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Diazepam: Drug information

Diazepam: Drug information
(For additional information see "Diazepam: Patient drug information" and see "Diazepam: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Special Alerts
FDA Extends Expiration Dates for Certain Meridian Autoinjectors: Updated July 2017

The FDA is alerting health care providers and emergency responders that certain lots of AtroPen (atropine), CANA (diazepam), morphine sulfate, and pralidoxime chloride autoinjectors manufactured by Meridian Medical Technologies can be used beyond the labeled expiration date, which should help mitigate potential shortages of these drugs. To ensure patient safety, products should be stored under the manufacturer’s labeled storage conditions.

Additional information may be found at http://www.fda.gov/Drugs/DrugSafety/ucm376367.htm.

ALERT: US Boxed Warning
Risks from concomitant use with opioids:

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

Abuse, misuse, and addiction:

The use of benzodiazepines, including diazepam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing diazepam and throughout treatment, assess each patient's risk for abuse, misuse, and addiction.

Dependence and withdrawal reactions:

Oral: The continued use of benzodiazepines, including diazepam, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of diazepam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue diazepam or reduce the dosage.

Injection, nasal spray, rectal gel: The continued use of benzodiazepines, including diazepam, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Although diazepam is indicated only for intermittent use, if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction may precipitate acute withdrawal reactions, which can be life-threatening. For patients using diazepam more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue diazepam.

Brand Names: US
  • Diastat AcuDial;
  • Diastat Pediatric;
  • diazePAM Intensol;
  • Valium;
  • Valtoco 10 MG Dose;
  • Valtoco 15 MG Dose;
  • Valtoco 20 MG Dose;
  • Valtoco 5 MG Dose
Brand Names: Canada
  • Diastat;
  • PMS-Diazepam [DSC];
  • Valium
Pharmacologic Category
  • Antiseizure Agent, Benzodiazepine;
  • Benzodiazepine
Dosing: Adult

Note: Reduce dose or avoid use in patients receiving opioids, with significant chronic disease (eg, respiratory compromise), or at increased risk for accumulation (eg, advanced cirrhosis). Oral diazepam is contraindicated in severe respiratory insufficiency or severe hepatic impairment. Avoid use in patients with a history of substance use, misuse of medications, or depression, except for acute or emergency situations (eg, status epilepticus) (Ref).

Anxiety

Anxiety:

Anxiety, acute/severe (monotherapy or adjunctive therapy):

IM, IV, Oral: 2 to 10 mg every 3 to 6 hours as needed up to 40 mg/day; adjust dose based on response and tolerability (Ref).

Anxiety disorders (monotherapy or adjunctive therapy) (alternative agent):

Note: Generally used short term for symptom relief until preferred therapy (eg, serotonin reuptake inhibitor) is effective (eg, 4 to 6 weeks, following by tapering). Long-term, low-dose (eg, 2.5 mg/day) therapy may be considered in select patients only when other treatments are ineffective or poorly tolerated (Ref). Use with caution in patients with posttraumatic stress disorder; benzodiazepines may worsen symptoms (Ref).

Initial: Oral: 2 to 5 mg once or twice daily; increase gradually based on response and tolerability up to 40 mg/day in 2 to 4 divided doses (Ref).

Procedural anxiety (premedication):

IV: 2 to 10 mg or 0.03 to 0.1 mg/kg once (maximum single dose: 10 mg) 5 to 15 minutes prior to procedure; if needed due to incomplete response and/or duration of procedure, may repeat the dose (usually 50% of the initial dose) after 5 to 30 minutes (Ref). Note: In obese patients, non-weight-based dosing is preferred (Ref).

Oral (off-label): 2 to 10 mg once 30 to 60 minutes prior to procedure; if needed due to incomplete response, may repeat the dose (usually 50% of the initial dose) after 30 to 60 minutes (Ref).

Hydroxychloroquine/chloroquine toxicity

Hydroxychloroquine/chloroquine toxicity (severe):

Note: Use is recommended in patients with severe toxicity (eg, hypotension, QTc prolongation, hypokalemia) in combination with other supportive measures (eg, mechanical ventilation, epinephrine, cardiovascular monitoring) (Ref).

IV: 2 mg/kg once administered over 30 minutes, followed by 1 to 2 mg/kg/day for 2 to 4 days (Ref).

Intoxication

Intoxication (cocaine, methamphetamine, and other sympathomimetics) (off-label use): Based on limited data.

IV: 2 to 10 mg every 3 to 10 minutes as needed for agitation, sedation, seizures, hypertension, and tachycardia until desired symptom control achieved; doses up to 20 mg may be considered in severe agitation based on response and tolerability. Large, cumulative doses may be required for some patients; monitor for respiratory depression and hypotension. Note: If IV access is not possible, consider IM administration; however, IM diazepam time to peak drug levels is slower than IM midazolam (Ref).

Muscle spasm, spasticity, and/or rigidity

Muscle spasm, spasticity, and/or rigidity (alternative agent):

Oral: Initial: 2 mg twice daily or 5 mg at bedtime; increase gradually based on response and tolerability, up to 40 to 60 mg/day in 3 to 4 divided doses (Ref).

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome (adjunctive therapy) (off-label use):

Note: Following withdrawal of causative agent while continuing supportive care, use for moderate to severe muscle rigidity with elevated creatine kinase. May also use for any patient experiencing agitation (Ref).

IV: 10 mg every 8 hours until symptom resolution (Ref).

Seizures

Seizures:

Note: If IV access is not available, IM diazepam is not recommended due to erratic absorption and slow time to peak drug levels (IM midazolam is recommended) (Ref).

Acute active seizures (non-status epilepticus):

Intranasal: 0.2 mg/kg as a single dose; may repeat once based on response and tolerability after ≥4 hours. Maximum dose: Two doses per episode. Do not use for more than 1 episode every 5 days or more than 5 episodes per month.

The following table (derived from manufacturer labeling) provides acceptable weight ranges for each dose, such that patients will receive between 90% and 180% of the calculated recommended dose.

Recommended Intranasal Diazepam Dosage for Adults

Weight

Dose (rounded from 0.2 mg/kg)

Number of nasal spray devices

Number of sprays

28 to 50 kg

10 mg

One 10 mg device

One spray in one nostril

51 to 75 kg

15 mg

Two 7.5 mg devices

One spray in each nostril

76 kg and up

20 mg

Two 10 mg devices

One spray in each nostril

IV: 5 to 10 mg as a single dose given at a maximum infusion rate of 5 mg/minute; may repeat at 3- to 5-minute intervals up to a total dose of 30 mg (Ref).

Rectal gel (generally for use in prehospital setting): 0.2 mg/kg (round dose up to the nearest 2.5 mg increment; maximum dose: 20 mg) or 10 to 20 mg as a single dose (Ref). Maximum duration: 5 episodes/month and 1 episode every 5 days (Ref).

