4hours Versus 9.6hours).
Anticoagulant: Alprazolam, 0.5mg, Administered 3times A Day For 14days, Did Not Affect Prothrombin Times Or Plasma Warfarin Levels In Male Volunteers Administered Sodium Warfarin Orally.
Clinical Trial: In A Placebo-controlled, 8-week Trial, Which Included 526patients With Diagnoses Of Panic Disorder With Or Without Agoraphobia, Alprazolam In A Dosage Range Of 1to 10mg/day (with A Mean Daily Dosage Of 5.7±2.27mg At The End Of The Treatment Period) Was Found Effective In Blocking Or Attenuating Panic Attacks And Reducing Phobic Avoidance.
Contraindications
Hypersensitivity to alprazolam or other benzodiazepines and in patients with myasthenia gravis and acute narrow angle glaucoma. However, alprazolam may be used in patients with open angle glaucoma who are receiving appropriate treatment.
Hypersensitivity to alprazolam or other benzodiazepines and in patients with myasthenia gravis and acute narrow angle glaucoma. However, alprazolam may be used in patients with open angle glaucoma who are receiving appropriate treatment.
Safety Information / Warning
Alprazolam is not effective in patients with personality disorders. Alprazolam is not recommended for the management of mood or psychotic disorders.
Dependence and Withdrawal Reactions, Including Seizures: Physical dependence with withdrawal symptoms may occur with benzodiazepine discontinuation and can be severe (e.g., seizures) if benzodiazepines are suddenly discontinued. Even after relatively short-term use at the doses recommended for the treatment of transient anxiety and anxiety disorder (i.e., 0.75to 3mg/day), there is some risk of dependence. Post-marketing surveillance data suggest that the risk of dependence and its severity appear to be greater in patients treated with relatively high doses (above 4mg/day) and for long periods (more than 8to 12weeks).
The Importance of Dose and the Risks of Alprazolam as a Treatment for Panic Disorder: Because the management of panic disorder often requires the use of average daily doses of alprazolam above 3mg, the risk of dependence among panic disorder patients may be higher than that among those treated for less severe anxiety. Randomized placebo-controlled discontinuation studies showed a high rate of rebound and withdrawal symptoms in patients treated with alprazolam compared to placebo-treated patients.
Relapse or return of illness was defined as a return of symptoms characteristic of panic disorder (primarily panic attacks) to levels approximately equal to those seen at baseline before active treatment was initiated. Rebound refers to a return of symptoms of panic disorder to a level substantially greater in frequency, or more severe in intensity, than seen at baseline. Withdrawal symptoms were identified as those which were generally not characteristic of panic disorder and which occurred for the first time more frequently during discontinuation than at baseline.
In a controlled clinical trial in which 63patients were randomized to alprazolam and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound or withdrawal.
In a larger database comprised of both controlled and uncontrolled studies in which 641 patients received alprazolam, discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with alprazolam and at a greater rate than the placebo-treated group are listed in TableII.
From the studies cited, it has not been determined whether these symptoms are clearly related to the dose and duration of therapy with alprazolam in patients with panic disorder.
In 2 controlled trials of 6to 8weeks' duration where the ability of patients to discontinue medication was measured, 71to 93% of patients treated with alprazolam tapered completely off therapy compared to 89to 96% of placebo treated patients. The ability of patients to completely discontinue therapy with alprazolam after long-term therapy has not been reliably determined.
Seizures attributable to alprazolam were seen after drug discontinuance or dose reduction in 8of 1980patients with panic disorder or in patients participating in clinical trials where doses of alprazolam greater than 4mg daily for over 3months were permitted. Five of these cases clearly occurred during abrupt dose reduction, or discontinuation from daily doses of 2to 10mg. Three cases occurred in situations where there was not a clear relationship to abrupt dose reduction or discontinuation. In one instance, seizure occurred after discontinuation from a single dose of 1mg after tapering at a rate of 1mg every 3days, from 6mg daily. In two other instances, the relationship to taper is indeterminate; in both of these cases the patients had been receiving doses of 3mg daily prior to seizure. The duration of use in the above 8cases ranged from 4to 22weeks. There have been occasional voluntary reports of patients developing seizures while apparently tapering gradually from alprazolam. The risk of seizure seems to be greatest 24to 72hours after discontinuation. In post-marketing surveillance, 128cases of alprazolam withdrawal seizures were reported, 52 of which occurred in patients taking alprazolam alone. The dose range was 0.5to 16mg/day (median dose=4mg/day). The duration of treatment was 1to 365days (median=35days). There are no reports of fatalities associated with alprazolam withdrawal. (see Dosage for recommended tapering and discontinuation schedule).
