Johns Hopkins Psychiatry Guide

Benzodiazepines

Paul M. Kim, M.D., Ph.D., Sujin Lee Weinstein, Pharm.D., BCPP

DRUG CLASS

  • Anxiolytics

INDICATIONS

FDA

NON-FDA APPROVED USES

  • Agitation
  • Alcohol withdrawal symptoms
  • Muscle spasms
  • Sedation
  • Restless legs syndrome
  • Sleepwalking disorder

MECHANISM

  • Benzodiazepines act through the gamma-aminobutyric acid (GABA) A receptor, which regulates chloride entry into neurons, resulting in neuronal hyperpolarization[1].

FORMS

brand name

preparation

manufacturer

route

form

dosage

cost*

Xanax

Alprazolam

Pfizer

Multiple generic manufacturers

PO

Tablet

ER tablet

ODT

Liquid

0.25 mg to 1 mg three times a day

Maximum 4 mg/day

Tablets:

Brand:

0.25 mg (100): $241.39

0.5 mg (100): $300.72

1 mg (100): $410.72

2 mg (100): $682.27

Generic:

0.25 mg (100): $69.50

0.5 mg (60): $128.95

1 mg (60): $160.40

2 mg (60): $212.90

3 mg (60): $319.35


ER Tablets:

Brand:

0.5 mg (60): $299.93

1 mg (60): $373.20

2 mg (60): $495.34

3 mg (60): $742.93

Generic:

0.5 mg (60): $135.40

1 mg (60): $168.46

2 mg (60): $223.58

3 mg (60): $335.36


ODT (generic only):

0.25 mg (100): $218.26

0.5 mg (100): $271.93

1 mg (100): $362.81

2 mg (100): $616.91

Liquid (1 mg/mL, 30-mL bottle):

Generic only: $81.05

Librium

Chlordiazepoxide

Multiple generic manufacturers

PO

Capsule

5 to 25 mg three times a day-four times a day

Maximum 100 mg/day

5 mg (100): $35.25

10 mg (100): $39.78

25 mg (100): $42.84

Klonopin

Clonazepam

Roche

Multiple generic manufacturers

PO

Tablet

ODT

0.5 to 1 mg three times a day

Maximum 20 mg/day

Tablets:

Brand:

0.5 mg (100): $245.48

1 mg (100): $280.03

2 mg (100): $388.01

Generic:

0.5 mg (100): $74.95

1 mg (100): $85.55

2 mg (100): $118.45

ODT:

Generic:

0.125 mg (60): $77.93

0.25 mg (60): $77.93

0.5 mg (60): $77.80

1 mg (60): $88.91

2 mg (60): $123.19

Valium

Diazepam

Roche

Multiple generic manufacturers

PO

Tablet

Liquid

5 to 25 mg three times a day-four times a day

Maximum 40 mg/day

Tablet:

Brand:

2 mg (100): $327.06

5 mg (100): $508.68

10 mg (100): $856.28

Generic:

2 mg (100): $10.45

5 mg (100): $16.35

10 mg (100): $31.25

Liquid (5 mg/5 mL, 500-mL bottle):

Generic only: $67.83

Ativan

Lorazepam

Multiple generic manufacturers

PO

Tablet

Liquid

0.5 to 1 mg three times a day-four times a day

Tablet:

Brand:

0.5 mg (100): $898.14

1 mg (100): $1199.78

2 mg (100): $1912.10

Generic:

0.5 mg (100): $67.75

1 mg (100): $88.25

2 mg (100): $128.45

Liquid (2 mg/1 mL, 30-mL bottle):

Generic only: $39.60

Serax

Oxazepam

Multiple generic manufacturers

PO

Capsule

10 to 30 mg three times a day-four times a day
Maximum 120 mg/day

10 mg (100): $115.19

15 mg (100): $145.45

30 mg (100): $210.39

ODT = orally disintegrating tablets

ER = extended release

*Prices represent cost per unit specified, and are representative of "Average Wholesale Price" (AWP)

ADULT DOSING

USUAL

  • The dosage of a benzodiazepine will vary depending on the patient and his or her history of sedative use.
  • Although similar in many ways, the choice of an agent is often based on its pharmacokinetic properties, especially onset of action, half-life, and metabolic pathway.
  • Oral dose equivalences of benzodiazepines[2]:

Agent

Relative Potency (mg)