Status epilepticus (alternative agent):

IV: 5 to 10 mg as a single dose given at a maximum infusion rate of 5 mg/minute; may repeat dose in 3 to 5 minutes if seizures continue; a nonbenzodiazepine antiseizure agent should follow to prevent seizure recurrence, even if seizures have ceased (Ref).

Rectal gel (generally for use in prehospital setting) (off-label): 0.2 to 0.5 mg/kg (round dose up to the nearest 2.5 mg increment; maximum dose: 20 mg) as a single dose (Ref).

Serotonin syndrome

Serotonin syndrome (serotonin toxicity) (off-label use):

IV: 5 to 10 mg every 8 to 10 minutes until symptoms resolve (Ref).

Substance withdrawal

Substance withdrawal:

Alcohol withdrawal syndrome:

Note: Symptom-triggered regimens preferred over fixed-dose regimens (Ref). Dosage and frequency may vary based on institution-specific protocols. Some experts recommend avoiding IM administration due to variable absorption (Ref). Example regimens are presented below.

Symptom-triggered regimen: IV, Oral: 5 to 20 mg as needed per institution-specific protocol until appropriate sedation achieved; dose and frequency determined by withdrawal symptom severity using a validated severity assessment scale, such as the Clinical Institute Withdrawal Assessment for Alcohol, revised scale (CIWA-Ar) (Ref). Note: An alternative front-loading regimen of 20 mg every 1 to 2 hours for 3 doses may precede the symptom-triggered regimen in a supervised setting for patients at high risk for severe withdrawal (Ref).

Fixed-dose regimen : IV, Oral: 10 to 20 mg every 6 to 12 hours on day 1; for the next 3 to 5 days, decrease the total daily dose by 25% to 50% each day by reducing the dose and/or frequency (Ref). Note: An alternative front-loading regimen of 20 mg every 1 to 2 hours for 3 doses may precede the fixed regimen in a supervised setting for patients at high risk for severe withdrawal (Ref).

Opioid withdrawal (autonomic instability and agitation) (alternative agent) (adjunctive therapy) (off-label use): Based on limited data.

IV: 10 to 20 mg every 5 to 10 minutes until hemodynamically stable and adequate sedation achieved (Ref).

Vertigo, acute episodes

Vertigo, acute episodes (alternative agent) (off-label use):

Note: Reserve use for symptomatic relief of episodes lasting several hours to days (maximum duration: 3 days); chronic use may impede adaptation and recovery (Ref).

IV, Oral: 1 to 5 mg every 12 hours as needed for up to 48 to 72 hours (Ref).

Discontinuation of therapy: Unless safety concerns require a more rapid withdrawal, gradually taper to detect reemerging symptoms and minimize rebound and withdrawal symptoms in patients receiving therapy ≥4 weeks or as appropriate based on patient-specific factors (Ref).

Low or moderate dose, no concerns for benzodiazepine use disorder: Taper total daily dose by 20% to 25% every week based on response and tolerability (taper increments will be limited by available dosage forms) (Ref).

Extended or high-dose therapy, or suspected benzodiazepine use disorder: Taper total daily dose by approximately 25% every 1 to 2 weeks based on response, tolerability, and individual patient factors (taper increments will be limited by available dosage forms) (Ref). Reduce dose more rapidly in the beginning, and slow the dose reduction as the taper progresses because earlier stages of withdrawal are easier to tolerate (Ref). The optimal duration and taper increment will vary; up to 6 months may be necessary for some patients on higher doses, and a taper rate of 50% every week may be tolerated in some patients (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: An increased incidence of CNS-related adverse effects has been reported in patients with hypoalbuminemia (which is frequently observed in patients with end-stage kidney disease or critical illness) (Ref).

Altered kidney function: No dosage adjustment necessary for any degree of kidney impairment; use with caution, especially with prolonged courses (Ref).

Hemodialysis, intermittent (thrice weekly): Unlikely to be significantly dialyzable (highly protein bound, large Vd): No supplemental dose or dosage adjustment necessary; use with caution, especially with prolonged courses (Ref).

Peritoneal dialysis: Unlikely to be significantly dialyzable (highly protein bound, large Vd): No dosage adjustment necessary; use with caution, especially with prolonged courses (Ref).

CRRT: No dosage adjustment necessary; use with caution, especially with prolonged courses (Ref).

PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary; use with caution, especially with prolonged courses (Ref).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; use with caution because distribution and half-life may increase, and clearance may decrease significantly. The oral tablets are contraindicated in severe hepatic impairment.

Dosing: Pediatric

(For additional information see "Diazepam: Pediatric drug information")

Seizures, acute

Seizures, acute:

Intranasal: Dosing varies with age; patients <12 years require a larger mg/kg/dose. May repeat dose in 4 hours; do not exceed 2 doses in 24 hours. Do not repeat dose if patient has difficulty breathing or excessive sedation. Do not exceed maximum treatment frequency of 1 episode every 5 days and 5 episodes per month.

Children 6 to 11 years:

Weight

Dose (mg)

Quantity and Type of Nasal Device

Number of Sprays

10 to <19 kg

5 mg

One 5 mg device

1 spray in 1 nostril

19 to <38 kg

10 mg

One 10 mg device

1 spray in 1 nostril

38 to <56 kg

15 mg

Two 7.5 mg devices

2 sprays delivered as 1 spray in each nostril

56 to 74 kg

20 mg

Two 10 mg devices

2 sprays delivered as 1 spray in each nostril

Children ≥12 years and Adolescents:

Weight

Dose (mg)

Quantity and Type of Nasal Device

Number of Sprays

14 to <28 kg

5 mg

One 5 mg device

1 spray in 1 nostril

28 to <51 kg

10 mg

One 10 mg device

1 spray in 1 nostril

51 to <76 kg

15 mg

Two 7.5 mg devices

2 sprays delivered as 1 spray in each nostril

≥76 kg

20 mg

Two 10 mg devices

2 sprays delivered as 1 spray in each nostril

Rectal gel formulation:

Infants and Children 6 months to 2 years: Rectal: Dose not established.

Children 2 to 5 years: Rectal: 0.5 mg/kg.

Children 6 to 11 years: Rectal: 0.3 mg/kg.

Children ≥12 years and Adolescents: Rectal: 0.2 mg/kg.

Note: Round dose up to the nearest 2.5 mg increment, not exceeding a 20 mg/dose; dose may be repeated in 4 to 12 hours if needed; do not use more than 5 times per month or more than once every 5 days.

Rectal: Undiluted 5 mg/mL parenteral formulation (filter if using ampul): Infants, Children, and Adolescents: 0.5 mg/kg/dose then 0.25 mg/kg/dose in 10 minutes if needed. Maximum dose: 20 mg/dose (Ref).