Status Epilepticus and its Treatment: The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of alprazolam. In most cases, only a single seizure was reported; however, multiple seizures and status epilepticus were reported as well. Ordinarily, the treatment of status epilepticus of any etiology involves use of i.v. benzodiazepines plus phenytoin or barbiturates, maintenance of a patent airway and adequate hydration. For additional details regarding therapy, consultation with an appropriate specialist may be considered.
Depression: Panic-related disorders have been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Therefore, the same precaution must be exercised when using the higher doses of alprazolam in treating patients with panic-related disorders as is exercised with the use of any psychotropic drug in treating depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans.
Interdose Symptoms: Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam have been reported in patients with panic disorder taking prescribed maintenance doses of alprazolam. These symptoms may reflect the development of tolerance or 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. In these situations, it is recommended that the same total daily dose be given, divided as more frequent administrations (see Dosage).
Risk of Dose Reduction: Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes purposeful tapering, but also includes inadvertent reduction of dose (e.g., the patient forgets, the patient is admitted to a hospital, etc.). Therefore, the dosage of alprazolam should be reduced or discontinued gradually (see Dosage).
Pregnancy: The safety of the use of alprazolam in pregnancy has not been established. Therefore, alprazolam is not recommended for use during pregnancy.
Teratogenic effects: Several studies have suggested an increased risk of congenital malformations associated with the use of benzodiazepines during the first trimester of pregnancy. Since alprazolam is also a benzodiazepine derivative, the administration of alprazolam is rarely justified in women of childbearing potential. Women of childbearing potential should be warned to consult their physician regarding the discontinuation of the drug if they are pregnant or intend to become pregnant.
Nonteratogenic effects: It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.
Labor and Delivery: Alprazolam has no established use in labor or delivery.
Lactation: Studies in rats have indicated that alprazolam and its metabolites are secreted into the milk. Therefore, nursing should not be undertaken while a patient is receiving alprazolam.
Children and Adolescents: The safety and efficacy of alprazolam in patients under the age of 18years have not been established.
Occupational Hazards: Driving and Hazardous Activities: Because of its CNS depressant effect, patients receiving alprazolam should be cautioned not to undertake activities requiring mental alertness, judgment and physical coordination such as driving or operating machinery. This is particularly true in the early phases of dose adjustment, and until it has been established that they do not become drowsy or dizzy while taking alprazolam. Alcohol or CNS depressant drugs should not be ingested during treatment with alprazolam.
Alprazolam is not effective in patients with personality disorders. Alprazolam is not recommended for the management of mood or psychotic disorders.
Dependence and Withdrawal Reactions, Including Seizures: Physical dependence with withdrawal symptoms may occur with benzodiazepine discontinuation and can be severe (e.g., seizures) if benzodiazepines are suddenly discontinued. Even after relatively short-term use at the doses recommended for the treatment of transient anxiety and anxiety disorder (i.e., 0.75to 3mg/day), there is some risk of dependence. Post-marketing surveillance data suggest that the risk of dependence and its severity appear to be greater in patients treated with relatively high doses (above 4mg/day) and for long periods (more than 8to 12weeks).
The Importance of Dose and the Risks of Alprazolam as a Treatment for Panic Disorder: Because the management of panic disorder often requires the use of average daily doses of alprazolam above 3mg, the risk of dependence among panic disorder patients may be higher than that among those treated for less severe anxiety. Randomized placebo-controlled discontinuation studies showed a high rate of rebound and withdrawal symptoms in patients treated with alprazolam compared to placebo-treated patients.
Relapse or return of illness was defined as a return of symptoms characteristic of panic disorder (primarily panic attacks) to levels approximately equal to those seen at baseline before active treatment was initiated. Rebound refers to a return of symptoms of panic disorder to a level substantially greater in frequency, or more severe in intensity, than seen at baseline. Withdrawal symptoms were identified as those which were generally not characteristic of panic disorder and which occurred for the first time more frequently during discontinuation than at baseline.
In a controlled clinical trial in which 63patients were randomized to alprazolam and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound or withdrawal.
In a larger database comprised of both controlled and uncontrolled studies in which 641 patients received alprazolam, discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with alprazolam and at a greater rate than the placebo-treated group are listed in TableII.