Alprazolam (Xanax XR®; Xanax®)

0.5

Chlordiazepoxide (Librium®)

10

Clonazepam (Klonopin®)

0.25-0.5

Diazepam (Diastat®, Valium®)

5

Lorazepam (Ativan®)

1

Oxazepam (Serax®)

15-30

  • Alprazolam (Xanax®): The initial dose is 0.25 mg two to three times a day; the dose can be increased by 0.5-1 mg daily every 3-4 days; the usual therapeutic dose is 2-3 mg total/day, with twice daily or three times a day dosing. The maximum dose is 4 mg/day.
  • Chlordiazepoxide (Librium®): The initial oral dose is 5-10 mg daily to twice a day; the dose can be increased by 5 mg daily; the usual therapeutic dose is 30-40 mg total/day, with twice daily or three times a day dosing. An intramuscular dose (not available in the U.S.) of 50-100 mg can be given every 4 hours if needed for alcohol withdrawal.
  • Clonazepam (Klonopin®): The initial dose is 0.25 mg daily to twice a day; the dose can be increased by 0.125-0.25 mg daily or two times a day every 2-3 days; the usual therapeutic dose is 1-4 mg total/day in divided doses.
  • Diazepam (Valium®): The initial dose is 2 mg two to four times a day; the dose can be increased by 1-2 mg daily; the usual therapeutic dose is 15-30 mg total/day, with twice daily or three times a day dosing. An IM dose of 10 mg can be administered every 4 hours if needed for alcohol withdrawal.
  • Lorazepam (Ativan®): The initial dose is 0.5 mg twice a day; the dose can be increased by 1 mg daily in divided doses (twice daily or three times a day); the usual therapeutic dose is 2-8 mg total/day, with twice daily or three times a day dosing.
  • Oxazepam (Serax®): the initial dose is 10-15 mg daily; the dose can be increased by 10 mg daily in divided doses (three times a day); the usual therapeutic dose is 90 mg total/day, with three times a day dosing.

GERIATRIC

Elderly patients often require lower benzodiazepine doses due to slower metabolism of the drugs.

  • Alprazolam: No dose adjustment is needed; increase as needed/tolerated
  • Chlordiazepoxide: Decrease the usual dose by 50%
  • Clonazepam: No dose adjustment is needed; increase as needed/tolerated
  • Diazepam: Use 2 mg daily initially, and increase as needed/tolerated
  • Lorazepam: Use an initial dose of 1 mg/day in divided doses, and increase as needed/tolerated
  • Oxazepam: The maximum dose is 45-60 mg total/day, in divided doses

RENAL

  • Alprazolam: No dose adjustment is needed; increase as needed/tolerated
  • Chlordiazepoxide: Patients with renal impairment (CrCl less than 10 mL/min) should have their doses decreased by 50%
  • Clonazepam: No dose adjustment is needed; increase as needed/tolerated
  • Diazepam: No dose adjustment is needed; increase as needed/tolerated
  • Lorazepam: No dose adjustment is needed for mild-to-moderate renal impairment; not recommended for patients with renal failure
  • Oxazepam: No dose adjustment is needed; increase as needed/tolerated

HEPATIC

  • Alprazolam: No dose adjustment is needed; increase as needed/tolerated
  • Chlordiazepoxide: The maximum dose is 20 mg total/day
  • Clonazepam: No dose adjustment is needed; increase as needed/tolerated
  • Diazepam: Reduce the usual dose by 50%
  • Lorazepam: No dose adjustment is needed for mild-to-moderate liver impairment; not recommended for patients with hepatic failure
  • Oxazepam: No dose adjustment is needed; increase as needed/tolerated

PREGNANCY

  • Benzodiazepines are category D drugs, primarily due to concerns with cleft lip/palate and urogenital and neurological malformations; however, recent literature does not show an increased risk of these[3].
  • When possible, avoid use during the first trimester
  • Minimize use; i.e., reserve for PRN use if possible
  • Weigh the benefit vs. the risk of continued therapy; if necessary, consider an agent with a short half-life, and use sparingly and intermittently
  • Consider initiating and/or maintaining patients on an antidepressant agent. With the exception of paroxetine (category D), all the antidepressants are in category C
  • Avoid use near the time of delivery, as the baby may experience withdrawal symptoms

BREASTFEEDING

  • Long-term effects from exposure are unknown, but all benzodiazepines can cross into the breast milk; thus, the baby may experience side effects, including respiratory depression, sedation, difficulty breastfeeding and hypotonia - also known as “floppy baby syndrome.”
  • In general, benzodiazepines may have a longer half-life in babies (who have not developed the mechanisms for metabolism).
  • If used, choose an agent with a shorter half-life.

