preloder

Alprazolam


Dosing
Adult Dose:
Important Note:
Beers Criteria:
Use caution or avoid

use as

potentially inappropriate in older adults.

General Dosage Information:
Decrease the daily dose by 0.5 mg every 3 days when discontinuing therapy
Patients receiving divided

doses of alprazolam

immediate-release tablets may be switched to

alprazolam extended-release tablets

at the same total daily dose taken once daily

Anxiety:
(Immediate-release or

orally disintegrating tablet

)
0.25 to 0.5 mg orally 3 times a day; may increase every 3 to 4 days if necessary; Maximum daily dose; 4 mg in divided doses

Depression:
2.5 to 3 mg orally daily in divided doses (off-label dosage)

Panic disorder:
(Immediate-release or orally disintegrating tablet)
0.5 mg orally 3 times a day; may increase dosage by up to 1 mg/day every 3 to 4 days; usual dosage range; 1 to 10 mg/day (mean; 5 to 6 mg/day)

(Extended-release tablet)
0.5 to

1 mg orally once daily

in the morning; may increase by up to 1 mg/day every 3 to 4 days; usual range is 3 to 6 mg/day

Pediatric Dose:
Beers Criteria:

Use caution

or

avoid use

as potentially inappropriate in older adults.

Indications
FDA LABELED INDICATIONS:
Anxiety
Panic disorder

NON FDA LABELED INDICATIONS:
Depression

Mechanism of Action



Alprazolam

; a CNS drug from the 1; 4 benzodiazepine class; possesses an unknown mechanism of action. It presumably exerts its effects by binding to various stereo-specific receptors in the CNS.

Alprazolam

has also been reported to exhibit antidepressant properties; which are not characteristic of conventional benzodiazepine derivatives.
Adverse Effect
Common:
Endocrine metabolic:
Decrease in appetite (7.3% to 27.8%)
Increased appetite (7% to 32.7%)
Weight increased (2.7% to 27.2%)

Gastrointestinal:
Constipation (8.1% to 26.2%)
Reduced salivation (32.8%)
Xerostomia (10.2% to 14.7%)

Neurologic:
Cognitive disorder (28.8%)
Confusion (1.5% to 10.4%)
Dysarthria (10.9% to 23.3%)
Incoordination (9.4% to 40.1%)
Lightheadedness (20.8%)
Memory impairment (15.4% to 33.1%)
Sedated (45.2%)
Somnolence (23% to 76.8%)

Psychiatric:
Irritability (immediate-release; 33.1%; extended-release 1% or more)

Reproductive:
Reduced libido (6% to 14.4%)

Other:
Fatigue (13.9% to 48.6%)

Serious:
Dermatologic:
Stevens-Johnson syndrome

Hepatic:
Liver failure

Neurologic:
Drug withdrawal seizure

Contraindication
Acute narrow angle glaucoma
Concomitant

use with

itraconazole or ketoconazole
Hypersensitivity to benzodiazepines
Interaction
Use with Other CNS Depressants :
If

alprazolam Tablets

are to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed, particularly with compounds which might potentiate the

action of benzodiazepines

. The benzodiazepines, including

alprazolam

, produce additive CNS depressant effects when co-administered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression.

Use with 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/day. The clinical significance of these changes is unknown.

Drugs that inhibit alprazolam metabolism via cytochrome P450 3A:
The initial step in

alprazolam metabolism

is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs which inhibit this metabolic pathway may have a profound effect on the

clearance of alprazolam



Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the basis of clinical studies involving alprazolam (caution is recommended during coadministration with alprazolam):
Fluoxetine—Coadministration of fluoxetine with

alprazolam

increased the maximum plasma

Concentration of alprazolam

by 46%, decreased clearance by 21%, increased half-life by 17% and decreased measured psychomotor performance.
Propoxyphene—Coadministration of propoxyphene decreased the maximum

plasma concentration of alprazolam

by 6%, decreased clearance by 38%, and increased half-life by 58%.
Oral Contraceptives—Coadministration of oral contraceptives increased the maximum

plasma concentration of alprazolam

by 18%, decreased clearance by 22%, and increased half-life by 29%.

Drugs demonstrated to be inducers of CYP3A:
Carbamazepine can increase

alprazolam metabolism

and therefore can decrease

plasma levels of alprazolam



Drugs and other substances demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to

alprazolam

or on the basis of in vitro studies with

alprazolam

or other benzodiazepines (caution is recommended during coadministration with alprazolam):

Available data from clinical studies of benzodiazepines other than

alprazolam

suggest a possible drug interaction with

alprazolam

for the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro

studies of alprazolam

suggest a possible drug interaction with

alprazolam

for the following: sertraline and paroxetine. However, data from an in vivo drug interaction study involving a

single dose of alprazolam

1 mg and steady state dose of sertraline (50 to 150 mg/day) did not reveal any clinically significant changes in the

pharmacokinetics of alprazolam

. Data from in vitro studies of benzodiazepines other than

alprazolam

suggest a possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during the coadministration of any of these with

alprazolam



Phamacokinetics
Absorption:
Time for Maximum Plasma Concentration (Tmax): 11.2 hours (Range: 6.3–26.9 hours)
Absolute bioavailability: 90%
Relative bioavailability: 100%
Extended-release tablet: 5 to 11 hours; decreased by 1 hour with night dosing
Immediate release tablet: 1 to 2 hours
A high-fat meal given up to 2 hours before dosing with

