Diazepam

Pharmacologic Category

Anticonvulsant, Benzodiazepine; Benzodiazepine

Dosing: Adult

Note: Avoid use in patients with, or at risk for, substance abuse disorders, except for acute or emergency situations (eg, status epilepticus).

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 (Bystritsky 2019; WFSBP [Bandelow 2012]).

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

Note: Most commonly used short term for immediate symptom relief until concurrent therapy is effective (eg, ≤12 weeks). Long-term therapy may be considered for select patients only when other treatments are ineffective or poorly tolerated (Katzman 2014; WFSBP [Bandelow 2012]).

Oral: Initial: 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 (Bystritsky 2019).

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 (Choy 2019; Ginsberg 1992; Zakko 1999). Note: In obese patients, non-weight-based dosing is preferred (Choy 2019).

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 (Choy 2019).

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) (Barry 2019; Ling Ngan Wong 2008; Marquardt 2001; McBeth 2015; Riou 1988).

IV: 2 mg/kg once administered over 30 minutes, followed by 1 to 2 mg/kg/day for 2 to 4 days (Barry 2019; Marquardt 2001).

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 (Arnold 2019; Boyer 2019b; Delgado 2020; Hall 1990; Wodarz 2017).

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 (Abrams 2019; Kita 2000; Olek 2020).

Neuroleptic malignant syndrome (adjunctive therapy) (off-label use): For management of muscle rigidity or anxiety in patients with severe symptoms at presentation (hyperthermia, evidence of rhabdomyolysis) and for those not responding to initial withdrawal of medication and supportive care.

IV: 10 mg every 8 hours until symptom resolution (Tsai 2010; Wijdicks 2019).

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) (Leppik 2015; Wichliński 1985).

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 (Drislane 2020; NCS [Brophy 2012]; manufacturer's labeling).

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 (Drappatz 2019; manufacturer's labeling).

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 (AES [Glauser 2016]; Drislane 2020; NCS [Brophy 2012]).

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 (AES [Glauser 2016]; Drislane 2020).

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

IV: 5 to 10 mg every 8 to 10 minutes until symptoms resolve (Boyer 2020).

Substance withdrawal:

Alcohol withdrawal syndrome:

Note: Symptom-triggered regimens preferred over fixed-dose regimens (WFSBP [Soyka 2017]). Dosage and frequency may vary based on institution-specific protocols. Some experts recommend avoiding IM administration due to variable absorption (Weintraub 2017).

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) (Hoffman 2019; Mayo-Smith 1997; WFSBP [Soyka 2017]).

Fixed-dose regimen: IV, Oral: 10 mg every 6 hours for 1 day, then 5 mg every 6 hours for 2 days; additional doses may be considered based on withdrawal symptoms and validated assessment scale scores (eg, CIWA-Ar) (Mayo-Smith 1997; WFSBP [Soyka 2017]).

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 (Stolbach 2019; Wightman 2018).

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

IV, Oral: 1 to 5 mg every 12 hours as needed for 24 to 48 hours (Furman 2019; Hain 2003; Moskowitz 2020). If vomiting, may consider rectal administration (Robertson 2019).

Discontinuation of therapy: In patients receiving extended or higher-dose benzodiazepine therapy, unless safety concerns require a more rapid withdrawal, gradually withdraw to detect reemerging symptoms and minimize rebound and withdrawal symptoms. Taper total daily dose by 10% to 20% every 1 to 2 weeks based on response and tolerability. The optimal taper rate and duration will vary; durations up to 6 months may be necessary for some patients on higher doses (Bystritsky 2019; Lader 2011; VA/DoD 2015). For patients on high doses, taper more rapidly in the beginning and slow the reduction rate as the taper progresses because early stages of withdrawal are easier to tolerate. For example, reduce the dose weekly by 25% until half of the dose remains. Thereafter, continue to reduce by ~12% every 4 to 7 days (VA/DoD 2015).

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

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

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.

Dosing: Renal Impairment: Adult

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: 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

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.

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 (Hegenbarth 2008; Kliegman 2007).

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 (AES [Glauser 2016]; NCS [Brophy 2012]).

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 (AES [Glauser 2016]; NCS [Brophy 2012]): 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: Limited data available: 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 (Rosman 1993; Steering Committee 2008).

Spasticity/muscle spasms:

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

Manufacturer's labeling: Infants ≥6 months, Children, and Adolescents: Oral: Initial: 1 to 2.5 mg 3 to 4 times daily; increase gradually as needed and tolerated.

Alternate dosing (Kliegman 2016):

Oral:

Infants ≥6 months and Children <12 years: 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: 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:

Weight-based dosing: Children: Oral: 0.01 to 0.3 mg/kg/day divided 2 or 4 times daily (Kliegman 2016).

