Mode of Action
Benzodiazepines act on GABA (gamma-aminobutyric acid) receptors by binding to the receptor complex to increase the efficiency of GABA, i.e., lowering the quantity of GABA needed to open the channel. Opening of the channel allows chloride ion flux to hyperpolarize the neuron and, consequently, enables GABAergic neurons to produce a larger inhibitory effect.1
Diagram of mechanism of action of the natural neurotransmitter GABA (gamma-aminobutyric acid) and benzodiazepines on nerve cells (neurons) in the brain2
Mechanism of action of the natural neurotransmitter GABA (gamma-aminobutyric acid) and benzodiazepines on nerve cells (neurons) in the brain
- Rickels K. Alprazolam extended-release in panic disorder. Exp Opin Pharmacother. 2004;5(7):1599-1611.
- Benzodiazepines: How They Work And How To Withdraw (aka The Ashton Manual. Available from: http://benzo.org.uk/manual/bzcha01.htm Accessed on: 8 July 2021.
Significant Relief of Anxiety.1
XANAX® and XANAX® XR, fast anxiety relief in panic disorder.1
The majority of patients with panic disorder receiving XANAX® and XANAX® XR reached a peak anxiolytic benefit within 1 hour of the first morning dose.1*
Speed of action in panic disorder after first morning dose.1
Adapted from Sheehan, et al. 2007
Baseline mean = 3.5 ± 2.6 mg/day. 1
†Mean dose = 4.6 ± 2.9 mg/day. 1
‡Mean dose = 4.5 ± 2.9 mg/day.1
*Open-label, cross-over study to compare the milligram equivalence and duration of action of XANAX® vs. XANAX® XR in patients with panic disorder with or without agoraphobia. An analysis was conducted to evaluate the speed of onset of action of both treatments. For 3 weeks, patients received XANAX®, administered in 0.5 mg or 1 mg tablets (depending on their previous dose), followed by a switch to an equivalent dose of XANAX® XR for 6 weeks. Primary efficacy measures were the Sheehan Panic Disorder Scale and the 21-item clinician-rated global improvement scale. Patients were required to keep a diary of their medications, panic attacks, and limited symptom attacks. Patients also kept an hourly record of the degree of anxiolytic benefit (on a 0- to 10-point scale) they received from each dose of medication.1
The mean ± SD dose of XANAX® at baseline was 3.5 ± 2.6 mg/day (median 2.5, range 0.75-10). The mean dose at the end of Week 3 was therefore higher than that at baseline, 4.6 ± 2.9 mg/day (median 4.5; range 1-10 mg). After the switch at Week 4, the mean dose of XANAX® XR was 4.5 ± 2.9 mg/day. It should be noted that the average first morning dose in milligrams used for these analyses was almost twice as high on XANAX® XR after the switch (2.9 ± 1.8 mg at Week 4 vs. 1.4 ± 0.8 mg at Week 3).1
XANAX® XR: Reduction of major panic attacks rapidly and effectively.2*
XANAX® XR demonstrated significant reductions in the frequency of major panic attacks vs. placebo from Week 1 through Week 6.2*
- 39% more patients experienced complete relief from panic attacks on XANAX® XR vs. placebo (85% vs 61%, P<0.01).
Frequency of major panic attacks over 6 weeks2
Adapted from Schweizer E, et al. 1993.
‡ P<0.05 vs. placebo.
† Last observation carried forward final evaluation, intent-to-treat population.
*A double-blind, randomized, placebo-controlled study that assessed the efficacy and safety of XANAX® XR in 194 patients with agoraphobia with panic attacks or panic disorder. Following a 7- to 10-day placebo washout period, patients were randomly assigned to receive XANAX® XR or placebo. XANAX® XR was initiated at 1 mg/day, administered in the morning, and increased every 3 to 4 days as tolerated to a maximum dose of 10 mg/day. Frequency of major panic attacks was the primary endpoint and was assessed based on a daily diary.2
Rapid and significant symptom relief in patients with Generalized Anxiety Disorder.3
Significant Improvements in Hamilton Rating Scale for Anxiety (HAM-A) total score were demonstrated with XANAX® vs. placebo as early as Week 2.3*
Changes in HAM-A total score over 6 weeks.3
Adapted from Enkelmann R., et al. 1991.