From the studies cited, it has not been determined whether these symptoms are clearly related to the dose and duration of therapy with alprazolam in patients with panic disorder.
In 2 controlled trials of 6to 8weeks' duration where the ability of patients to discontinue medication was measured, 71to 93% of patients treated with alprazolam tapered completely off therapy compared to 89to 96% of placebo treated patients. The ability of patients to completely discontinue therapy with alprazolam after long-term therapy has not been reliably determined.
Seizures attributable to alprazolam were seen after drug discontinuance or dose reduction in 8of 1980patients with panic disorder or in patients participating in clinical trials where doses of alprazolam greater than 4mg daily for over 3months were permitted. Five of these cases clearly occurred during abrupt dose reduction, or discontinuation from daily doses of 2to 10mg. Three cases occurred in situations where there was not a clear relationship to abrupt dose reduction or discontinuation. In one instance, seizure occurred after discontinuation from a single dose of 1mg after tapering at a rate of 1mg every 3days, from 6mg daily. In two other instances, the relationship to taper is indeterminate; in both of these cases the patients had been receiving doses of 3mg daily prior to seizure. The duration of use in the above 8cases ranged from 4to 22weeks. There have been occasional voluntary reports of patients developing seizures while apparently tapering gradually from alprazolam. The risk of seizure seems to be greatest 24to 72hours after discontinuation. In post-marketing surveillance, 128cases of alprazolam withdrawal seizures were reported, 52 of which occurred in patients taking alprazolam alone. The dose range was 0.5to 16mg/day (median dose=4mg/day). The duration of treatment was 1to 365days (median=35days). There are no reports of fatalities associated with alprazolam withdrawal. (see Dosage for recommended tapering and discontinuation schedule).
Status Epilepticus and its Treatment: The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of alprazolam. In most cases, only a single seizure was reported; however, multiple seizures and status epilepticus were reported as well. Ordinarily, the treatment of status epilepticus of any etiology involves use of i.v. benzodiazepines plus phenytoin or barbiturates, maintenance of a patent airway and adequate hydration. For additional details regarding therapy, consultation with an appropriate specialist may be considered.
Depression: Panic-related disorders have been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Therefore, the same precaution must be exercised when using the higher doses of alprazolam in treating patients with panic-related disorders as is exercised with the use of any psychotropic drug in treating depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans.
Interdose Symptoms: Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam have been reported in patients with panic disorder taking prescribed maintenance doses of alprazolam. These symptoms may reflect the development of tolerance or 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. In these situations, it is recommended that the same total daily dose be given, divided as more frequent administrations (see Dosage).
Risk of Dose Reduction: Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes purposeful tapering, but also includes inadvertent reduction of dose (e.g., the patient forgets, the patient is admitted to a hospital, etc.). Therefore, the dosage of alprazolam should be reduced or discontinued gradually (see Dosage).
Pregnancy: The safety of the use of alprazolam in pregnancy has not been established. Therefore, alprazolam is not recommended for use during pregnancy.
Teratogenic effects: Several studies have suggested an increased risk of congenital malformations associated with the use of benzodiazepines during the first trimester of pregnancy. Since alprazolam is also a benzodiazepine derivative, the administration of alprazolam is rarely justified in women of childbearing potential. Women of childbearing potential should be warned to consult their physician regarding the discontinuation of the drug if they are pregnant or intend to become pregnant.
Nonteratogenic effects: It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.
Labor and Delivery: Alprazolam has no established use in labor or delivery.
Lactation: Studies in rats have indicated that alprazolam and its metabolites are secreted into the milk. Therefore, nursing should not be undertaken while a patient is receiving alprazolam.
Children and Adolescents: The safety and efficacy of alprazolam in patients under the age of 18years have not been established.
Occupational Hazards: Driving and Hazardous Activities: Because of its CNS depressant effect, patients receiving alprazolam should be cautioned not to undertake activities requiring mental alertness, judgment and physical coordination such as driving or operating machinery. This is particularly true in the early phases of dose adjustment, and until it has been established that they do not become drowsy or dizzy while taking alprazolam. Alcohol or CNS depressant drugs should not be ingested during treatment with alprazolam.
Precautions
Geriatrics: Elderly and debilitated patients have been found to be prone to the CNS depressant activity of benzodiazepines, even after low doses. Manifestations of this CNSdepressant activity include ataxia, oversedation and hypotension. Therefore, medication should be administered with caution to these patients, particularly if a drop in blood pressure might lead to cardiac complications. Initial doses should be low and increments should be made gradually, depending on the response of the patient, in order to avoid oversedation, neurological impairment and other possible adverse reactions (see Pharmacology and Dosage).