Alprazolam Tablets

increased the mean Cmax by about 25%

Distribution:
Plasma Protein binding: 80%

Metabolism:
Hepatic: Extensive via CYP3A4

Excretion:
Renal: 80%; as unchanged drug and metabolites
Fecal: 7%
Renal clearance: 371 mL/hour
Total body clearance: 76 mL/min

Elimination:
Extended-release tablet: 10.7 to 15.8 hours
Orally disintegrating tablet: 12.5 hours
Immediate release tablet: 11.2 hours
Asians: 25% higher than Caucasian
Alcoholic liver disease: 19.7 hours
Elderly: 16.3 hours
Precaution
Access:
Patients receiving concomitant therapy with benzodiazepines or CNS depressants should not be denied access to medication-assisted treatment drugs (eg; methadone and buprenorphine); if concomitant

use is

necessary; careful management and monitoring recommended.
Beers Criteria:
Avoid

use in

elderly due to greater benzodiazepine sensitivity; especially in patients with a history of falls or fractures (unless safer alternatives are not available); cognitive impairment or dementia; or with delirium or at high risk for delirium. May increase risk of syncope; falls fractures; ataxia; cognitive or psychomotor impairment; motor vehicle accidents; delirium; or other adverse CNS effects (may be appropriate for seizure disorders; rapid eye movement sleep disorders; benzodiazepine or ethanol withdrawal; severe generalized anxiety disorder; periprocedural anesthesia; and end-of-life care).

Concomitant Use:
Concomitant

use with

potent CYP3A inhibitors not recommended

Debilitated:
Patients may be at increased risk of ataxia or oversedation; dose adjustment recommended

Hepatic:
Advanced hepatic disease may increase systemic exposure; dose adjustment recommended
Alcoholic liver disease or obesity may increase systemic exposure

Neurologic:
Risk of seizure recurrence upon rapid discontinuation; slow taper recommended for patients with history of seizures

Psychiatric:
Suicidality risk in patients with history of or current suicidal behavior
Depression; increased risk of hypomania and mania; and may increase suicidality
Increased risk of physical and psychological dependence at doses greater than 4 mg/day or with

prolonged use


Drug abuse and dependence risk in patients with history of alcohol or drug abuse; monitoring recommended

Reproductive:
Birth defect risk in newborns when used by pregnant women;

avoid use

during first trimester

Respiratory:
Severe pulmonary disease may increase the risk of adverse events; including rare fatalities

Withdrawal of Therapy:
Withdrawal symptoms; including life-threatening seizures; may occur with missed doses; abrupt dose reduction; or discontinuation; gradual dose reduction

Pregnancy Category
D (FDA)
C (AUS)

Breast Feeding
AAP:
Drugs for which the effect on nursing infants is unknown but may be of concern
Monitoring
Reduction in symptoms of anxiety or panic disorder indicates efficacy
Blood counts; urinalysis; and blood chemistry; periodically during chronic therapy
Respiratory depression or sedation; in patients using concomitant opioids
How to Take or Administration
Oral:
(Extended-release tablets)
Do not break, chew, or crush
Administration in the morning is preferred

(Disintegrating tablets)
Remove tablet from bottle with dry hands
Consume tablet immediately once it is removed from the bottle; allow tablet to disintegrate on top of the tongue, then swallow with saliva
Discard any unused portion of an orally disintegrating tablet, as it may not remain stable

Dosage Form
Oral Tablet:
0.25 MG
0.5 MG

1 MG


2 MG

Oral Tablet; Disintegrating:
0.25 MG
0.5 MG

1 MG


2 MG

Oral Tablet; Extended Release:
0.5 MG

1 MG


2 MG
3 MG

Treatment
Supportive care with attention to the airway; breathing; and circulation is the mainstay of treatment. Benzodiazepine overdose as a single agent may cause coma but generally does not cause loss of airway reflexes. However; when combined with other sedating drugs (eg; ethanol; opioids; muscle relaxants; antipsychotics; anticonvulsants); airway protection may be necessary. Even with large overdoses; patients generally remain hemodynamically stable.

MANAGEMENT OF MILD TO MODERATE TOXICITY:
Supportive care

MANAGEMENT OF SEVERE TOXICITY:
Coma and respiratory depression require intubation. Hypotension responds to fluids and rarely vasopressors.

Toxicology
Deaths from benzodiazepine overdose are extremely rare. A patient with multiple severe medical problems expired following an overdose of

7.5 mg of alprazolam

. In general; the toxic-to-therapeutic ratio is very high for benzodiazepines; making them remarkably safe medications
Patient Counselling or Clinical Teaching
Patient should avoid activities requiring mental alertness or coordination until drug effects are realized.
This drug may cause increased appetite; changes in weight; constipation; dizziness; dysarthria; memory impairment; somnolence; depression; or reduced libido.
Advise patient and family to monitor for confusion with

use

; especially with elderly patients.
Advise patient against abrupt discontinuation of drug to prevent withdrawal symptoms.
Patient should avoid alcohol while taking drug.
Patient should not eat grapefruit or drink grapefruit juice while taking drug.



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