PEDIATRIC DOSING

USUAL

  • Alprazolam: Safety has not been established in children
  • Chlordiazepoxide: Not recommended for children younger than 6 years of age. For children older than 6 years of age, use 5 mg two to four times a day. This can be increased to 10 mg two to three times a day
  • Clonazepam: Safety has not been established in children
  • Diazepam: Start at 1 mg two to four times a day, and increase gradually as needed/tolerated
  • Lorazepam: Safety has not been established in children
  • Oxazepam: Safety has not been established for children under 6 years of age. No guideline has been established for children between 6 and 12 years of age. For children over 12 years of age, use 10-15 mg three to four times a day

RENAL

  • Chlordiazepoxide: Dose adjustment may be needed in children with renal impairment.
  • Diazepam: No dose adjustment needed
  • Oxazepam: No dose adjustment needed

ADVERSE DRUG REACTIONS

GENERAL

  • Most benzodiazepines can cause these side effects due to their inhibitory effects on brain neurotransmission:
    • Anterograde amnesia
    • Confusion
    • Dizziness
    • Depression
    • Sedation
  • Withdrawal symptoms from benzodiazepines (seizures, hallucinations, agitation, tremors) are most common when using benzodiazepines with shorter half-lives

COMMON

  • Alprazolam: Changes in appetite (decrease or increase), weight gain, reduced mucosal production leading to xerostomia and constipation, confusion, sedation, cognitive impairment, memory impairment, irritability
  • Chlordiazepoxide: Edema, constipation, nausea, confusion, sedation, cognitive impairment, memory impairment, irritability
  • Clonazepam: Depression, ataxia, dizziness, confusion, sedation, cognitive impairment, memory impairment, irritability, upper respiratory infection, respiratory depression
  • Diazepam: Hypotension, ataxia, dizziness, confusion, sedation, cognitive impairment
  • Lorazepam: Depression, ataxia, dizziness, confusion, sedation, cognitive impairment
  • Oxazepam: Dizziness, headache, sedation

OCCASIONAL

  • Alprazolam: Decreased libido
  • Chlordiazepoxide: Irregular menses, decreased libido
  • Clonazepam: Suicidal ideation
  • Diazepam: Muscle weakness, respiratory depression; rash and diarrhea can occur with rectal gel use
  • Lorazepam: Delirium (especially in elderly patients), weakness

RARE

  • Alprazolam: Stevens-Johnson Syndrome, liver failure
  • Chlordiazepoxide: Agranulocytosis, liver failure
  • Diazepam: Neutropenia
  • Lorazepam: Acidosis

DRUG INTERACTIONS

  • Benzodiazepine and alcohol can have a synergistic interaction, leading to CNS depression and death.
  • + = Contraindication
  • This list is not all-inclusive. Please refer to standard drug information resources to check for specific interactions.

Drug-to-Drug Interactions

Drug

Effect of Interaction

Recommendations/Comments

Alprazolam – boceprevir (Victrelis)

Increased levels of alprazolam

Adjust dose of alprazolam as needed

Alprazolam – carbamazepine (Tegretol)

Reduced levels of alprazolam

Adjust dose of alprazolam as needed

Clonazepam – carbamazepine (Tegretol)

Reduced levels of clonazepam

Adjust dose of clonazepam as needed

Alprazolam – clarithromycin (Biaxin)

Increased levels of alprazolam

Adjust dose of alprazolam as needed

Alprazolam – cobicistat (Stribild)

Increased levels of alprazolam

Adjust dose of alprazolam as needed

Alprazolam – delavirdine (Rescriptor)+

Increased levels of alprazolam

Avoid use

If necessary, adjust dose of alprazolam as needed

Alprazolam, diazepam – digoxin (Lanoxin)

Increased levels of digoxin

Monitor levels of digoxin, and reduce dose as needed

Diazepam – disulfiram (Antabuse)

Increased levels of diazepam

Adjust dose of diazepam as needed, or change to a benzodiazepine eliminated by glucuronidation