Status epilepticus

Status epilepticus:

IV (preferred route):

Weight-directed: Infants >30 days, Children, and Adolescents: IV: 0.15 to 0.2 mg/kg/dose slow IV; may repeat dose once in 5 minutes; maximum dose: 10 mg/dose (Ref).

Fixed dosing: Manufacturer's labeling:

Infants >30 days and Children <5 years: IV: 0.2 to 0.5 mg slow IV every 2 to 5 minutes up to a maximum total dose of 5 mg; repeat in 2 to 4 hours if needed.

Children ≥5 years and Adolescents: IV: 1 mg slow IV every 2 to 5 minutes up to a maximum of 10 mg; repeat in 2 to 4 hours if needed.

Rectal (Ref): Note: For use when IV access unavailable.

Children 2 to 5 years: Rectal: 0.5 mg/kg; maximum dose: 20 mg/dose.

Children 6 to 11 years: Rectal: 0.3 mg/kg; maximum dose: 20 mg/dose.

Children ≥12 years and Adolescents: Rectal: 0.2 mg/kg; maximum dose: 20 mg/dose.

Febrile seizure, prophylaxis

Febrile seizure, prophylaxis: Limited data available:

Note: Although there is evidence that prophylaxis with diazepam may reduce recurrence of febrile seizures, use is not routinely recommended since risks of toxicity generally outweigh the benefits (Ref).

Children: Oral: 1 mg/kg/day divided every 8 hours; initiate therapy at first sign of fever and continue for 24 hours after fever resolves (Ref).

Spasticity/muscle spasms

Spasticity/muscle spasms:

General dosing: Note: Initiate therapy with lowest dose; dose should be individualized and titrated to effect and tolerability:

Fixed dosing: Infants ≥6 months, Children, and Adolescents: Oral: Initial: 1 to 2.5 mg 3 to 4 times daily; increase gradually as needed and tolerated (Ref).

Weight-directed dosing (Ref):

Infants ≥6 months and Children <12 years: Oral: 0.12 to 0.8 mg/kg/day in divided doses every 6 to 8 hours; maximum dose: 10 mg/dose.

Children ≥12 years and Adolescents: Oral: 2 to 10 mg 2 to 4 times daily.

Cerebral palsy-associated spasticity: Limited data available. Note: Dose should be individualized and titrated to effect and tolerability. Diazepam should be considered short-term treatment as there is insufficient evidence regarding motor function improvement (Ref).

Weight-directed dosing: Children: Oral: 0.01 to 0.3 mg/kg/day divided 2 or 4 times daily (Ref).

Fixed dosing: Children ≥5 years and Adolescents: Oral: Initial: 1 to 2 mg/dose 3 times daily; may titrate to response (Ref). Doses up to 5 mg 4 times daily have been reported (Ref).

Low-dose fixed bedtime dosing (Ref): Children <12 years: Oral:

<8.5 kg: 0.5 to 1 mg at bedtime.

8.5 to 15 kg: 1 to 2 mg at bedtime.

Tetanus-associated spasm:

Fixed dosing (Ref): Note: Respiratory support should be available during therapy.

Infants >30 days and children <5 years: IV, IM: 1 to 2 mg every 3 to 4 hours as needed.

Children ≥5 years and Adolescents: IV, IM: 5 to 10 mg every 3 to 4 hours as needed.

Weight-directed dosing (Ref): Infants, Children, and Adolescents: IV: Initial: 0.1 to 0.2 mg/kg/dose every 2 to 6 hours; titrate as needed. Note: Initial recommended adult dose is 5 mg/dose.

Muscle spasm/spasticity associated with chronic/terminal illness (eg, palliative care settings): Limited data available: Infants, Children, and Adolescents:

Oral: 0.12 to 0.8 mg/kg/day divided every 6 to 12 hours; maximum dose: 10 mg/dose (Ref).

IM, IV: 0.05 to 0.2 mg/kg/dose every 6 to 12 hours; maximum total dose: 0.6 mg/kg cumulative in 8 hours (Ref); Note: In palliative situations, the usual initial dose for children <5 years is 5 mg/dose and in children ≥5 years and adolescents is 10 mg/dose (Ref).

Sedation, anxiolysis, and amnesia prior to procedure

Sedation, anxiolysis, and amnesia prior to procedure: Limited data available:

Oral:

Infants ≥6 months: 0.2 to 0.3 mg/kg 45 to 60 minutes prior to procedure. Maximum dose: 10 mg/dose (Ref).

Children: 0.2 to 0.5 mg/kg 45 to 60 minutes prior to procedure; maximum dose: 10 mg/dose (Ref).

Adolescents: 0.2 to 0.3 mg/kg 45 to 60 minutes prior to procedure. Maximum dose: 10 mg/dose (Ref).

IV:

Infants and Children: Initial: 0.05 to 0.1 mg/kg over 3 to 5 minutes, titrate slowly to effect (maximum total dose: 0.25 mg/kg) (Ref).

Adolescents: IV: 5 mg; may repeat with 2.5 mg if needed (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Hemodialysis: Not dialyzable (0% to 5%); supplemental dose is not necessary.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling; use with caution. The oral tablets are contraindicated in severe hepatic impairment.

Dosing: Older Adult

Elderly and/or debilitated patients:

IM, IV: Initial: 2 to 5 mg; increase gradually based on response and tolerability.

Intranasal: Due to the increased half-life in elderly patients, consider reducing dose.

Oral: Initial: 2 to 2.5 mg 1 to 2 times daily; increase gradually based on response and tolerability.

Rectal gel: Due to the increased half-life in elderly and debilitated patients, consider reducing dose.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Concentrate, Oral:

diazePAM Intensol: 5 mg/mL (30 mL) [contains alcohol, usp; unflavored flavor]

Generic: 5 mg/mL (30 mL)

Gel, Rectal:

Diastat AcuDial: 10 mg (1 ea); 20 mg (1 ea) [contains alcohol, usp, benzoic acid, sodium benzoate]

Diastat Pediatric: 2.5 mg (1 ea) [contains benzoic acid, benzyl alcohol, propylene glycol, sodium benzoate]

Generic: 2.5 mg (1 ea); 10 mg (1 ea); 20 mg (1 ea)

Liquid, Nasal:

Valtoco 10 MG Dose: 10 mg/0.1 mL (1 ea) [contains alcohol, usp]

Valtoco 5 MG Dose: 5 mg/0.1 mL (1 ea) [contains alcohol, usp]

Liquid Therapy Pack, Nasal:

Valtoco 15 MG Dose: 2 devices, 7.5 mg/0.1 mL each (1 ea) [contains alcohol, usp]

Valtoco 20 MG Dose: 2 devices, 10 mg/0.1 mL each (1 ea) [contains alcohol, usp]

Solution, Injection:

Generic: 5 mg/mL (2 mL, 10 mL)

Solution, Oral:

