BENZODIAZEPINES

All dosing is for ADULTS unless otherwise specified. All benzodiazepines are DEA Schedule IV.
PRICING INFO


References:
Drug Dosage forms Dosing Other
Alprazolam

Xanax®
Tablet
  • 0.25 mg
  • 0.5 mg
  • 1 mg
  • 2 mg

Orally disintegrating tablet
  • 0.25 mg
  • 0.5 mg
  • 1 mg
  • 2 mg

Solution
  • 1 mg/ml
  • Comes in 30 ml bottles
Anxiety disorders and transient anxiety
  • Starting: 0.25 - 0.5 mg three times a day as needed
  • Maximum: 4 mg/day
  • Elderly: starting dose is 0.25 mg given two to three times a day as needed
  • Increase dose every 3 - 4 days as needed
  • When discontinuing after chronic therapy, decrease daily dose by no more than 0.5 mg a day every 3 days
Pharmacokinetics
  • Peak plasma concentration: 1 - 2 hours
  • Half-life: 11.2 hours (range: 6.3 – 26.9 hours)
  • Average half-life is prolonged in elderly (16.3 hours), liver disease (19.7 hours), and obesity (21.8 hours)

Other
  • Alprazolam is a CYP3A4 sensitive substrate. Use caution with CYP3A4 inducers and inhibitors.
  • Disulfiram (Antabuse®) does not appear to affect the metabolism of alprazolam [10]

Price
  • Generic (30 tablets) - $
  • Generic (30 disintegrating tablets) - $-$$
  • Generic (30 ml solution) - $$
Alprazolam

Xanax XR®
Extended-release tablet
  • 0.5 mg
  • 1 mg
  • 2 mg
  • 3 mg
Panic disorder
  • Starting: 0.5 - 1 mg once daily
  • Maintenance: 3 - 6 mg once daily
  • Maximum: 10 mg once daily
  • Increase dose every 3 - 4 days in increments of no more than 1 mg/day
  • When tapering off, decrease dose by no more than 0.5 mg/day every 3 days

Switching from Xanax to Xanax XR
  • Total daily Xanax dose may be given as once daily Xanax XR tablet
Pharmacokinetics
  • Xanax XR has the same pharmacokinetics as immediate-release Xanax except that it is absorbed more slowly. The slower absorption rate results in a relatively constant concentration that is maintained between 5 and 11 hours after the dosing.
  • High-fat meals increase the absorption of Xanax XR
  • Peak plasma concentration: 1 - 2 hours
  • Half-life: 11.2 hours (range: 6.3 – 26.9 hours)
  • Average half-life is prolonged in elderly (16.3 hours), liver disease (19.7 hours), and obesity (21.8 hours)

Other
  • Do not cut, chew, crush, or break tablets
  • Alprazolam is a CYP3A4 sensitive substrate. Use caution with CYP3A4 inducers and inhibitors.

Price
  • Generic (30 tablets) - $

Drug Dosage forms Dosing Other
Chlordiazepoxide

Librium®
Capsule
  • 5 mg
  • 10 mg
  • 25 mg
Anxiety
  • Mild-to-moderate: 5 - 10 mg three to four times a day as needed
  • Severe: 20 - 25 mg three to four times a day as needed
  • Elderly: 5 mg two to four times a day as needed

Alcohol withdrawal
  • Fixed dose regimen:
    • Day 1: 20 - 30 mg four times daily
    • Day 2: 20 - 30 mg three times daily
    • Day 3: 20 - 30 mg twice daily
    • Day 4: 20 - 30 mg at bedtime [2]

See NICE clinical guidelines on alcohol withdrawal for more
Pharmacokinetics
  • Peak plasma concentration: 2 hours
  • Half-life: 24 - 48 hours

Price
  • Generic (30 capsules) - $
Chlordiazepoxide + clidinium

Librax®
Capsule
Chlordiazepoxide : clidinium
  • 5 mg : 2.5 mg
Anxiety-related gastrointestinal disorders
  • 1 - 2 capsules three to four times a day as needed
  • Take before meals and at bedtime
Other
Price
  • Generic (30 capsules) - $
Chlordiazepoxide + amitriptyline

Limbitrol®
Tablet
Chlordiazepoxide : amitriptyline
  • 5 mg : 12.5 mg
  • 10 mg : 25 mg
Depression associated with anxiety
  • 3 or 4 tablets daily given in divided doses
  • Reduce dose to minimum effective dose
  • Do not exceed 6 tablets a day
Other
Price
  • Generic (30 tablets) - $-$$

