ALPRAZOLAM 2mg. Tablets.

BOXED WARNING

As with other benzodiazepines, alprazolam should be avoided in patients with pulmonary disease if possible. Additionally, avoid coadministration with other CNS depressants, especially opioids, unless no other alternatives are available as coadministration significantly increases the risk for respiratory depression, low  blood pressure, and death. Alprazolam should be avoided if possible in patients with respiratory depression severe chronic obstructive pulmonary disease (COPD), or sleep apnea because the drug can exacerbate ventilatory failure. In rare instances, death has occurred in patients with severe pulmonary disease shortly after the initiation of alprazolam.

DEA CLASS

Rx, schedule IV

DESCRIPTION

Oral benzodiazepine used for the management of anxiety including panic disorder; relatively shorter half-life and absence of active metabolites; potential for significant CYP3A4 interactions.

COMMON BRAND NAMES

Niravam, Xanax, Xanax XR

HOW SUPPLIED

Alprazolam Oral Sol: 1mg, 1mL
Alprazolam/Niravam Oral Tab Orally Dis: 0.25mg, 0.5mg, 1mg, 2mg
Alprazolam/Xanax Oral Tab: 0.25mg, 0.5mg, 1mg, 2mg
Alprazolam/Xanax XR Oral Tab ER: 0.5mg, 1mg, 2mg, 3mg

DOSAGE & INDICATIONS

†Indicates off-label use

MAXIMUM DOSAGE

10 mg/day PO.

10 mg/day PO.

Safety and efficacy have not been established; 0.06 mg/kg/day PO (immediate-release tablets or oral solution) has been suggested for the treatment of anxiety.

7 years and older: Safety and efficacy have not been established; 0.06 mg/kg/day PO (immediate-release tablets or oral solution) has been suggested for the treatment of anxiety.
Less than 7 years: Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Quantitative guidelines are not available for the immediate-release product; consider initial dose reduction in those with hepatic impairment. A lower initial adult dose of extended-release alprazolam (e.g., 0.5 mg PO once daily) is suggested. Titrate as needed and tolerated to attain clinical goals.

Guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

ADMINISTRATION

STORAGE

Generic:
– Discard opened bottle after 90 days
– Protect from light
– Store at room temperature (between 59 to 86 degrees F)
Niravam:
– Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
Xanax:
– Protect from light
– Store at controlled room temperature (between 68 and 77 degrees F)
Xanax XR:
– Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

CONTRAINDICATIONS / PRECAUTIONS

Alprazolam is contraindicated in any patient with a known alprazolam or other benzodiazepine hypersensitivity or known allergies to any component of the formulation.

Alprazolam can cause physical and psychological dependence, and should be used with caution in patients with known, suspected, or a history of substance abuse. The risk of dependence with alprazolam appears to be most probable with daily dosages greater than 4 mg and with a treatment period of more than 12 weeks. Abrupt discontinuation of alprazolam after prolonged use should be avoided. Abrupt discontinuation of benzodiazepine therapy has been reported to cause a withdrawal syndrome (see Adverse Effects), especially following high dose or prolonged benzodiazepine therapy. However, benzodiazepine dependence can occur with therapeutic doses administered for as few as 1—2 weeks and withdrawal symptoms may be seen following the discontinuance of therapy. Benzodiazepine withdrawal also can be more intense if the benzodiazepine involved possesses a relatively short duration of action such as alprazolam. Panic rebound may be particularly problematic for patients receiving higher doses for panic disorder. Patients with a history of a seizure disorder or who are taking other drugs that lower the seizure threshold (i.e., TCAs, phenothiazines) should not be withdrawn abruptly from alprazolam due to the risk of precipitating seizures; status epilepticus has also been reported during therapy with immediate-release alprazolam. During withdrawal, the greatest risk of seizure appears to be during the first 24 to 72 hours. Seizures have also been reported with the use of the extended-release formulation of alprazolam, due to abrupt withdrawal and/or concomitant alcohol intake. Alprazolam (immediate-release or extended-release formulations) should be withdrawn slowly, using a gradual tapering schedule. Flumazenil, a benzodiazepine receptor antagonist, is indicated for partial or complete reversal of the depressive effects of benzodiazepines, and may be useful in overdose situations (see Flumazenil monograph). The prescriber should be aware of the risk for seizure activity with flumazenil use, particularly in long-term users of benzodiazepines or patients presenting with a cyclic antidepressant overdose.