Low-dose fixed dosing (Mathew 2005): 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.

Fixed dosing: Children ≥5 years and Adolescents: Oral: Initial: 1.25 mg 3 times daily; may titrate to 5 mg 4 times daily (Engle 1966).

Tetanus-associated spasm:

Manufacturer's labeling:

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.

Alternate dosing (WHO 2010):

Infants and Children: IV: Initial: 0.1 to 0.2 mg/kg/dose every 2 to 6 hours; titrate as needed.

Adolescents: IV: Initial: 5 mg every 2 to 6 hours, titrate as needed. Large doses may be required.

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 (Wustoff 2007).

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 (Wustoff 2007); 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 (Kliegman 2016).

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 (Zeltzer 1990).

Children: 0.2 to 0.5 mg/kg 45 to 60 minutes prior to procedure; maximum dose: 10 mg/dose (Everitt 2002; Fell 1985; Tyagi 2012; Zeltzer 1990).

Adolescents: 0.2 to 0.3 mg/kg 45 to 60 minutes prior to procedure. Maximum dose: 10 mg/dose (Zeltzer 1990).

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) (Krauss 2006).

Adolescents: IV: 5 mg; may repeat with 2.5 mg if needed (Zeltzer 1990).

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

Dosing: Renal 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.

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); management of select, refractory epilepsy patients on stable regimens of antiepileptic drugs requiring intermittent use of diazepam to control episodes of increased seizure activity (rectal); 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 (intranasal); adjunct in severe recurrent convulsive seizures (injection).

Status epilepticus (injection): Adjunct in status epilepticus.

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

​Hydroxychloroquine/chloroquine toxicity (severe)Level of Evidence [C]

Data from a limited number of patients studied in case reports and a prospective case control study, as well as expert opinion, suggest that diazepam may be beneficial for the treatment of severe hydroxychloroquine and chloroquine toxicity when used in combination with other supportive care measures (eg, mechanical ventilation, epinephrine) Ref.

​Intoxication (cocaine, methamphetamine, and other sympathomimetics)Level of Evidence [G]

Based on German consensus- and evidence-based guidelines for the management of acute methamphetamine-related disorders and toxicity, benzodiazepines such as diazepam are first-line agents for methamphetamine intoxication, particularly in cases of acute agitation or aggression Ref. Other experts also recommend benzodiazepines for agitation, seizures, hypertension, and tachycardia associated with intoxication from cocaine and other sympathomimetics Ref.

​Neuroleptic malignant syndromeLevel of Evidence [C]

Data from a limited number of patients studied in case reports suggest that diazepam may be beneficial for the treatment of neuroleptic malignant syndrome Ref. Some experts suggest use of benzodiazepines in patients with severe symptoms (eg, muscle rigidity, agitation, hyperthermia) not responsive to supportive therapies Ref.

​Opioid withdrawal (autonomic instability and agitation)Level of Evidence [C]

Data from a limited number of patients studied in case reports suggest that diazepam may be beneficial for the treatment opioid withdrawal Ref. Some experts recommend benzodiazepines for management of agitation and autonomic instability associated with opioid withdrawal Ref.

​Serotonin syndrome (serotonin toxicity)Level of Evidence [C]

No formal studies have evaluated use of diazepam for management of serotonin syndrome; however, experts recommend use of benzodiazepines for symptomatic management (eg, muscle rigidity, agitation, hyperthermia, autonomic instability, tremor) of serotonin syndrome Ref.

​Vertigo, acute episodes, treatmentLevel of Evidence [C, G]

Data from a limited number of patients studied suggest that diazepam may be beneficial for the treatment of vertigo Ref.

Based on the American Academy of Otolaryngology Head and Neck Surgery Foundation clinical practice guideline for benign paroxysmal positional vertigo (BPPV), benzodiazepines, including diazepam, are not routinely recommended for the treatment of BPPV based on limited evidence and the risk-benefit profile. Use may be considered for short-term management of severe symptoms (eg, nausea, vomiting), for patients refusing other treatment options, and for patients requiring prophylaxis for canalith-repositioning procedures.

Based on the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) guidelines for the treatment of Ménière disease, diazepam may be considered for the treatment of acute vertigo attacks in patients with Ménière disease Ref.