Drug Dosage forms Dosing Other
Clonazepam

Klonopin®
Tablet
  • 0.5 mg
  • 1 mg
  • 2 mg

Orally disintegrating tablet
  • 0.125 mg
  • 0.25 mg
  • 0.5 mg
  • 1 mg
  • 2 mg
Adults
    Panic disorder
    • Starting: 0.25 mg twice a day
    • Maintenance: 0.5 mg twice a day
    • Maximum: 2 mg twice a day
    • Increase in increments of 0.125 - 0.25 mg/dose at intervals of 3 days
    • Total daily dose may be given once daily at bedtime to minimize side effects
    • When discontinuing, decrease by 0.125 mg/dose every 3 days

    Seizure disorder
    • Starting: 0.5 mg three times a day
    • Maximum: 20 mg/day
    • Increase in increments of 0.5 - 1 mg/day every 3 days

Children
    Seizure disorder (up to 10 years old or 30 kg)
    • Starting: 0.01 - 0.03 mg/kg/day given in 2 or 3 divided doses
    • Maintenance: 0.1 - 0.2 mg/kg/day given in 3 divided doses
    • Maximum: 0.2 mg/kg/day
    • Increase daily dosage by no more than 0.25 - 0.5 mg every third day
Pharmacokinetics
  • Peak plasma concentration: 1 - 4 hours
  • Half-life: 30 - 40 hours

Other
Price
  • Generic (30 tablets) - $

Drug Dosage forms Dosing Other
Diazepam

Valium®
Tablet
  • 2 mg
  • 5 mg
  • 10 mg

Solution
  • 1 mg/ml

Concentrate - Intensol
  • 5 mg/ml
Adults
    Anxiety disorder
    • 2 - 10 mg two to four times a day as needed

    Acute alcohol withdrawal
    • Day 1: 10 mg three to four times a day as needed
    • Day 2 and on: 5 mg three to four times a day as needed

    Muscle spasm
    • 2 - 10 mg three to four times a day as needed

    Elderly patients
    • Starting: 2 - 2.5 mg one to two times a day as needed

Children (≥ 6 months)
    No indication specified
    • Dosing: 1 - 2.5 mg three to four times a day as needed. Increase gradually as needed and tolerated.
Pharmacokinetics
  • Peak plasma concentration: 1 - 1.5 hours
  • Half-life:
    • Diazepam - up to 48 hours
    • Active metabolite - up to 100 hours
    • Half-life increases by approximately 1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age

Other
  • Food slows absorption
  • Diazepam is a CYP3A4 and CYP2C19 sensitive substrate. Use caution with CYP3A4 and CYP2C19 inhibitors and inducers.

Price
  • Generic (30 tablets) - $
  • Generic (1 mg/ml, 180 ml) - $
  • Generic (5 mg/ml, 30 ml) - $
Diazepam

Diastat® AcuDial
Rectal gel
  • Comes in 2.5 mg, 10 mg, and 20 mg delivery system
  • 10 mg delivery system may be dialed to 5, 7.5, and 10 mg doses
  • 20 mg delivery system may be dialed to 12.5, 15, 17.5, and 20 mg doses
  • Comes in pack with 2 delivery systems
Children
    Acute seizure
    • 2 - 5 years: 0.5 mg/kg
    • 6 - 11 years: 0.3 mg/kg
    • ≥ 12 years: 0.2 mg/kg

    • Dose should be rounded up to next available dose
    • A second dose may be given 4 - 12 hours after the first dose
    • It takes ∼ 3 minutes for therapeutic concentrations to reach the brain with the rectal route [13]
Pharmacokinetics
  • Peak plasma concentration: 1.5 hours
  • Half-life:
    • Diazepam - 46 hours
    • Active metabolite - 71 hours
  • It takes ∼ 3 minutes for therapeutic concentrations to reach the brain with the rectal route [13]

Other
  • Comes in a single dose rectal delivery system
  • Applicator can be dialed to appropriate dose
  • See patient instructions for proper delivery technique

Price
  • Generic (2 delivery systems) - $$$-$$$$

Drug Dosage forms Dosing Other
Flurazepam

Dalmane®
Capsule
  • 15 mg
  • 30 mg
Insomnia
  • 30 mg one time before bedtime as needed
  • 15 mg may be sufficient in elderly and debilitated patients
Pharmacokinetics
  • Peak plasma concentration: 30 - 60 minutes
  • Half-life:
    • Flurazepam: 2.3 hours
    • Active metabolite: 47 - 100 hours [3]

Price
  • Generic (30 capsules) - $

Drug Dosage forms Dosing Other
Lorazepam

Ativan®
Tablet
  • 0.5 mg
  • 1 mg
  • 2 mg

Solution
  • 2 mg/ml
  • Comes in 30 ml bottle
Anxiety
  • Starting: 2 - 3 mg/day given in two to three divided doses
  • Maintenance: 2 - 6 mg/day given in two to three divided doses
  • Elderly: 1 - 2 mg/day given in two to three divided doses