Impaired Renal or Hepatic Function: If treatment is necessary in patients with impaired hepatic or renal function, therapy should be initiated at a very low dose and the dosage increased only to the extent that it is compatible with the degree of residual function of these organs. Such patients should be followed closely and have periodic laboratory assessments. (see Pharmacology and Dosage).
Dependence Liability: Physical and psychological dependence may occur with benzodiazepines, including alprazolam. Patients who are prone to abuse drugs should be under careful surveillance when receiving alprazolam. Patients with a history of alcohol or drug abuse are at higher risk for developing psychological dependence.
Withdrawal symptoms can range from mild dysphoria and insomnia to a major syndrome that may include irritability, nervousness, insomnia, agitation, diarrhea, abdominal cramps, vomiting, sweating, tremors and convulsions. Since symptoms may be similar to those for which the patient is being treated, it may be difficult to differentiate between relapse and withdrawal upon discontinuation. Consequently, dosage must be gradually tapered to minimize withdrawal reactions. To discontinue treatment in patients taking alprazolam, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.5mg every 3days. Some patients may require an even slower dosage reduction. A decrease of 0.5mg every 2to 3weeks is more appropriate when a dose of 6mg daily or more has been administered even for only a few months. Once a dose of 2mg daily is achieved, the dose should be decreased by 0.25mg per 2to 3weeks (see Dosage).
Laboratory Tests: If alprazolam is administered for repeated cycles of therapy, periodic blood counts and liver function tests are advisable.
Drug Interactions : Benzodiazepines, including alprazolam, may potentiate or produce additive CNS depressant effects when combined with other psychotropic medication, alcohol, narcotics, bartiturates, antihistamines or anticonvulsants. Therefore, if alprazolam is to be combined with other drugs acting on the CNS, careful consideration should be given to the pharmacology of the agents involved because of the possible additive or potentiating effects. Patients should also be advised against the simultaneous use of other CNS depressant drugs and should be cautioned not to take alcohol during the administration of alprazolam.
Pharmacokinetic interactions can occur when alprazolam is administered along with drugs that interfere with its metabolism. Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450IIIA4) may increase the concentration of alprazolam and enhance its activity. Data from clinical studies with alprazolam, in vitro studies with alprazolam, and clinical studies with drugs metabolized similarly to alprazolam provide evidence for varying degrees of interaction and possible interaction with alprazolam for a number of drugs.
Based on the degree of interaction and the type of data available, the following recommendations are made: The coadministration of alprazolam with ketoconazole, itraconazole, or other azole-type antifungals is not recommended. This is based on results of drug interaction studies of triazolam and midazolam, benzodiazepines metabolized similarly to alprazolam, with ketoconazole and itraconazole. In addition, an in vitro study showed ketoconazole to be a potent inhibitor of alprazolam metabolism.
Caution and consideration of dose reduction is recommended when alprazolam is coadministered with nefazodone, fluvoxamine and cimetidine.
When alprazolam (1mg b.i.d.) and nefazodone (200mg b.i.d.) were coadministered to steady state, peak concentrations, AUC and half-life values for alprazolam increased by approximately 2fold. Nefazodone plasma concentrations were unaffected by alprazolam, although levels of the mCPP metabolite were increased. The concomitant use of alprazolam and nefazodone was also associated with an increase in psychomotor impairment presumably due to increased alprazolam plasma concentrations. If alprazolam is coadministered with nefazodone, a reduction in the alprazolam dosage may be appropriate; no dosage adjustment is required for nefazodone. The interactive effects of higher doses of these agents, such as the dosage levels of alprazolam used in panic disorder, have not been studied.
When alprazolam 1mg and fluvoxamine (50mg once daily for 3days followed by 100mg once daily for 7days) were coadministered the AUC of alprazolam was approximately doubled, the C max of alprazolam increased by about 50% and the half-life of alprazolam increased from 19.8hours to 33.9hours. C max and AUC of fluvoxamine were decreased by about 25%. Psychomotor performance tests on day 10showed significant decreases in performance.
Coadministration of alprazolam and cimetidine results in an approximate doubling of the C max of alprazolam and a statistically significant increase in the AUC of alprazolam. The half-life of alprazolam increased from 12.2hours to 14.2hours.