Generic: 5 mg/5 mL (5 mL, 473 mL, 500 mL)

Solution Auto-injector, Intramuscular:

Generic: 10 mg/2 mL (2 mL)

Tablet, Oral:

Valium: 2 mg [DSC] [scored]

Valium: 2 mg [scored; contains corn starch]

Valium: 5 mg [DSC] [scored]

Valium: 5 mg [scored; contains corn starch, fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]

Valium: 10 mg [DSC] [scored]

Valium: 10 mg [scored; contains corn starch, fd&c blue #1 (brilliant blue)]

Generic: 2 mg, 5 mg, 10 mg

Generic Equivalent Available: US

May be product dependent

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Gel, Rectal:

Diastat: 10 mg (2 mL) [contains alcohol, usp, benzoic acid, benzyl alcohol, propylene glycol, sodium benzoate]

Solution, Injection:

Generic: 5 mg/mL (2 mL)

Solution, Oral:

Generic: 1 mg/mL ([DSC])

Solution Auto-injector, Intramuscular:

Generic: 10 mg/2 mL ([DSC])

Tablet, Oral:

Valium: 5 mg

Generic: 2 mg, 5 mg, 10 mg

Controlled Substance

C-IV

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Valium: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/013263s094lbl.pdf#page=14

Valtoco nasal spray: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/211635s007lbl.pdf#page=22

Administration: Adult

Oral: Administer with food or water. Dilute or mix oral concentrate with water, juice, soda, applesauce, or pudding before use; measure dose only with calibrated dropper provided.

Intranasal: Do not test or prime before use. Administer one spray into one nostril. Some doses require an additional spray into the alternate nostril; refer to dosing for additional details. Do not administer a second dose if the patient is having trouble breathing or is excessively sedated.

IM: Administer (undiluted) deep into the muscle mass.

IV: Administer undiluted by slow IV push; do not mix with other solutions or medications. Rapid injection may cause respiratory depression or hypotension. In adults, maximum infusion rate is 5 mg/minute. Do not administer through small veins (eg, dorsum of hand/wrist). Avoid intra-arterial administration. Continuous infusion is not recommended because of precipitation in IV fluids and absorption of drug into infusion bags and tubing.

Vesicant; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation.

Extravasation management: If extravasation occurs, stop IV administration immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. Apply dry cold compresses (Ref).

Rectal gel: Prior to administration, confirm that prescribed dose is visible and correct and that the green "ready" band is visible. Place patient on side (facing person responsible for monitoring), with top leg bent forward. Insert rectal tip (lubricated) gently into rectum until rim fits snugly against rectal opening; push plunger gently over 3 seconds. After additional 3 seconds, remove syringe; hold buttocks together while slowly counting to 3 to prevent leakage; keep patient on side, facing towards you, and continue to observe patient; discard any unused medication, syringe, and all used materials; do not reuse; see manufacturer's Administration and Disposal Instructions. May consider use of parenteral formulation rectally if gel not available (Ref).

Administration: Pediatric

Intranasal: Device comes ready to use; do not test or prime device before use. Each device delivers 1 spray only. Administer 1 spray into 1 nostril from a single device. If a second device is needed for the full dose, administer the second spray in the alternate nostril from a new device. A second dose should not be administered if the patient is having trouble breathing or excessive sedation.

Oral: Administer with food or water.

Oral concentrate solution (5 mg/mL): Dilute or mix product with water, juice (except grapefruit juice), soda, applesauce, or pudding before use. Measure dose only with calibrated dropper provided.

Parenteral:

IM: Administer undiluted (5 mg/mL) deep into muscle mass.

IV: Administer undiluted (5 mg/mL) direct IV; do not mix with other solutions or medications. Rapid injection may cause respiratory depression or hypotension; infants and children: Do not exceed 1 to 2 mg/minute IV push; adults: 5 mg/minute. Continuous infusion is not recommended because of precipitation in IV fluids and absorption of drug into infusion bags and tubing.

Vesicant; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation. If extravasation occurs, stop IV administration immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. Apply dry cold compresses (Ref).

Rectal: Diastat AcuDial: Prescribed dose must be "dialed in" and locked before dispensing; consult package insert for directions on setting prescribed dose. Prior to administration, confirm that the prescribed dose is visible and correct and that the green "ready" band is visible.

Diastat AcuDial and Diastat: Place patient on side (facing person responsible for monitoring), with top leg bent forward. Insert rectal tip (lubricated) gently into rectum until rim fits snug against rectal opening; push plunger gently over 3 seconds. After additional 3 seconds, remove syringe; hold buttocks together while slowly counting to 3 to prevent leakage; keep patient on side, facing towards you and continue to observe patient; discard any unused medication, syringe, and all used materials safely away from children; do not reuse; see Administration and Disposal Instructions that come with product.

Use: Labeled Indications

Alcohol withdrawal syndrome (oral and injection): Symptomatic relief of acute agitation, tremor, impending or acute delirium, delirium tremens, and hallucinosis associated with alcohol withdrawal.

Anxiety, acute/severe (oral and injection): Short-term relief of severe anxiety symptoms.

Anxiety disorders (oral and injection): Management of anxiety disorders.

Muscle spasm, spasticity, and/or rigidity (oral and injection): As an adjunct for the relief of skeletal muscle spasm due to reflex spasm caused by local pathology (eg, inflammation of muscles or joints, secondary to trauma); spasticity caused by upper motor neuron disorders (eg, cerebral palsy, paraplegia); athetosis; stiff-man syndrome; and tetanus.

Procedural anxiety, premedication (injection): Relief of anxiety and tension in patients undergoing surgical procedures; prior to cardioversion for the relief of anxiety and tension and to diminish patient's recall (IV only); as an adjunct prior to endoscopic procedures for apprehension, anxiety, or acute stress reactions and to diminish patient's recall.

Note: Use of diazepam in patients undergoing cardioversion or endoscopic procedures has been superseded by agents with a more pharmacokinetically favorable profile (eg, midazolam) (Thomas 2014; Triantafillidis 2013).

Seizures, acute, active: Adjunct in convulsive disorders (oral); treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern in patients with epilepsy (≥6 years of age [intranasal], ≥2 years of age [rectal]); adjunct in severe recurrent convulsive seizures (injection).

Status epilepticus (injection): Adjunct in status epilepticus.

Use: Off-Label: Adult

Hydroxychloroquine/chloroquine toxicity (severe); Intoxication (cocaine, methamphetamine, and other sympathomimetics); Neuroleptic malignant syndrome; Opioid withdrawal (autonomic instability and agitation); Serotonin syndrome (serotonin toxicity); Vertigo, acute episodes

Medication Safety Issues
Sound-alike/look-alike issues:

DiazePAM may be confused with diazoxide, dilTIAZem, Ditropan, LORazepam

Valium may be confused with Valcyte

Older Adult: High-Risk Medication:

Beers Criteria: Diazepam is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older due to an increased risk of impaired cognition, delirium, falls, fractures, and motor vehicle accidents with benzodiazepine use. Older adults also have slower metabolism of long-acting benzodiazepines (eg, diazepam). However, diazepam may be appropriate in older adults when used for seizure disorders, rapid eye movement sleep behavior disorders, benzodiazepine or ethanol withdrawal, severe generalized anxiety disorder, or periprocedural anesthesia (Beers Criteria [AGS 2019]).