Insomnia
  • 2 - 4 mg given once at bedtime
Pharmacokinetics
  • Peak plasma concentration: 2 hours
  • Half-life: 12 hours
  • Lorazepam is metabolized by glucuronide conjugation
  • Liver and kidney disease only have a minor effect on lorazepam pharmacokinetics [4]

Other
  • Lorazepam is safe in breastfeeding [5]
  • Disulfiram (Antabuse®) does not appear to affect the metabolism of lorazepam [9]

Price
  • Generic (30 tablets) - $

Drug Dosage forms Dosing Other
Oxazepam

Serax®
Capsule
  • 10 mg
  • 15 mg
  • 30 mg
Mild-to-moderate anxiety
  • 10 - 15 mg three to four times a day as needed

Severe anxiety
  • 15 - 30 mg three to four times a day as needed

Alcohol withdrawal
  • 15 - 30 mg three to four times a day as needed

Elderly
  • Starting: 10 mg three times a day as needed
  • Maintenance: 15 mg three to four times a day as needed

Pharmacokinetics
  • Peak plasma concentration: 3 hours
  • Half-life: 8.2 hours
  • Oxazepam is metabolized by glucuronide conjugation

Other
  • Oxazepam is safe in breastfeeding [6]
  • Oxazepam is the short-acting metabolite of diazepam [6]
  • Disulfiram (Antabuse®) does not appear to affect the metabolism of oxazepam [9]

Price
  • Generic (30 capsules) - $

Drug Dosage forms Dosing Other
Quazepam

Doral®
Tablet
  • 15 mg
Insomnia
  • Starting: 7.5 mg once at bedtime
  • Maintenance: 7.5 - 15 mg once at bedtime
Pharmacokinetics
  • Peak plasma concentration: 2 hours
  • Half-life:
    • Quazepam: 39 hours
    • Active metabolite: 73 hours

Other
  • Tablet is scored so that it can be halved

Price
  • Generic (30 capsules) - ?, not currently available

Drug Dosage forms Dosing Other
Temazepam

Restoril®
Capsule
  • 7.5 mg
  • 15 mg
  • 22.5 mg
  • 30 mg
Insomnia
  • Starting: 15 mg one time at bedtime
  • Maintenance: 7.5 - 30 mg one time at bedtime
  • Elderly: 7.5 mg one time at bedtime
Pharmacokinetics
  • Peak plasma concentration: 1.5 hours
  • Half-life (biphasic):
    • Short: 0.4 - 0.6 hours
    • Terminal: 8.8 hours

Other
  • Temazepam is a metabolite of diazepam [7]
  • Temazepam appears to be safe in breastfeeding [7]

Price
  • Generic (30 capsules) - $

BENZODIAZEPINE SIDE EFFECTS
  • Drowsiness
  • Loss of coordination
  • Memory impairment
  • Trouble speaking (dysarthria)
  • Fatigue/tiredness
  • Confusion
  • Altered libido - increased or decreased
  • Appetite changes - increased or decreased
  • Low blood pressure (hypotension)
  • Dizziness
  • Increased salivation - clonazepam

BENZODIAZEPINE PRECAUTIONS / CONTRAINDICATIONS
    All benzodiazepines
    • Pregnancy - benzodiazepines may cause fetal harm and should be avoided in pregnancy
    • Acute narrow angle glaucoma - acute narrow angle glaucoma is listed as a contraindication in most benzodiazepine package inserts. In the medical literature, there is very little information regarding this interaction. It's unclear if benzodiazepines have any effect on narrow-angle glaucoma. [8]
    • Drug addiction and abuse - benzodiazepines are both psychologically and physically addictive medications. Use caution in susceptible patients.
    • Withdrawal reactions - abrupt withdrawal reactions including heightened perception, impaired concentration, alteration in sense of smell, paresthesias, muscle cramps, diarrhea, headache, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, and decreased appetite may occur
    • Seizure - abrupt withdrawal or dose reductions may lead to seizures. Patients on higher doses and longer courses of therapy are at greater risk. Doses should be tapered slowly when appropriate.
    • Decreased alertness - benzodiazepines depress CNS activity and may impair the ability to operate motor vehicles and other dangerous machinery
    • Respiratory depression - benzodiazepines may suppress respiratory drive. Use with caution in patients with respiratory disease.
    • Allergic reactions - in rare cases, benzodiazepines have been associated with anaphylactoid reactions including angioedema
    • Neonatal withdrawal - infants born to mothers who are taking benzodiazepines may be at risk for withdrawal symptoms. Flaccidity and respiratory depression may occur immediately after birth.
    • Nursing - most benzodiazepines are excreted in breastmilk and may cause lethargy and weight loss in exposed infants. Lorazepam, oxazepam, and temazepam appear to be safe in breastfeeding. [5,6,7]
    • Kidney disease - elimination may be reduced. Use caution.
    • Liver disease - elimination may be reduced. Use caution.