Caution is recommended when alprazolam is coadministered with fluoxetine, propoxyphene, oral contraceptives, sertraline, diltiazem, or macrolide antibiotics such as erythromycin and troleandomycin.
A pharmacokinetic interaction has been noted between alprazolam and carbamazepine; significant reductions in alprazolam concentration have been noted after carbamazepine treatment has been initiated. Pharmacokinetic interactions between alprazolam and phenytoin have not been observed.
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 4mg/day. The clinical significance of these changes is unknown.
Alprazolam 0.5mg, administered 3times a day for 14days, did not affect prothrombin times or plasma warfarin levels in male volunteers administered sodium warfarin orally.
Geriatrics: Elderly and debilitated patients have been found to be prone to the CNS depressant activity of benzodiazepines, even after low doses. Manifestations of this CNSdepressant activity include ataxia, oversedation and hypotension. Therefore, medication should be administered with caution to these patients, particularly if a drop in blood pressure might lead to cardiac complications. Initial doses should be low and increments should be made gradually, depending on the response of the patient, in order to avoid oversedation, neurological impairment and other possible adverse reactions (see Pharmacology and Dosage).
Impaired Renal or Hepatic Function: If treatment is necessary in patients with impaired hepatic or renal function, therapy should be initiated at a very low dose and the dosage increased only to the extent that it is compatible with the degree of residual function of these organs. Such patients should be followed closely and have periodic laboratory assessments. (see Pharmacology and Dosage).
Dependence Liability: Physical and psychological dependence may occur with benzodiazepines, including alprazolam. Patients who are prone to abuse drugs should be under careful surveillance when receiving alprazolam. Patients with a history of alcohol or drug abuse are at higher risk for developing psychological dependence.
Withdrawal symptoms can range from mild dysphoria and insomnia to a major syndrome that may include irritability, nervousness, insomnia, agitation, diarrhea, abdominal cramps, vomiting, sweating, tremors and convulsions. Since symptoms may be similar to those for which the patient is being treated, it may be difficult to differentiate between relapse and withdrawal upon discontinuation. Consequently, dosage must be gradually tapered to minimize withdrawal reactions. To discontinue treatment in patients taking alprazolam, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.5mg every 3days. Some patients may require an even slower dosage reduction. A decrease of 0.5mg every 2to 3weeks is more appropriate when a dose of 6mg daily or more has been administered even for only a few months. Once a dose of 2mg daily is achieved, the dose should be decreased by 0.25mg per 2to 3weeks (see Dosage).
Laboratory Tests: If alprazolam is administered for repeated cycles of therapy, periodic blood counts and liver function tests are advisable.
Drug Interactions : Benzodiazepines, including alprazolam, may potentiate or produce additive CNS depressant effects when combined with other psychotropic medication, alcohol, narcotics, bartiturates, antihistamines or anticonvulsants. Therefore, if alprazolam is to be combined with other drugs acting on the CNS, careful consideration should be given to the pharmacology of the agents involved because of the possible additive or potentiating effects. Patients should also be advised against the simultaneous use of other CNS depressant drugs and should be cautioned not to take alcohol during the administration of alprazolam.
Pharmacokinetic interactions can occur when alprazolam is administered along with drugs that interfere with its metabolism. Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450IIIA4) may increase the concentration of alprazolam and enhance its activity. Data from clinical studies with alprazolam, in vitro studies with alprazolam, and clinical studies with drugs metabolized similarly to alprazolam provide evidence for varying degrees of interaction and possible interaction with alprazolam for a number of drugs.
Based on the degree of interaction and the type of data available, the following recommendations are made: The coadministration of alprazolam with ketoconazole, itraconazole, or other azole-type antifungals is not recommended. This is based on results of drug interaction studies of triazolam and midazolam, benzodiazepines metabolized similarly to alprazolam, with ketoconazole and itraconazole. In addition, an in vitro study showed ketoconazole to be a potent inhibitor of alprazolam metabolism.
Caution and consideration of dose reduction is recommended when alprazolam is coadministered with nefazodone, fluvoxamine and cimetidine.
When alprazolam (1mg b.i.d.) and nefazodone (200mg b.i.d.) were coadministered to steady state, peak concentrations, AUC and half-life values for alprazolam increased by approximately 2fold. Nefazodone plasma concentrations were unaffected by alprazolam, although levels of the mCPP metabolite were increased. The concomitant use of alprazolam and nefazodone was also associated with an increase in psychomotor impairment presumably due to increased alprazolam plasma concentrations. If alprazolam is coadministered with nefazodone, a reduction in the alprazolam dosage may be appropriate; no dosage adjustment is required for nefazodone. The interactive effects of higher doses of these agents, such as the dosage levels of alprazolam used in panic disorder, have not been studied.