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions may vary by route of administration.

>10%: Nervous system: Drowsiness (23%)

1% to 10%:

Cardiovascular: Hypotension (≥1%), vasodilation (2%)

Dermatologic: Skin rash (3%)

Gastrointestinal: Abdominal pain (≥1%), diarrhea (4%), dysgeusia (3%), hiccups (≥1%)

Nervous system: Abnormality in thinking (≥1%), agitation (≥1%), ataxia (3%), confusion (≥1%), dizziness (3%), dysarthria (≥1%), emotional lability (≥1%), euphoria (3%), headache (5%), nervousness (≥1%), pain (≥1%), speech disturbance (≥1%), vertigo (≥1%)

Neuromuscular & skeletal: Asthenia (1%)

Respiratory: Asthma (2%), epistaxis (2%), nasal discomfort (6%), rhinitis (≥1%)

<1%:

Cardiovascular: Bradycardia, circulatory shock, syncope

Dermatologic: Diaphoresis, pruritus, urticaria

Gastrointestinal: Anorexia, vomiting

Genitourinary: Urinary tract infection

Hematologic & oncologic: Anemia, lymphadenopathy, neutropenia

Infection: Infection

Nervous system: Tonic clonic type of status epilepticus

Neuromuscular & skeletal: Hyperkinetic muscle activity

Ophthalmic: Mydriasis, nystagmus disorder

Respiratory: Increased cough

Frequency not defined:

Cardiovascular: ECG changes, localized phlebitis, venous thrombosis

Endocrine & metabolic: Change in libido

Gastrointestinal: Altered salivation, constipation, gastrointestinal distress, nausea

Genitourinary: Urinary incontinence, urinary retention

Hematologic & oncologic: Neutropenia

Hepatic: Increased serum alkaline phosphatase, increased serum transaminases, jaundice

Nervous system: Anterograde amnesia, central nervous system depression, depression, drug abuse, drug dependence, drug withdrawal, fatigue, hypoactivity, lethargy, myasthenia, paradoxical central nervous system stimulation, psychiatric signs and symptoms, rebound anxiety, slurred speech

Neuromuscular & skeletal: Tremor

Ophthalmic: Blurred vision, diplopia

Respiratory: Hypoventilation

Postmarketing: Miscellaneous: Paradoxical reaction

Contraindications

Hypersensitivity to diazepam or any component of the formulation; acute narrow-angle glaucoma.

Injection: Additional contraindications: Untreated open-angle glaucoma.

Oral: Additional contraindications: Untreated open-angle glaucoma; use in infants <6 months of age, myasthenia gravis, severe respiratory impairment, severe hepatic impairment, sleep apnea syndrome.

Documentation of allergenic cross-reactivity for benzodiazepines is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Warnings/Precautions

Concerns related to adverse effects:

• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia (Nelson 1999).

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

• Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines; risk may be increased in adolescent/pediatric, geriatric patients, or patients with a history of alcohol use disorder or psychiatric/personality disorders (Mancuso 2004).

• Sleep-related activities: Hazardous sleep-related activities such as sleep-driving, cooking and eating food, and making phone calls while asleep have been noted with benzodiazepines (Dolder 2008).

• Suicidal ideation: Intranasal: Pooled analysis of trials involving various antiseizure medications (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% of treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify health care provider immediately if symptoms occur.

Disease-related concerns:

• Convulsive disorders: When used as an adjunct in treating convulsive disorders, an increase in frequency/severity of tonic-clonic seizures may occur and require dose adjustment of antiseizure medication. Abrupt withdrawal may result in a temporary increase in the frequency and/or severity of seizures.

• Depression: Avoid use in patients with depression because of concerns about worsening mood symptoms, particularly if suicidal risk may be present, except for acute or emergency situations (eg, acute agitation, status epilepticus) (Craske 2022).

• Glaucoma: May be used in patients with open-angle glaucoma who are receiving appropriate therapy; contraindicated in acute narrow-angle glaucoma and untreated open-angle glaucoma.

• Hepatic impairment: Use with caution in patients with hepatic impairment. Oral tablet is contraindicated in patients with severe hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment.

• Respiratory disease: Reduce dose or avoid use in patients with respiratory disease, including chronic obstructive pulmonary disease or sleep apnea. Benzodiazepines may cause significant respiratory depression. Oral tablet is contraindicated in patients with severe respiratory impairment or sleep apnea syndrome.

Concurrent drug therapy issues:

• Concomitant use with opioids: [US Boxed Warning]: Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death; reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate, and limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

Special populations:

• Debilitated patients: Use with caution; active metabolites with extended half-lives may lead to delayed accumulation and adverse effects; limit dose to smallest effective amount and increase gradually and as tolerated to avoid adverse reactions.

• Older adult patients: Use with caution; active metabolites with extended half-lives may lead to delayed accumulation and adverse effects; limit dose to smallest effective amount and increase gradually and as tolerated to avoid adverse reactions. Older adults may be at an increased risk of death with use; risk has been found highest within the first 4 months of use in older adult dementia patients (Jennum 2015; Saarelainen 2018).

• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury (Nelson 1999).

• Obese patients: Use benzodiazepines with caution in obese patients; may have prolonged action when discontinued.

• Psychotic patients: Use of diazepam is not recommended in place of appropriate therapy.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol and/or sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol and/or benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.

• Parenteral: Vesicant; ensure proper needle or catheter placement prior to and during administration; avoid extravasation. Acute hypotension, muscle weakness, apnea, and/or cardiac arrest have occurred with parenteral administration. Acute effects may be more prevalent in patients receiving concurrent barbiturates, opioids, or ethanol. Appropriate resuscitative equipment and qualified personnel should be available during administration and monitoring. Avoid use of the injection in patients in shock, coma, or in acute ethanol intoxication with depression of vital signs. Intra-arterial injection should be avoided. Tonic status epilepticus has been precipitated in patients treated with diazepam IV for absence status or absence variant status.

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated with hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP ["Inactive" 1997]; Wilson 2000; Wilson 2005; Zar 2007).

• Rectal gel: Administration of rectal gel should only be performed by individuals trained to recognize characteristic seizure activity for which the product is indicated, and capable of monitoring response to determine need for additional medical intervention. Not recommended for chronic, daily use. Use with caution in patients with neurologic damage.