†P<0.05 vs. placebo.
*The HAM-A is a 14-item scale for assessment of general anxiety symptoms.
The HAM-A rating scale quantifies the severity of both psychic (e.g., mental agitation and psychological distress) and somatic anxiety (e.g., physical symptoms).4
*A randomized, double-blind, placebo-controlled study in 94 adult outpatients with GAD, a baseline HAM-A score ≥18, a Covi Anxiety Scale total score of ≥7, and a Raskin Depression Scale total score <7. Following a 3- to 7-day placebo washout period, patients were randomly assigned to treatment with XANAX® 0.5 mg, buspirone 5 mg, or placebo. The initial dosage of one capsule daily was increased to one capsule three times daily by day 4. Subsequently the dosage was adjusted to achieve the desired efficacy. The primary outcome measure was a change from baseline in HAM-A3 total score.
- Sheehan DV, Sheehan HK, Raj BA. The speed of onset of action of alprazolam-XR compared to alprazolam-CT in panic disorder. Psychopharmacol Bull. 2007;40:63–81.
- Schweizer E, Patterson W, Rickels K, et al. Double-blind, placebo-controlled study of once-a-day, sustained-release preparation of alprazolam for the treatment of panic disorder. Am J Psychiatry. 1993;150:1210–1210.
- Enkelmann R. Alprazolam versus buspirone in the treatment of outpatients with generalized anxiety disorder. Psychopharmacology (Berl). 1991;105:428–432.
- Thompson E. Hamilton rating scale for anxiety (HAM-A). Occupational Medicine. 2015 Oct 1;65(7):601.
Safety & Tolerability
XANAX® XR is generally well tolerated.1
XANAX® XR was well tolerated in short-term placebo-controlled trials.1
The most commonly observed adverse events in panic disorder patients treated with XANAX® XR (incidence of 5% or greater and at least twice the incidence in placebo patients) were: sedation, somnolence, memory impairment, dysarthria, coordination abnormal, ataxia, libido decreased.1
Adverse events with ≥5% incidence and greater than placebo.1
XANAX® is generally well tolerated.2
In placebo-controlled trials of patients with anxiety disorders, XANAX® demonstrated a low incidence of adverse events.2
Adverse events with ≥5% incidence and greater than placebo.2
Compared to diazepam, XANAX® has a clinical research history demonstrating lower incidence of several common side effects.3
XANAX® is a well-tolerated, short-acting benzodiazepine, with significant reductions in the following adverse events versus diazepam (P<0.005) in placebo-controlled clinical trials:3
- Blurred vision
- Benzodiazepines, including XANAX®, produce additive CNS depressant effects, including respiratory depression, when co-administered with opioids, other psychotropic medications, anticonvulsants, antihistaminics, alcohol and other drugs which themselves produce CNS depression.4
- Pharmacokinetic interactions can occur when XANAX® is administered along with drugs that interfere with its metabolism. Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450 3A4) may increase the concentration of XANAX® and enhance its activity.4
- Based on the degree of interaction and the type of data available, the following recommendations are made:
- The co-administration of XANAX® with ketoconazole, itraconazole, or other azole-type antifungals is not recommended.4
- Caution and consideration of dose reduction is recommended when XANAX® is co-administered with nefazodone, fluvoxamine, and cimetidine.4
- Caution is recommended when XANAX® is co-administered with fluoxetine, propoxyphene, oral contraceptives, diltiazem, or macrolide antibiotics such as erythromycin and troleandomycin.4
- Interactions involving HIV protease inhibitors (e.g., ritonavir) and XANAX® are complex and time-dependent. Low doses of ritonavir resulted in a large impairment of alprazolam clearance, prolonged its elimination half-life and enhanced clinical effects. However, upon extended exposure to ritonavir, CYP3A induction offset this inhibition. This interaction will require a dose adjustment or discontinuation of XANAX®.1
- Increased digoxin concentrations have been reported when XANAX® was given, especially in the elderly (>65 years of age). Patients who receive XANAX® and digoxin should therefore be monitored for signs and symptoms related to digoxin toxicity.1
- US FDA XANAX® XR Package Insert. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021434s018lbl.pdf. Last accessed 26 Jun 2021
- US FDA XANAX® Package Insert. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/018276s055lbl.pdf. Last accessed 26 Jun 2021.