When alprazolam 1mg and fluvoxamine (50mg once daily for 3days followed by 100mg once daily for 7days) were coadministered the AUC of alprazolam was approximately doubled, the C max of alprazolam increased by about 50% and the half-life of alprazolam increased from 19.8hours to 33.9hours. C max and AUC of fluvoxamine were decreased by about 25%. Psychomotor performance tests on day 10showed significant decreases in performance.
Coadministration of alprazolam and cimetidine results in an approximate doubling of the C max of alprazolam and a statistically significant increase in the AUC of alprazolam. The half-life of alprazolam increased from 12.2hours to 14.2hours.
Caution is recommended when alprazolam is coadministered with fluoxetine, propoxyphene, oral contraceptives, sertraline, diltiazem, or macrolide antibiotics such as erythromycin and troleandomycin.
A pharmacokinetic interaction has been noted between alprazolam and carbamazepine; significant reductions in alprazolam concentration have been noted after carbamazepine treatment has been initiated. Pharmacokinetic interactions between alprazolam and phenytoin have not been observed.
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 4mg/day. The clinical significance of these changes is unknown.
Alprazolam 0.5mg, administered 3times a day for 14days, did not affect prothrombin times or plasma warfarin levels in male volunteers administered sodium warfarin orally.
Side Effects / Adverse Effects
Side effects to alprazolam if they occur, are generally observed at the beginning of therapy and usually disappear upon continued medication or decreased dosage.
The data cited in TablesIII and IV are estimates of untoward clinical event incidence among patients who participated under the following clinical conditions: relatively short duration (i.e., 4weeks) placebo-controlled clinical studies with dosages up to 4mg/day of alprazolam (for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety) and short-term (up to 10weeks) placebo-controlled clinical studies with dosages up to 10mg/day of alprazolam in patients with panic disorder, with or without agoraphobia.
In addition to the relatively common (i.e., greater than 1%) untoward events listed in TablesIII andIV, the following events have been reported to occur with alprazolam and other benzodiazepines: seizures, loss of coordination, concentration difficulties, memory impairment/transient amnesia, dystonia, irritability, anorexia, fatigue, sedation, slurred speech, musculoskeletal weakness, changes in libido, menstrual irregularities, incontinence, urinary retention, abnormal liver function, jaundice, pruritus and diplopia. Increased intraocular pressure has been rarely reported.
As with all benzodiazepines, paradoxical reactions such as stimulation, agitation, rage, increased muscle spasticity, sleep disturbances, hallucinations and other adverse behavioral effects may occur in rare instances and in a random fashion. Should these occur, use of the drug should be discontinued.
In some of the spontaneous case reports of adverse behavioral effects such as stimulation, agitation, concentration difficulties, confusion and hallucinations, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Patients with 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 discontinuance of alprazolam in patients with post-traumatic stress disorder.
Side effects to alprazolam if they occur, are generally observed at the beginning of therapy and usually disappear upon continued medication or decreased dosage.
The data cited in TablesIII and IV are estimates of untoward clinical event incidence among patients who participated under the following clinical conditions: relatively short duration (i.e., 4weeks) placebo-controlled clinical studies with dosages up to 4mg/day of alprazolam (for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety) and short-term (up to 10weeks) placebo-controlled clinical studies with dosages up to 10mg/day of alprazolam in patients with panic disorder, with or without agoraphobia.
In addition to the relatively common (i.e., greater than 1%) untoward events listed in TablesIII andIV, the following events have been reported to occur with alprazolam and other benzodiazepines: seizures, loss of coordination, concentration difficulties, memory impairment/transient amnesia, dystonia, irritability, anorexia, fatigue, sedation, slurred speech, musculoskeletal weakness, changes in libido, menstrual irregularities, incontinence, urinary retention, abnormal liver function, jaundice, pruritus and diplopia. Increased intraocular pressure has been rarely reported.
As with all benzodiazepines, paradoxical reactions such as stimulation, agitation, rage, increased muscle spasticity, sleep disturbances, hallucinations and other adverse behavioral effects may occur in rare instances and in a random fashion. Should these occur, use of the drug should be discontinued.
In some of the spontaneous case reports of adverse behavioral effects such as stimulation, agitation, concentration difficulties, confusion and hallucinations, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Patients with 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 discontinuance of alprazolam in patients with post-traumatic stress disorder.