Worsening of daytime anxiety has been reported with the use of some hypnotic benzodiazepines, such as alprazolam, as few as 10 days after continuous use. In some patients this may be due to interdose withdrawal. If increased daytime anxiety is observed, it may be advisable to discontinue treatment gradually.

Although alprazolam is occasionally beneficial for patients with major depression, the drug should be administered to these patients with careful monitoring. According to the manufacturer, alprazolam typically has no use in the treatment of psychosis; use with extreme caution if at all in patients with suicidal ideation. Alprazolam should be used cautiously in patients with bipolar disorder because mania and hypomania have been reported in conjunction with the use of alprazolam in depressive disorders.

As with other benzodiazepines, alprazolam should be avoided in patients with pulmonary disease if possible. Additionally, avoid coadministration with other CNS depressants, especially opioids, unless no other alternatives are available as coadministration significantly increases the risk for respiratory depression, low  blood pressure, and death. Alprazolam should be avoided if possible in patients with respiratory depression severe chronic obstructive pulmonary disease (COPD), or sleep apnea because the drug can exacerbate ventilatory failure. In rare instances, death has occurred in patients with severe pulmonary disease shortly after the initiation of alprazolam.

Due to CNS depression, patients should be cautioned against driving or operating machinery until they know how alprazolam may affect them. Some patients may experience excessive sedation and an impaired ability to perform tasks; although this is usually less than that seen with intermediate- or long-acting benzodiazepines. Increased CNS effects may be seen with concurrent use of alprazolam and other CNS depressant agents, and in patients with acute ethanol intoxication, or psychosis. Patients with ethanol intoxication who have also consumed alprazolam have an increased risk of respiratory depression and coma. Ethanol should be avoided during treatment with alprazolam. Benzodiazepines should be used cautiously in patients in shock or coma due to the increased risk of respiratory depression. Anterograde amnesia may occur with any short-acting benzodiazepine if given in sufficient doses.

Alprazolam is contraindicated in patients with acute closed-angle glaucoma. However, the benzodiazepine may be used in patients with open-angle glaucoma who are receiving appropriate therapy. The mechanistic rational for this contraindication has been questioned, as benzodiazepines do not have antimuscarinic activity and do not raise intraocular pressure; few cases have been reported.

Alprazolam should be used with extreme caution in patients with myasthenia gravis because the drug can exacerbate this condition.

Patients with late stage Parkinson’s disease may experience worsening of their psychosis or impaired cognition with administration of benzodiazepines, such as alprazolam. Benzodiazepines may also cause incoordination or paradoxical reactions that may worsen symptoms of Parkinson’s disease.

The administration of alprazolam can exacerbate acute intermittent porphyria, so the drug should be used with caution in patients with this condition.

Alprazolam is classified as FDA pregnancy risk category D because it could harm the fetus when administered to pregnant women. Positive evidence of human fetal risk exists based on investigational, marketing, or human studies, but the potential benefit to the mother may outweigh the potential risks to the fetus. In general, the use of benzodiazepines is not life-saving and thus should be avoided in pregnancy whenever possible. An increased risk of congenital malformations and other developmental abnormalities is associated with benzodiazepine use during the first trimester. If alprazolam is to be used during pregnancy or the patient becomes pregnant while taking alprazolam, the patient should be apprised of the potential hazard to the fetus. The possibility that a woman of childbearing age may be pregnant when initiating therapy with alprazolam should be considered. Patients who become pregnant or intend to become pregnant while taking alprazolam should be advised to discuss the possibility of discontinuing the drug with their physician. It should be anticipated that neonates may experience withdrawal symptoms if the mother has been using benzodiazepines during pregnancy. Neonatal flaccidity has been reported in an infant whose mother was using benzodiazepines during pregnancy. Alprazolam has no established use in labor or obstetric delivery.