    Alprazolam (Xanax®)
    • Asian patients - maximal concentrations and half-life are 15 - 25% higher in Asian patients
    • Cigarette smoking - alprazolam concentrations may be reduced by as much as 50% in smokers compared to nonsmokers
    • Uricosuric effect - alprazolam has a weak uricosuric effect
BENZODIAZEPINE DRUG INTERACTIONS
    All benzodiazepines
    • Central Nervous System (CNS) Depressants - benzodiazepines may potentiate the effects of other CNS depressants (e.g. opiates, alcohol, anticonvulsants, antihistamines, etc.). Risk for adverse events may be increased. Use caution when combining.

    Alprazolam (Xanax®)
    • CYP3A4 inducers and inhibitors - alprazolam is a CYP3A4 sensitive substrate. Use caution with CYP3A4 inducers and inhibitors.
    • Ketoconazole and itraconazole - alprazolam should not be given with ketoconazole or itraconazole since they are strong CYP3A4 inhibitors and toxicity may occur
    • Digoxin - alprazolam may increase blood levels of digoxin
    • Desipramine and imipramine - alprazolam may increase blood levels of desipramine and imipramine

    Chlordiazepoxide (Librium®)
    • Disulfiram (Antabuse®) - disulfiram decreases the clearance of chlordiazepoxide. Consider using another benzodiazepine that has not been shown to interact with disulfiram (alprazolam, oxazepam, lorazepam). [9]

    Clonazepam (Klonopin®)
    Diazepam (Valium®)
    • CYP3A4 inducers and inhibitors - diazepam is a CYP3A4 sensitive substrate. Use caution with CYP3A4 inducers and inhibitors.
    • CYP2C19 inducers and inhibitors - diazepam is a CYP2C19 sensitive substrate. Use caution with CYP2C19 inducers and inhibitors.
    • Disulfiram (Antabuse®) - disulfiram decreases the clearance of diazepam. Consider using another benzodiazepine that has not been shown to interact with disulfiram (alprazolam, oxazepam, lorazepam). [9,11]

    Lorazepam (Ativan®)
    • Valproate - valproate decreases lorazepam clearance. Lorazepam dose should be decreased by 50% when taken with valproate.
    • Probenecid - probenecid decreases lorazepam clearance. Lorazepam dose should be decreased by 50% when taken with probenecid.

    Temazepam (Restoril®)
    • Disulfiram (Antabuse®) - disulfiram may decrease the clearance of temazepam. Consider using another benzodiazepine that has not been shown to interact with disulfiram (alprazolam, oxazepam, lorazepam). [12]
BENZODIAZEPINE WITHDRAWAL SYMPTOMS
    Overview
    • Withdrawal symptoms typically develop within 2 - 3 days with shorter-acting agents and within 5 - 10 days with longer-acting agents
    • Withdrawal symptoms can be psychiatric, autonomic, and neurologic

    Psychiatric symptoms
    • Anxiety
    • Insomnia
    • Depression
    • Irritability
    • Psychosis/delirium
    Autonomic symptoms
    • Tremor
    • Sweating
    • Nausea and vomiting
    • Shortness of breath
    • Increased heart rate
    • Elevated blood pressure
    • Muscle tension
    Neurologic symptoms
    • Seizures
    • Cognitive impairment
    • Memory impairment
    • Sound sensitivity
    • Photophobia
    • Hypersomnia
    • Muscle tension/spasms
    • Motor tics
BENZODIAZEPINE WITHDRAWAL PREVENTION / TREATMENT
Prevention - taper dose
  • In order to prevent withdrawal symptoms, benzodiazepines should be tapered over a period of 4 - 8 weeks
  • Patients who are taking multiple benzodiazepines should be switched to one, preferably diazepam because it has a long half-life
    • Regimens for tapering include the following:
      • Reduce the dose by 50% every week OR
      • Reduce the daily dose by 10 - 25% every 2 weeks [14]
Treatment
  • Patients taking very high doses (e.g. ≥ 100 mg of diazepam or equivalent a day) should have inpatient withdrawal
  • Treatment of withdrawal symptoms may include the following:
    • Insomnia - trazodone, mirtazapine, melatonin, antihistamines
    • Depression and mood disorders - SSRIs, mood stabilizer (e.g. carbamazepine), antipsychotics
    • Anxiety - beta blockers, SSRIs, gabapentin, hydroxyzine, buspirone [14]