Overdose
ymptoms: Manifested as an extension of alprazolam's pharmacologic activity. Thus, varying degrees of CNS depressant effects such as somnolence, confusion, impaired coordination, diminished reflexes and coma may ensue. As in the management of overdose with any drug, it should be remembered that multiple agents may have been ingested.
Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including alprazolam, and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality.
Treatment: Vomiting may be induced if the patient is fully awake. Vital signs should be monitored and general supportive measures should be employed as indicated. Gastric lavage should be instituted as soon as possible.I.V. fluids may be administered and an adequate airway should be maintained.
Experiments in animals have indicated that cardiopulmonary collapse can occur with massive i.v.doses of alprazolam. This could be reversed with positive mechanical respiration and the i.v. infusion of norepinephrine. Animal experiments with alprazolam and related compounds have suggested that hemodialysis and forced diuresis are probably of little value.
ymptoms: Manifested as an extension of alprazolam's pharmacologic activity. Thus, varying degrees of CNS depressant effects such as somnolence, confusion, impaired coordination, diminished reflexes and coma may ensue. As in the management of overdose with any drug, it should be remembered that multiple agents may have been ingested.
Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including alprazolam, and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality.
Treatment: Vomiting may be induced if the patient is fully awake. Vital signs should be monitored and general supportive measures should be employed as indicated. Gastric lavage should be instituted as soon as possible.I.V. fluids may be administered and an adequate airway should be maintained.
Experiments in animals have indicated that cardiopulmonary collapse can occur with massive i.v.doses of alprazolam. This could be reversed with positive mechanical respiration and the i.v. infusion of norepinephrine. Animal experiments with alprazolam and related compounds have suggested that hemodialysis and forced diuresis are probably of little value.
Recommended Dosage
Should be individualized for maximal benefit. The lowest possible effective dose should be administered and the need for continued treatment reassessed frequently. The risk of dependence may increase with dose and duration of treatment.
Anxiety Disorders: Adult: The initial adult dosage of alprazolam is 0.25mg given 2or 3times daily. If required, increases may be made in 0.25mg increments according to the severity of symptoms and patient response. It is recommended that the evening dose be increased before the daytime doses. Very severe manifestations of anxiety may require larger initial daily doses. The optimal dosage is one that permits symptomatic control of excessive anxiety without impairment of mental and motor function. Exceptionally, it may be necessary to increase dosage to a maximum of 3mg daily, given in divided doses.
Elderly or Debilitated Patients: The initial dosage is 0.125mg given 2or 3times daily. If necessary, this dosage may be increased gradually depending on patient tolerance and response. The elderly may be especially sensitive to the effects of benzodiazepines.
Patients with Impaired Hepatic or Renal Function: In patients with advanced liver or renal disease, the usual dose is 0.125 to 0.25mg, given 2or 3times daily. This may be gradually increased if needed and tolerated.
Panic Disorders: The usual starting dose is 0.5 to 1mg at bedtime or 0.5mg 3times daily. The dose should be adjusted until the patient is free of attacks. Dosage adjustments should be in increments no greater than 1mg every 3to 4days. Interdose symptoms may be lessened by using a schedule that provides for administration 3or 4times/day.
In controlled trials conducted to establish the efficacy of alprazolam in panic disorders, doses in the range of 1to 10mg daily were used. The mean dosage employed was approximately 5to 6mg daily. Among the approximately 1700 patients participating in the panic disorder development program, about 300 received maximum alprazolam doses of greater than 7mg/day, including approximately 100patients who received maximum dosages of greater than 9mg/day. Occasional patients required as much as 10mg/day to receive a successful response.
The necessary duration of treatment for panic disorder is unknown at this time. After a period of extended freedom from panic attacks, a supervised tapered discontinuation may be attempted.
Discontinuation: To discontinue treatment in patients taking alprazolam, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.5mg every 3days. Some patients may require an even slower dosage reduction. A decrease of 0.5mg every 2to 3weeks is more appropriate when a dose of 6mg daily or more has been administered even for only a few months. Once a dose of 2mg daily is achieved, the dose should be decreased by 0.25mg per 2to 3weeks.
Information for the Patient: See Blue Section--Information for the Patient “Xanax”.
Should be individualized for maximal benefit. The lowest possible effective dose should be administered and the need for continued treatment reassessed frequently. The risk of dependence may increase with dose and duration of treatment.