Many benzodiazepines distribute into breast milk. Because of the potential for adverse effects in the nursing infant, such as sedation, feeding difficulties, and weight loss, alprazolam generally is not recommended during breast-feeding. The estimated dose that a breast-feeding infant would receive based on breat milk concentrations after single oral doses of 0.5 mg has been reported to be 0.5—5 mcg/kg/day or approximately 3% of the maternal weight-adjusted dose. Irritability and withdrawal symptoms have been reported in babies exposed to alprazolam through breast milk upon discontinuation of either breast-feeing or alprazolam. Alprazolam is listed by the American Academy of Pediatrics as a drug whose effect on the nursing infant is not known but may be of concern, particularly with prolonged exposure. If occasional maternal therapy with a benzodiazepine is required, a shorter-acting agent such as lorazepam may be considered. Some experts have concluded that occasional maternal treatment with usual doses of lorazepam would pose little risk to a nursing infant. If any benzodiazepine is used by a breast-feeding mother, monitor the infant for adverse effects, such as sedation. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding baby experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Alprazolam should be administered cautiously to patients with severe hepatic disease because the elimination half-life of the drug can be prolonged, possibly resulting in toxicity. Patients with hepatic disease are more likely to experience adverse CNS reactions and should receive reduced initial dosages. Additionally, alprazolam is significantly metabolized via the hepatic microsomal P450 isoenzyme CYP3A4. Concomitant administration of alprazolam and potent inhibitors of CYP3A4 is contraindicated. Medications considered to be potent CYP3A4 inhibitors which should not be used concurrently with alprazolam include systemically-administered azole antifungals, some macrolide antibiotics, and anti-retroviral protease inhibitors (see Drug Interactions). Other CYP3A4 inhibitors could potentially cause alprazolam toxicity (see Drug Interactions). This list is not inclusive of all agents that may potently inhibit CYP3A4. Reduced elimination of alprazolam has also been reported in obesity.

Patients with renal impairment, including renal failure, should be carefully monitored during prolonged treatment with benzodiazepines, such as alprazolam, in order to avoid the adverse reactions that may occur from drug accumulation.

Use alprazolam with caution in geriatric adults as the clearance and/or elimination of alprazolam are reduced. The mean half-life of alprazolam is prolonged to 16.3 hours in the geriatric population compared to 11.2 hours in healthy adult subjects. Delayed elimination can either intensify or prolong the actions of adverse reactions of the drug. It is recommended that the dosage be limited to the smallest effective dose to preclude the development of ataxia or oversedation which may be a particular problem in debilitated or geriatric patients. The impairment of cognitive and motor function may be more marked in this patient group and a lower dosage is recommended together with close monitoring. Benzodiazepines have been associated with falls in the elderly. According to the Beers Criteria, benzodiazepines are considered potentially inappropriate medications (PIMs) for use in geriatric patients and avoidance is generally recommended, although some agents from this class may be appropriate for conditions such as rapid eye movement sleep disorders, severe generalized anxiety disorder, and end of life care. Older adults have an increased sensitivity to benzodiazepines. In general, all benzodiazepines increase the risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents in older adults. The Panel recommends avoiding benzodiazepines in geriatric patients with the following disease states or symptoms due to the potential for exacerbation of the condition or increased risk of adverse effects: delirium (possible new-onset or worsening delirium), dementia (adverse CNS effects), and history of falls/fractures (ataxia, impaired psychomotor function, syncope, and additional falls). If a benzodiazepine must be used in a patient with a history of falls or fractures, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). Specific criteria for anxiolytics must be met, including 1) limiting use to indications specified in the OBRA guidelines (e.g., generalized anxiety disorder, panic disorder, significant anxiety to a situational trigger, alcohol withdrawal) which meet the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for the indication, and 2) evidence exists that other possible reasons for the individual’s distress have been considered, and 3) use results in maintenance or improvement in mental, physical, and psychosocial well-being as reflected on the Minimum Data Set (MDS) or other assessment tool. Anxiolytics should be used for delirium, dementia, or other cognitive disorders only when there are associated behaviors that are 1) quantitatively and objectively documented, and 2) are persistent, and 3) are not due to preventable or correctable reasons, and 4) constitute clinically significant distress or dysfunction to the LTCF resident or represent a danger to the resident or others. There are exceptions that may warrant the use of an anxiolytic such as a long-acting benzodiazepine for withdrawal from a short-acting benzodiazepine, use for neuromuscular syndromes (e.g., tardive dyskinesia, restless legs syndrome, seizure disorder, cerebral palsy), or end of life care. Benzodiazepines may increase the risk of confusion, sedation, and falls. OBRA provides dosing guidance for alprazolam as an anxiolytic. When a medication is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.

The safe and effective use of alprazolam in neonates, infants, children and adolescents less than 18 years old has not been established. Children are generally more sensitive to the CNS effects of benzodiazepines.