- Dawson GW, Jue SG, Brogden RB. Alprazolam: A review of its pharmacodynamic properties and efficacy in the treatment of anxiety and depression. Drugs. 1984;27(2):132–147.
- XANAX® / XANAX® XR HSA Approved Prescribing Information May 2021
Dosing & Administration
XANAX®, a choice of immediate and extended-release formulations to fit your patient’s needs.1
XANAX® immediate-release tablets are available in 0.25 mg, 0.5 mg, 1 mg, and 2 mg doses.2
XANAX® extended-release tablets are available in 0.5 mg, 1 mg, 2 mg, and 3 mg doses.1
XANAX® XR is formulated for fast onset and uniform release over time.3
The extended-release tablets:3
- Lack an enteric coating, allowing for a quick initial release of some alprazolam.
- Contain a polymer matrix which absorbs water and forms a gel layer that facilitates a uniform release of alprazolam over time.
XANAX® XR provides smooth, continuous drug release in a single dose.4*
XANAX® XR eliminated the peaks and troughs associated with the pharmacokinetics of standard-release tablets administered four times daily.4*
Pharmacokinetic profile of XANAX® XR and XANAX® over 24 hours.4
† Administered as two 3 mg tablets each morning.
‡ Administered as one 1 mg tablet and one 0.5 mg tablet four times a day.
* Pharmacokinetic analysis of blood samples from 20 healthy male volunteers who each received a total daily dose of 6 mg alprazolam, either as a single dose XANAX® XR (two 3-mg tablets), or four doses of XANAX® (1.5 mg each), in a 6-day cross-over study.4
XANAX® and XANAX® XR provide the power to titrate based on individual patient needs.1
* If side effects occur, the dose should be lowered
Viatris is committed to responsible benzodiapine use.
Guidelines for responsible benzodiazepine use.5
- Prescribe the lowest dose of benzodiazepines for the shortest duration necessary to achieve the desired outcomes.
- Discuss with patients the potential risks of sedation and decreased concentration on the ability to drive safely.
- Advise patients to obtain all benzodiazepine prescriptions from the same doctor so that risk of dependence may be monitored.
- Advise all patients of the risk of physical and psychological dependence associated with long-term use.
- Avoid prescribing benzodiazepines to known poly-drug users, including those with history of drug or alcohol dependence.
Dose reduction and discontinuation5
- Benzodiazepine dose reduction should be initiated with the patient’s consent and co-operation.
- Discontinuation of benzodiazepines may be facilitated by changing patients to a medication with a long half-life (e.g., diazepam), followed by gradual dose reduction.
Discontinuation in the elderly5
- For patients in care facilities, benzodiazepines can be discontinued gradually if the patient, family, and nursing staff co-operate.
- Medication may occasionally be required to control anxiety, agitation, or other challenging behaviours. Staff should be knowledgeable in appropriate management of challenging behaviours.
Counselling and review5
- Treatment review should include a review of the indication(s) for continued use of the benzodiazepine, medication dose and possible adverse effects. For all patients receiving long-term benzodiazepines review is particularly relevant.
- Non-medication management of anxiety and insomnia includes clarification of the problem, counselling, specific advice, and referral where the diagnosis is uncertain or assistance in management is required.
- One-to-one counselling may be supplemented by self-help support programs during withdrawal.
SSRIs and SNRIs are recommended first-line treatments in panic disorder.5
- XANAX® / XANAX® XR HSA Approved Prescribing Information May 2021.
- US FDA XANAX® Package Insert. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/018276s055lbl.pdf. Last accessed: 26 Jun 2021.
- Sheehan DV, Sheehan HK, Raj BA. The speed of onset of action of alprazolam-XR compared to alprazolam-CT in panic disorder. Psychopharmacol Bull. 2007;40:63–81.
- Wright E. Clinical pharmacokinetics of alprazolam extended release: A summary. Curr Ther Res. 1995;56:947–956.