Anxiety Disorders: Adult: The initial adult dosage of alprazolam is 0.25mg given 2or 3times daily. If required, increases may be made in 0.25mg increments according to the severity of symptoms and patient response. It is recommended that the evening dose be increased before the daytime doses. Very severe manifestations of anxiety may require larger initial daily doses. The optimal dosage is one that permits symptomatic control of excessive anxiety without impairment of mental and motor function. Exceptionally, it may be necessary to increase dosage to a maximum of 3mg daily, given in divided doses.
Elderly or Debilitated Patients: The initial dosage is 0.125mg given 2or 3times daily. If necessary, this dosage may be increased gradually depending on patient tolerance and response. The elderly may be especially sensitive to the effects of benzodiazepines.
Patients with Impaired Hepatic or Renal Function: In patients with advanced liver or renal disease, the usual dose is 0.125 to 0.25mg, given 2or 3times daily. This may be gradually increased if needed and tolerated.
Panic Disorders: The usual starting dose is 0.5 to 1mg at bedtime or 0.5mg 3times daily. The dose should be adjusted until the patient is free of attacks. Dosage adjustments should be in increments no greater than 1mg every 3to 4days. Interdose symptoms may be lessened by using a schedule that provides for administration 3or 4times/day.
In controlled trials conducted to establish the efficacy of alprazolam in panic disorders, doses in the range of 1to 10mg daily were used. The mean dosage employed was approximately 5to 6mg daily. Among the approximately 1700 patients participating in the panic disorder development program, about 300 received maximum alprazolam doses of greater than 7mg/day, including approximately 100patients who received maximum dosages of greater than 9mg/day. Occasional patients required as much as 10mg/day to receive a successful response.
The necessary duration of treatment for panic disorder is unknown at this time. After a period of extended freedom from panic attacks, a supervised tapered discontinuation may be attempted.
Discontinuation: To discontinue treatment in patients taking alprazolam, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.5mg every 3days. Some patients may require an even slower dosage reduction. A decrease of 0.5mg every 2to 3weeks is more appropriate when a dose of 6mg daily or more has been administered even for only a few months. Once a dose of 2mg daily is achieved, the dose should be decreased by 0.25mg per 2to 3weeks.
Information for the Patient: See Blue Section--Information for the Patient “Xanax”.
Supplied / Packaging
Xanax: 0.25mg: Each white, single score tablet, embossed with “Upjohn29,” contains: alprazolam 0.25mg (250µg). Nonmedicinal ingredients: cornstarch, docusate sodium, lactose, magnesium stearate, microcrystalline cellulose and silicon dioxide. Gluten-free. Bottles of 100 and 1000.
0.5mg: Each peach, single score tablet, embossed “Upjohn55,” contains: alprazolam 0.5mg (500µg). Nonmedicinal ingredients: cornstarch, docusate sodium, FD&C Yellow #6, lactose, magnesium stearate, microcrystalline cellulose and silicon dioxide. Gluten-free. Bottles of 100 and 1000.
1mg: Each lavender, single score tablet, embossed “Upjohn90”, contains: alprazolam 1mg (1000µg). Nonmedicinal ingredients: cornstarch, docusate sodium, erythrosin sodium, FD&C Blue #2, lactose, magnesium stearate, microcrystalline cellulose and silicon dioxide. Gluten-free. Bottles of 100.
Store at controlled room temperature (15to 30°C).
Xanax: 0.25mg: Each white, single score tablet, embossed with “Upjohn29,” contains: alprazolam 0.25mg (250µg). Nonmedicinal ingredients: cornstarch, docusate sodium, lactose, magnesium stearate, microcrystalline cellulose and silicon dioxide. Gluten-free. Bottles of 100 and 1000.
0.5mg: Each peach, single score tablet, embossed “Upjohn55,” contains: alprazolam 0.5mg (500µg). Nonmedicinal ingredients: cornstarch, docusate sodium, FD&C Yellow #6, lactose, magnesium stearate, microcrystalline cellulose and silicon dioxide. Gluten-free. Bottles of 100 and 1000.
1mg: Each lavender, single score tablet, embossed “Upjohn90”, contains: alprazolam 1mg (1000µg). Nonmedicinal ingredients: cornstarch, docusate sodium, erythrosin sodium, FD&C Blue #2, lactose, magnesium stearate, microcrystalline cellulose and silicon dioxide. Gluten-free. Bottles of 100.
Store at controlled room temperature (15to 30°C).