Diazepam – etravirine (Intelence)

Increased levels of diazepam

Adjust dose of diazepam as needed

Alprazolam – fluvoxamine (Luvox)

Increased levels of alprazolam

Reduce starting dose of alprazolam by 50%; adjust dose further as needed

Diazepam - fluvoxamine (Luvox)

Increased levels of diazepam

Adjust dose of diazepam as needed, or change to a benzodiazepine eliminated by glucuronidation

Alprazolam, diazepam – Fosamprenavir (Lexiva)

Increased levels of benzodiazepine

Adjust dose of benzodiazepine as needed

Alprazolam – indinavir (Crixivan)+

Increased levels of alprazolam

Avoid use

If necessary, adjust dose of alprazolam as needed

Alprazolam – itraconazole (Sporanox)+

Increased levels of alprazolam

Avoid use

If necessary, adjust dose of alprazolam as needed

Diazepam - itraconazole (Sporanox)

Increased levels of diazepam

Adjust dose of diazepam as needed

Alprazolam – ketoconazole+

Increased levels of alprazolam

Avoid use

If necessary, adjust dose of alprazolam as needed

Chlordiazepoxide, clonazepam – ketoconazole

Increased levels of benzodiazepine

Adjust dose of benzodiazepine as needed

Diazepam, lorazepam – olanzapine (Zyprexa)

Increased risk of cardiorespiratory depression

Avoid use of parenteral benzodiazepines and IM olanzapine

Diazepam – phenyton (Dilantin), fosphenytoin (Cerebyx)

Reduced levels of phenytoin

Monitor phenytoin levels, and adjust dose as needed

Lorazepam - probenecid

Increased levels of lorazepam

Reduce lorazepam starting dose by 50%; adjust dose further as needed

Alprazolam, clonazepam, diazepam – ritonavir (Norvir)

Increased levels of benzodiazepine

Adjust dose of benzodiazepine as needed

Alprazolam, diazepam – saquinavir (Invirase)

Increased levels of benzodiazepine

Adjust dose of benzodiazepine as needed

Alprazolam – telaprevir (Incivek)

Increased levels of alprazolam

Adjust dose of alprazolam as needed

Lorazepam – valproate (Depakote)

Increased levels of lorazepam

Reduce lorazepam starting dose by 50%; adjust dose further as needed

General Precautions:

CNS Depressants

Increased sedative/CNS depressant effects

Monitor for sedative effects, and adjust dose of one or both as needed

Clozapine (Clozari)

Increased sedative/CNS depressant effects

Decrease dose of benzodiazepine

Monitor for increased sedative/CNS depressant effects

Hydrocodone (Lortab)

Increased sedative/CNS depressant effects

Reduce hydrocodone dose ~25%

Methadone

Increased sedative/CNS depressant effects

Monitor for sedative effects, and adjust dose of one or both as needed

Sodium oxybate (Xyrem)

Increased sedative/CNS depressant effects

Monitor for sedative effects, and adjust dose of one or both as needed

Tapentadol (Nucynta)

Increased sedative/CNS depressant effects

Start tapentadol at 1/3 to 1/2 the usual starting dose

Zolpidem (Ambien)

Increased sedative/CNS depressant effects

Monitor for sedative effects, and adjust dose of one or both as needed

PHARMACOKINETIC

Absorption

  • Alprazolam[4]: Well-absorbed orally; bioavailability 90%; time to peak concentration 1-2 hours (intermediate)
  • Chlordiazepoxide[5]: Well-absorbed orally; time to peak concentration several hours (intermediate)
  • Clonazepam[6]: Well-absorbed orally; bioavailability 90%; time to peak concentration 1-4 hours (intermediate)
  • Diazepam: Well-absorbed orally; bioavailability 90%; time to peak concentration 0.5-6 hours (rapid)
  • Lorazepam: Well-absorbed orally; bioavailability 90%; time to peak concentration 1-2 hours (intermediate)
  • Oxazepam[7][8]: Well-absorbed orally; bioavailability 93%; Time to peak concentration 3 hours (intermediate – slow)