- RACPG Prescribing drug dependence in general practice (Part B) 2015.
Abbreviated Prescribing Information
Note: Please refer to the full prescribing information before prescribing
Indication: Treatment of anxiety states (anxiety neuroses), mixed anxiety-depression, neurotic or reactive depression and panic-related disorders.
Dosage: Individualized dosage. XANAX® tablet Anxiety Initially 0.25-0.5 mg three times a day. Usual dosage range: 0.5-4 mg daily in divided doses. Elderly and debilitated patient Initially 0.25 mg twice or thrice daily. Usual dosage range: 0.5-0.75 mg daily in divided doses; to be gradually increased if needed and tolerated. Panic-related disorders Initially 0.5-1 mg at bedtime or 0.5 mg three times a day. Usual dosage range: Adjust in increments ≤ 1 mg every 3-4 days. Max: 10 mg daily. XANAX®Extended-release tablet Anxiety Initially 1 mg daily in 1 or 2 doses. Depression Initially 1 mg daily in 1 or 2 doses. Usual dosage range: 0.5-4.5 mg daily in 1 or 2 doses. Elderly Initially 0.5-1 mg daily; may be gradually increased if needed and tolerated. Usual dosage range: 0.5-1 mg daily in 1 or 2 doses. Panic-related disorders Initially 0.5-1 mg at bedtime or 0.5 mg twice a day. Usual dosage range: Mean maintenance dose: Between 5 and 6 mg /day as a single daily dose or divided in 2 doses daily, with occasional patients needing up to 10 mg/day. Adjust in increments ≤ 1 mg every 3-4 days. The risk of dependence may increase with dose and duration of treatment, therefore, the lowest possible effective dose and duration should be used and the need for continued treatment reassessed frequently.
Administration: Take with or without food. Side effects eg. Sleepiness/drowsiness may be reduced if taken immediately after meals. Extended-release tablet: Swallow whole, do not chew/crush
Contraindications: Hypersensitivity to benzodiazepines and alprazolam
Special Precautions: Limit dosages and durations to the minimum required when concomitantly used with benzodiazepines and opioids, as concomitant use may result in profound sedation, respiratory depression, coma, and death. Renal or hepatic impairment. Habituation and emotional/physical dependence. History of alcoholism or drug abuse. Not established for depression with psychiatric features, bipolar disorder or “endogenous” depression (ie. severely depressed in-patients) Avoid abrupt withdrawal of treatment. Monitor for any occurrence of primary and secondary major depressive disorders, suicidal behavior and episodes of hypomania and mania; severely depressed or suicidal patient. May affect ability to drive or operate machinery. Pregnancy (especially 1st and 3rd trimester) and lactation. Children less than 18 years old.
Adverse Reactions: Depression; sedation, somnolence, ataxia, memory impairment, dysarthria, dizziness, headache; constipation, dry mouth; fatigue, irritability; decreased appetite; confusional state, disorientation, increased or decreased libido, anxiety, insomnia, nervousness; balance disorder, abnormal coordination, disturbance in attention, hypersomnia, lethargy, tremor; blurred vision; nausea; dermatitis; sexual dysfunction; increased or decreased weight.
Drug Interactions: Additive CNS depressant effects, including respiratory depression, with opioids, other psychotropics, anticonvulsants, antihistaminics, alcohol, and other CNS depressants. Increased steady-state plasma concentration of imipramine and desipramine. Ketoconazole, itraconazole and other azole-type antifungals; nefazodone, fluvoxamine, cimetidine; fluoxetine, propoxyphene, oral contraceptives, sertraline, diltiazem, macrolides (eg. Erythromycin and troleandomycin). Human immunodeficiency virus (HIV)-protease inhibitor eg. Ritonavir. Increased concentration of digoxin.
Presentation and Packing: XANAX® tablet 0.25 mg x 100’s. 0.5 mg x 100’s. 1 mg x 100’s. 2 mg x 100’s. XANAX® Extended Release tablet 0.5 mg x 30’s. 1 mg x 30’s. 2 mg x 30’s. 3 mg x 30’s.
Pregnancy Safety (US): D
- XANAX®/XANAX XR ® Abbreviated Prescribing Information.