Other warnings/precautions:

• Abuse, misuse, and addiction: [US Boxed Warning]: The use of benzodiazepines, including diazepam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Assess each patient's risk for abuse, misuse, and addiction prior to and throughout treatment; counsel patients at increased risk on proper use and monitoring for signs and symptoms of abuse, misuse, and addiction. Institute early treatment or refer patients in whom substance use disorder is suspected. Limit dosages and durations to the minimum required.

• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties.

• Dependence and withdrawal reactions: [US Boxed Warning]: The continued use of benzodiazepines, including diazepam, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of diazepam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue diazepam or reduce the dosage. Some patients may develop a protracted withdrawal syndrome lasting >12 months; may be difficult to differentiate withdrawal symptoms from reemergence or continuation of symptoms for which benzodiazepines were prescribed. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.

• Tolerance: Diazepam is a long half-life benzodiazepine. Duration of action after a single dose is determined by redistribution rather than metabolism. Tolerance develops to the sedative, hypnotic, and antiseizure effects. It does not develop to the anxiolytic or skeletal muscle relaxing effects (Vinkers 2012). Chronic use of this agent may increase the perioperative benzodiazepine dose needed to achieve desired effect.

Warnings: Additional Pediatric Considerations

Neonates and young infants have decreased metabolism of diazepam and desmethyldiazepam (active metabolite), both can accumulate with repeated use and cause increased toxicity.

Some dosage forms may contain propylene glycol; in neonates, large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009). Diazepam Intensol Oral Solution (Concentration) contains 19% alcohol.

Metabolism/Transport Effects

Substrate of CYP1A2 (minor), CYP2B6 (minor), CYP2C19 (major), CYP2C9 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Ajmaline: DiazePAM may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CloZAPine: Benzodiazepines may enhance the adverse/toxic effect of CloZAPine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Monitor for respiratory depression, hypotension, and other toxicities if these agents are combined. Risk D: Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Cosyntropin: May enhance the hepatotoxic effect of DiazePAM. Risk C: Monitor therapy

CYP2C19 Inducers (Moderate): May decrease the serum concentration of DiazePAM. Risk C: Monitor therapy

CYP2C19 Inhibitors (Moderate): May increase the serum concentration of DiazePAM. Risk C: Monitor therapy

CYP2C19 Inhibitors (Strong): May increase the serum concentration of DiazePAM. Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of DiazePAM. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of DiazePAM. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of DiazePAM. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of DiazePAM. Risk C: Monitor therapy

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Disulfiram: May enhance the adverse/toxic effect of Products Containing Ethanol. Management: Do not use disulfiram with dosage forms that contain ethanol. Risk X: Avoid combination

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

Fosphenytoin-Phenytoin: May decrease the serum concentration of DiazePAM. DiazePAM may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Melatonin: May enhance the sedative effect of Benzodiazepines. Risk C: Monitor therapy

Methadone: Benzodiazepines may enhance the CNS depressant effect of Methadone. Management: Clinicians should generally avoid concurrent use of methadone and benzodiazepines when possible; any combined use should be undertaken with extra caution. Risk D: Consider therapy modification

Methotrimeprazine: Products Containing Ethanol may enhance the adverse/toxic effect of Methotrimeprazine. Specifically, CNS depressant effects may be increased. Management: Avoid products containing alcohol in patients treated with methotrimeprazine. Risk X: Avoid combination

Metoclopramide: May enhance the CNS depressant effect of DiazePAM. Metoclopramide may increase the serum concentration of DiazePAM. Risk C: Monitor therapy

MetroNIDAZOLE (Systemic): May enhance the adverse/toxic effect of Products Containing Propylene Glycol. A disulfiram-like reaction may occur. Risk X: Avoid combination

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Nirmatrelvir and Ritonavir: May increase the serum concentration of DiazePAM. Nirmatrelvir and Ritonavir may decrease the serum concentration of DiazePAM. Risk C: Monitor therapy

OLANZapine: Benzodiazepines may enhance the adverse/toxic effect of OLANZapine. Management: Monitor closely for hypotension, respiratory or central nervous system depression, and bradycardia if olanzapine is combined with benzodiazepines. Use of parenteral benzodiazepines with IM olanzapine is not recommended. Risk C: Monitor therapy

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Ombitasvir, Paritaprevir, and Ritonavir: May decrease serum concentrations of the active metabolite(s) of DiazePAM. Ombitasvir, Paritaprevir, and Ritonavir may decrease the serum concentration of DiazePAM. Risk C: Monitor therapy

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May decrease serum concentrations of the active metabolite(s) of DiazePAM. Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may decrease the serum concentration of DiazePAM. Risk C: Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Ornidazole: May enhance the adverse/toxic effect of Products Containing Ethanol. Specifically, a disulfiram-like reaction may occur. Risk X: Avoid combination

Ornidazole: May enhance the adverse/toxic effect of Products Containing Propylene Glycol. Specifically, a disulfiram-like reaction may occur. Risk X: Avoid combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: Benzodiazepines may enhance the CNS depressant effect of Oxybate Salt Products. Risk X: Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Ritonavir: May increase the serum concentration of DiazePAM. Ritonavir may decrease the serum concentration of DiazePAM. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Secnidazole: Products Containing Ethanol may enhance the adverse/toxic effect of Secnidazole. Risk X: Avoid combination

Secnidazole: Products Containing Propylene Glycol may enhance the adverse/toxic effect of Secnidazole. Risk X: Avoid combination

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Teduglutide: May increase the serum concentration of Benzodiazepines. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk C: Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Pregnancy Considerations

Diazepam and its metabolites (N-desmethyldiazepam, temazepam, and oxazepam) cross the placenta. Teratogenic effects have been observed with diazepam; however, additional studies are needed. The incidence of premature birth and low birth weights may be increased following maternal use of benzodiazepines; hypoglycemia and respiratory problems in the neonate may occur following exposure late in pregnancy. Neonatal withdrawal symptoms may occur within days to weeks after birth and "floppy infant syndrome" (which also includes withdrawal symptoms) has been reported with some benzodiazepines (including diazepam) (Bergman 1992; Iqbal 2002; Wikner 2007). A combination of factors influences the potential teratogenicity of antiseizure therapy. When treating women with epilepsy, monotherapy with the lowest effective dose and avoidance of medications known to have a high incidence of teratogenic effects is recommended (Harden 2009; Wlodarczyk 2012).

Patients exposed to diazepam during pregnancy are encouraged to enroll themselves into the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.

Breastfeeding Considerations

Diazepam and its metabolites are present in breast milk.

Using data from one study, the relative infant dose (RID) of diazepam is 8.9% when compared to a weight-adjusted maternal dose of 10 mg/day.

In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000). However some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Larsen 2015).

