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)

Protein Binding

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

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

Metabolism

  • 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

Half Life

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

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. 2003;64 Suppl 3:3-6.  [PMID:12662127]
  2. Chouinard G. Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J Clin Psychiatry. 2004;65 Suppl 5:7-12.  [PMID:15078112]
  3. Bellantuono C, Tofani S, Di Sciascio G, et al. Benzodiazepine exposure in pregnancy and risk of major malformations: a critical overview. Gen Hosp Psychiatry. 2013;35(1):3-8.  [PMID:23044244]
  4. Greenblatt DJ, Wright CE. Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clin Pharmacokinet. 1993;24(6):453-71.  [PMID:8513649]
  5. Greenblatt DJ, Shader RI, MacLeod SM, et al. Clinical pharmacokinetics of chlordiazepoxide. Clin Pharmacokinet. 1978;3(5):381-94.  [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. 1975;9(2-3):155-9.  [PMID:1233263]
  7. Boudinot FD, Homon CA, Jusko WJ, et al. Protein binding of oxazepam and its glucuronide conjugates to human albumin. Biochem Pharmacol. 1985;34(12):2115-21.  [PMID:4004929]
  8. Sonne J, Loft S, Døssing M, et al. Bioavailability and pharmacokinetics of oxazepam. Eur J Clin Pharmacol. 1988;35(4):385-9.  [PMID:3197746]
  9. Offidani E, Guidi J, Tomba E, et al. Efficacy and tolerability of benzodiazepines versus antidepressants in anxiety disorders: a systematic review and meta-analysis. Psychother Psychosom. 2013;82(6):355-62.  [PMID:24061211]
  10. Davidson JR. Use of benzodiazepines in social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. J Clin Psychiatry. 2004;65 Suppl 5:29-33.  [PMID:15078116]
Last updated: December 19, 2016