Metabolism and Excretion

  • Alprazolam: Metabolized by the liver (CYP3A4). Excreted primary by kidneys and some via feces
  • Chlordiazepoxide: Metabolized by the liver and excreted primary by kidneys
  • Clonazepam: Metabolized by the liver (CYP3A4: oxidation and reduction) and excreted primary by kidneys
  • Diazepam: Metabolized by the liver (CYP2C19 and CYP3A4: glucuronidation, methylation, oxidation, and hydroxylation) and excreted primary by kidneys
  • Lorazepam: Metabolized by the liver (glucuronidation). Excreted primary by kidneys and some via feces
  • Oxazepam: Metabolized by the liver and excreted primary by kidneys

Protein Binding

  • Alprazolam: 80%
  • Chlordiazepoxide: 96%
  • Clonazepam: 85%
  • Diazepam: 95-98%
  • Lorazepam: 85-91%
  • Oxazepam: 94-97%

T1/2

  • Alprazolam: 12-15 hours
  • Chlordiazepoxide: 24-48 hours
  • Clonazepam: 18-50 hours
  • Diazepam: 20-80 hours
  • Lorazepam: 10-20 hours
  • Oxazepam: 5-11 hours

Distribution

  • Alprazolam: 0.8-1.3 L/kg
  • Chlordiazepoxide: 0.25-0.5 L/kg
  • Clonazepam: 1.5-4.4 L/kg
  • Diazepam: 1 L/kg
  • Lorazepam: 1.3 L/kg
  • Oxazepam: 0.59 L/kg

COMMENTS

  • Benzodiazepines are often used to “bridge” patients who are starting an "antidepressant" for anxiety, since the therapeutic effects may be delayed, and patients may experience stimulating side effects initially.
  • Benzodiazepines may be more effective than antidepressants for social anxiety disorder[9][10].
    • However, benzodiazepines may worsen symptoms in patients with comorbid depression or PTSD[10].
  • Although beneficial for the acute relief of anxiety, long-term use of benzodiazepines is not recommended due to the risk of dependence. Although tolerance to the anxiolytic effects is uncommon, avoid use in patients with a history of substance use disorder. The risk of dependence is increased with the agents that are rapidly absorbed and with shorter half-lives, i.e., alprazolam and diazepam.
  • Benzodiazepines may be beneficial for long-term use in refractory cases.
  • One may preferably choose lorazepam or oxazepam: both are metabolized through conjugation and do not produce active metabolites (fewer CYP 450 drug interactions).

References

  1. Nemeroff CB: Anxiolytics: past, present, and future agents. J Clin Psychiatry 64 Suppl 3:3, 2003  [PMID:12662127]
  2. Chouinard G: Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J Clin Psychiatry 65 Suppl 5:7, 2004  [PMID:15078112]
  3. Bellantuono C et al: Benzodiazepine exposure in pregnancy and risk of major malformations: a critical overview. Gen Hosp Psychiatry 35:3, 2013 Jan-Feb  [PMID:23044244]
  4. Greenblatt DJ, Wright CE: Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clin Pharmacokinet 24:453, 1993  [PMID:8513649]
  5. Greenblatt DJ et al: Clinical pharmacokinetics of chlordiazepoxide. Clin Pharmacokinet 3:381, 1978 Sep-Oct  [PMID:359214]
  6. Berlin A, Dahlström H: Pharmacokinetics of the anticonvulsant drug clonazepam evaluated from single oral and intravenous doses and by repeated oral administration. Eur J Clin Pharmacol 9:155, 1975  [PMID:1233263]
  7. Boudinot FD et al: Protein binding of oxazepam and its glucuronide conjugates to human albumin. Biochem Pharmacol 34:2115, 1985  [PMID:4004929]
  8. Sonne J et al: Bioavailability and pharmacokinetics of oxazepam. Eur J Clin Pharmacol 35:385, 1988  [PMID:3197746]
  9. Offidani E et al: Efficacy and tolerability of benzodiazepines versus antidepressants in anxiety disorders: a systematic review and meta-analysis. Psychother Psychosom 82:355, 2013  [PMID:24061211]
  10. Davidson JR: Use of benzodiazepines in social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. J Clin Psychiatry 65 Suppl 5:29, 2004  [PMID:15078116]

Benzodiazepines is a sample topic from the Johns Hopkins Psychiatry Guide.

To view other topics, please or purchase a subscription.

Official website of the Johns Hopkins Antibiotic (ABX), HIV, Diabetes, and Psychiatry Guides, powered by Unbound Medicine. Johns Hopkins Guide App for iOS, iPhone, iPad, and Android included. Learn more.

Last updated: May 8, 2015