The RID of diazepam was calculated using a milk concentration of 85 ng/mL, providing an estimated daily infant dose via breast milk of 0.01275 mg/kg/day. This was the highest milk concentration obtained in one study following maternal administration of diazepam 10 mg once daily at bedtime to four postpartum women (this sample was obtained after five maternal doses) (Brandt 1976). Higher milk concentrations have been reported; however, milk concentration related to maternal dose was not stated (Dusci 1990; Wesson 1985). The active metabolites of diazepam (desmethyldiazepam, oxazepam, and temazepam) have also been detected in breast milk and the urine of exposed infants (Brandt 1976; Cole 1975; Dusci 1990; Erkkola 1972; Wesson 1985). Relative infant doses of up to 11% have been reported (McElhatton 1994).

Sedation and weight loss have been observed in some infants exposed to diazepam via breast milk (Patrick 1972; Wesson 1985)

Diazepam has a long half-life and may accumulate in the breastfed infant, especially preterm infants or those exposed to chronic maternal doses (Davanzo 2013). Significant accumulation may occur even if the maternal dose is low (Wesson 1985). A single maternal dose may be compatible with breastfeeding (WHO 2002). If chronic use of a benzodiazepine is needed in breastfeeding women, use of shorter acting agents is preferred (Davanzo 2013; WHO 2002). Infants should be monitored for drowsiness, decreased feeding, and poor weight gain (Veiby 2015).

Monitoring Parameters

Heart rate, respiratory rate, blood pressure, and mental status; liver enzymes and CBC with long-term therapy; clinical signs of propylene glycol toxicity (for continuous high-dose and/or long duration intravenous use) including serum creatinine, BUN, serum lactate, osmol gap. Note: An osmol gap of ≥10 was predictive of elevated propylene glycol concentrations; values of ≥12 suggest propylene glycol toxicity (Arroliga 2004; Barnes 2006; Yahwak 2008).

Mechanism of Action

Long-acting benzodiazepine. Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization. Benzodiazepine receptors and effects appear to be linked to the GABA-A receptors. Benzodiazepines do not bind to GABA-B receptors.

Pharmacokinetics

Onset of action:

Sedation: Pediatric patients: IV: 4 to 5 minutes (Krauss 2006).

Status epilepticus: IV: 1 to 3 minutes; Rectal: 2 to 10 minutes.

Duration of action:

Classified as a long-acting benzodiazepine; classification based on benzodiazepines with half-life >40 hours (Griffin 2013).

Indication-specific durations:

Sedation: Pediatric patients: IV: 60 to 120 minutes (Krauss 2006).

Absorption:

Oral: Well absorbed (>90%); delayed and decreased when administered with a moderate fat meal.

Rectal: Well absorbed.

Distribution: Vd:

Intranasal: 0.8 to 1 L/kg.

IV: 1.2 L/kg (range: 0.6 to 2 L/kg) (Greenblatt 1989a).

Oral: 1.1 L/kg (range: 0.6 to 1.8 L/kg (Greenblatt 1989b).

Rectal: 1 L/kg.

Protein binding:

Intranasal: 95% to 98%.

Oral: Neonates: 84% to 86% (Milsap 1994; Morselli 1980); Adults: 98%.

Rectal: 95% to 98%.

Metabolism: Hepatic; diazepam is N-demethylated by CYP3A4 and 2C19 to the active metabolite N-desmethyldiazepam, and is hydroxylated by CYP3A4 to the active metabolite temazepam. N-desmethyldiazepam and temazepam are both further metabolized to oxazepam. Temazepam and oxazepam are largely eliminated by glucuronidation.

Bioavailability:

IM: >90% (Lamson 2011).

Intranasal: 97%.

Oral: >90%.

Rectal: 90%.

Half-life elimination: Note: Diazepam accumulates upon multiple dosing and the terminal elimination half-life is slightly prolonged.

IM:

Premature neonates (GA: 28 to 34 weeks): 54 hours.

Infants: ~30 hours (Morselli 1973).

Children 3 to 8 years: 18 hours (Morselli 1973).

Adults: Parent: ~60 to 72 hours; Desmethyldiazepam: ~152 to 174 hours (Lamson 2011).

Intranasal: ~49 hours.

IV: Parent: 33 to 45 hours; Desmethyldiazepam: 87 hours (Cloyd 1998; Greenblatt 1989a).

Oral: Parent: 44 to 48 hours; Desmethyldiazepam: 100 hours (Greenblatt 1989b).

Rectal: Parent: 45 to 46 hours; Desmethyldiazepam: 71 to 99 hours (Cloyd 1998).

Time to peak:

IM: Median: 1 hour (range: 0.25 to 2 hours) (Lamson 2011).

Intranasal: ~1.5 hours.

IV: ~1 minute (Cloyd 1998).

Oral: 15 minutes to 2.5 hours (1.25 hours when fasting; 2.5 hours with food) (Greenblatt 1989b).

Rectal: 1.5 hours.

Excretion: Urine (predominantly as glucuronide conjugates).

Pharmacokinetics: Additional Considerations

Hepatic function impairment: In mild and moderate cirrhosis, the average half-life increases 2- to 5-fold, with individual half-lives over 500 hours reported. There is also an increase in volume of distribution, and average clearance decreases by almost half. Half-life is also prolonged with hepatic fibrosis to 90 hours (range: 66 to 104 hours), with chronic active hepatitis to 60 hours (range: 26 to 76 hours), and with acute viral hepatitis to 74 hours (range: 49 to 129 hours). In chronic active hepatitis, clearance is decreased by almost half.

Older adult: The half-life is increased by approximately 1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age, as the volume of distribution is increased, and clearance is decreased. Consequently, there may be lower peak concentrations, higher trough concentration with multiple doses, and it may take longer to reach steady state.

Pricing: US

Concentrate (diazePAM Intensol Oral)

5 mg/mL (per mL): $1.43

Concentrate (diazePAM Oral)

5 mg/mL (per mL): $1.25 - $5.00

Gel (Diastat AcuDial Rectal)

10 mg (per each): $420.90

20 mg (per each): $420.90

Gel (Diastat Pediatric Rectal)

2.5 mg (per each): $354.82

Gel (diazePAM Rectal)

2.5 mg (per each): $306.90

10 mg (per each): $364.06

20 mg (per each): $364.06

Liquid (Valtoco 10 MG Dose Nasal)

10MG/0.1ML (per each): $373.97

Liquid (Valtoco 5 MG Dose Nasal)

5MG/0.1ML (per each): $373.97

Liquid Therapy Pack (Valtoco 15 MG Dose Nasal)

7.5MG/0.1ML (per each): $373.97

Liquid Therapy Pack (Valtoco 20 MG Dose Nasal)

10MG/0.1ML (per each): $373.97

Solution (diazePAM Injection)

5 mg/mL (per mL): $11.18 - $16.69

Solution Auto-injector (diazePAM Intramuscular)

10 mg/2 mL (per mL): $21.53

Tablets (diazePAM Oral)

2 mg (per each): $0.10 - $0.24

5 mg (per each): $0.16 - $0.32

10 mg (per each): $0.31 - $0.43

Tablets (Valium Oral)

2 mg (per each): $4.51

5 mg (per each): $7.01

10 mg (per each): $11.80

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Aliseum (IT);
  • Alsaval (SY);
  • Anlin (TW);
  • Ansiolin (IT);
  • Antenex (AU);
  • Anxicalm (IE);
  • Apaurin (CZ, HR, RU, SI, SK);
  • Apo-diazepam (CZ);
  • Apozepam (DK);
  • Assival (IL);
  • Azepam (BD);
  • Azepan (AE, CY, IQ, IR, JO, KW, LY, OM, SA, SY, YE);
  • Baogin (TW);
  • Benzopin (ZA);
  • Calium (EG);
  • Calmpose (BF, BJ, CI, ET, GH, GM, GN, IN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZA, ZM, ZW);
  • Calmvita (LK);
  • Cercine (JP);
  • Ceregulart (JP);
  • Compaz (BR);
  • Condition (JP);
  • Dalpam (HR);
  • Dialag (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW);
  • Diapam (FI, TR);
  • Diapine (MY, SG, TH, TW);
  • Diapo (MY);
  • Diazem (TR);
  • Diazemuls (GB, IE, IT);
  • Diazepam (HK);
  • Diazepam Desitin (HU);
  • Diazepam-Eurogenerics (LU);
  • Diazepam-ratiopharm (LU);
  • Diazepan (AE, BF, BJ, CI, CY, ES, ET, GH, GM, GN, IQ, IR, JO, KE, KW, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, SA, SC, SD, SL, SN, SY, TN, TZ, UG, YE, ZM, ZW);
  • Diazepeks (LV);
  • Diazetop (BE);
  • Dipezona (AR);
  • Dizam (ZW);
  • Dizep (BD);
  • Doval (ZA);
  • Dupin (TW);
  • DZP (MY);
  • Elcion CR (IN);
  • Epival (EG);
  • Euphorin (JP);
  • Evalin (BD);
  • Gewacalm (AT);
  • Horizon (JP);
  • Ifa Fonal (MX);
  • Kratium (BF, BJ, BM, BS, BZ, CI, ET, GH, GM, GN, GY, JM, KE, LB, LR, MA, ML, MR, MU, MW, NE, NG, NL, PR, SC, SD, SL, SN, SR, TN, TR, TT, TZ, UG, ZM, ZW);
  • Lembrol (AR);
  • Melode (KR);
  • Nercon (CR, DO, GT, HN, MX, NI, PA, SV);
  • Nivalen (AE, BF, BJ, CI, CY, ET, GH, GM, GN, IQ, IR, JO, KE, KW, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, SA, SC, SD, SL, SN, SY, TN, TZ, UG, YE, ZM, ZW);
  • Nixtensyn (PH);
  • Noan (BR, IT);
  • Normabel (HR);
  • Orinil (BD);
  • Ortopsique (CR, DO, GT, HN, MX, NI, PA, SV);
  • Paceum (CH);
  • Pacitran (PE);
  • Pamizep (PH);
  • Paranten (CR, DO, GT, HN, NI, PA, SV);
  • Pax (ZA);
  • Paxum (IN);
  • Placidox 10 (IN);
  • Placidox 2 (IN);
  • Placidox 5 (IN);
  • Plidan (AR);
  • Prozepam (ID);
  • Psychopax (AT, CH);
  • Radizepam (AE, BF, BJ, CI, CY, ET, GH, GM, GN, IQ, IR, JO, KE, KW, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, SA, SC, SD, SL, SN, SY, TN, TZ, UG, YE, ZM, ZW);
  • Ranzepam (AU);
  • Relanium (LT, PL, RU, UA);
  • Remedium (MT, TR);
  • Renborin (JP);
  • Sedium (PY);
  • Seduxen (BD, BM, BS, BZ, EE, GY, JM, NL, PR, SR, TT, VN);
  • Serenzin (JP);
  • Sibazon (UA);
  • Sincronex (UY);
  • Sipam (TH);
  • Solina (LK);
  • Stedon (MT);
  • Stesolid (AE, CH, CY, DE, DK, ES, FI, ID, IE, IL, IQ, IR, IS, JO, LK, LY, NO, NZ, OM, SA, SE, SY, YE);
  • Stesolid Rectal Tube (DE, HK);
  • Sunzepam (MX);
  • Sunzepan (CR, DO, GT, HN, NI, PA, SV);
  • Talema (VE);
  • Tranquirit (IT);
  • Valaxona (DK);
  • Valdimex (ID);
  • Valiquid (DE);
  • Valisanbe (ID);
  • Valium (AE, AR, AT, AU, BB, BE, BF, BG, BH, BJ, BR, CH, CI, CR, CU, CY, DE, DK, DO, EC, EE, ES, ET, FR, GH, GM, GN, GR, GT, HN, HR, IE, IN, IQ, IR, IT, JO, KE, KR, KW, LB, LR, LU, LY, MA, ML, MR, MT, MU, MW, MX, MY, NE, NG, NI, NO, OM, PA, PE, PH, PK, PL, PT, PY, QA, SA, SC, SD, SK, SL, SN, SV, SY, TN, TR, TZ, UG, UY, VN, YE, ZM, ZW);
  • Valiuzam (AE, CY, IQ, IR, JO, KW, LY, OM, SA, SY, YE);
  • Valpam (AE, AU, CY, EG, HK, IQ, IR, JO, KW, LY, OM, SA, SY, YE);
  • Valzepam (PH);
  • Vanconin (TW);
  • Vatran (IT);
  • Vescopam (TH);
  • Vexepam (PH);
  • Vodin (ID);
  • Zopam (MY, TH)


For country code abbreviations (show table)
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  29. Diazepam carpuject [prescribing information]. Lake Forest, IL: Hospira; March 2014.
  30. Diazepam injection multi-dose vial [prescribing information]. Upper Saddle River, NJ: DASH Pharmaceuticals, LLC; July 2019.
  31. Diazepam injection prefilled syringe [prescribing information]. Upper Saddle River, NJ: DASH Pharmaceuticals, LLC; March 2021.
  32. Diazepam Intensol (diazepam) [prescribing information]. Eatontown, NJ: West-Ward Pharmaceuticals Corp; February 2021.
  33. Diazepam intramuscular autoinjector [prescribing information]. Columbia, MD: Meridian Medical Technologies; July 2005.
  34. Diazepam oral solution [prescribing information]. Eatontown, NJ: West-Ward Pharmaceuticals Corp; January 2021.
  35. Diazepam oral solution and Diazepam Intensol oral solution concentrate [prescribing information]. Eatontown, NJ: West-Ward Pharmaceuticals Corp; May 2020.
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