Level of Evidence Definitions

​Level of Evidence Scale

Class and Related Monographs

Benzodiazepines

Comparative Efficacy

• DIAZEPAM NASAL SPRAY

Clinical Practice Guidelines

Anxiety:

American Psychiatric Association, "Practice Guideline for the Treatment of Patients with Panic Disorder," January 2009

WFSBP, "Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders, First Revision," 2008

WFSBP, "Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorder in Primary Care," 2012

Status Epilepticus:

American Epilepsy Society, “Treatment of Convulsive Status Epilepticus in Children and Adults,” January 2016

Neurocritical Care Society (NCS), “Guidelines for the Evaluation and Management of Status Epilepticus,” April 2012

Substance Withdrawal:

American Psychiatric Association, “Practice Guideline for the Treatment of Patients with Substance Use Disorders,” April 2007

World Federation of Societies of Biological Psychiatry, “WFSBP Guidelines for the Biological Treatment of Substance Use and Related Disorders, Part 1: Alcoholism,” 2008

Vertigo:

American Academy of Otolaryngology Head and Neck Surgery Foundation, “Clinical Practice Guideline: Benign Paroxysmal Positional Vertigo (BPPV),” 2017

American Academy of Otolaryngology–Head and Neck Surgery Foundation, "Clinical Practice Guideline: Ménière's Disease," April 2020

Administration: IM

Administer (undiluted) deep into the muscle mass.

Administration: 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 (Hurst 2004).

Administration: Injectable Detail

pH: 6.2 to 6.9 (5 mg/mL solution in vial)

Administration: 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.

Administration: 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.

Administration: Rectal

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 (Remy 1992).

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 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 (Hurst 2004).

Rectal: Diastat AcuDial: 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.

Vesicant/Extravasation Risk

Vesicant

Storage/Stability

Injection: Store at 20°C to 25°C (68°F to 77°F). Protect from light. Do not refrigerate autoinjector.

Nasal spray: Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F). Do not freeze. Protect from light. Only open blister pack immediately prior to administration.

Oral solution: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Discard opened bottle of concentrated oral solution after 90 days.

Rectal gel: Store at 25°C (77°F); excursion permitted to 15°C to 30°C (59°F to 86°F).

Tablet: Store at 15°C to 30°C (59°F to 86°F).

Preparation for Administration: Pediatric

Oral: Oral concentrate solution (5 mg/mL): Dilute or mix with water, juice (except grapefruit juice), soda, applesauce, or pudding before use.

Rectal: Diastat AcuDial: Prescribed dose must be "dialed in" and locked before dispensing; consult package insert for directions on setting prescribed dose.

Compatibility

See Trissel’s IV Compatibility Database

Open Trissel's IV Compatibility

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to relax muscles.

• It is used to treat alcohol withdrawal.

• It is used to treat anxiety.

• It is used to help control certain kinds of seizures.

• It may be given for other reasons.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Fatigue

• Loss of strength or energy

• Headache

• Muscle weakness

• Nose irritation

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Depression like thoughts of suicide, anxiety, agitation, irritability, panic attacks, mood changes, behavioral changes, or confusion

• Shortness of breath

• Change in balance

• Confusion

• Sensing things that seem real but are not

• Trouble with memory

• Severe dizziness

• Passing out

• Seizures

• Muscle spasms

• Twitching

• Trouble sleeping

• Vision changes

• Severe injection site redness, burning, swelling, pain, blisters, skin sores, or leaking of fluid

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Medication Safety Issues

​Sound-alike/look-alike issues:

​Geriatric Patients: High-Risk Medication:

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/2020/211635s000lbl.pdf#page=23

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 antiepileptics (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 anticonvulsant. Abrupt withdrawal may result in a temporary increase in the frequency and/or severity of seizures.

• Depression: Use caution in patients with depression or anxiety associated with depression, particularly if suicidal risk may be present.

• Drug abuse: Use with extreme caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance and psychological and physical dependence may occur with prolonged use (generally >10 days).

• 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: Use with caution in patients with respiratory disease; a lower dose is recommended for chronic respiratory insufficiency. 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.

• Elderly 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. Elderly patients may be at an increased risk of death with use; risk has been found highest within the first 4 months of use in elderly 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:

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

• 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 anticonvulsant 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.

• Withdrawal: Rebound or withdrawal symptoms may occur following abrupt discontinuation or large decreases in dose. Use caution when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms. The benzodiazepine receptor antagonist flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

Due to its long-acting metabolite, diazepam is not considered a drug of choice in the elderly. Long-acting benzodiazepines have been associated with falls in the elderly. Guidelines from the Centers for Medicare and Medicaid Services (CMS) strongly discourage the use of this agent in residents of long-term care facilities.

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.

Pregnancy Risk Factor

D

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 anticonvulsant 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.

Breast-Feeding 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).

Briggs' Drugs in Pregnancy & Lactation

• Diazepam

Adverse Reactions

Adverse reactions may vary by route of administration.

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

1% to 10%:

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

Dermatologic: Skin rash (3%)

Gastrointestinal: Abdominal pain (≥1%), diarrhea (4%), dysgeusia (2%)

Nervous system: Abnormality in thinking (1% to 2%), agitation (≥1%), ataxia (3%), confusion (≥1%), dizziness (3%), emotional lability (≥1%), euphoria (3%), headache (5%), nervousness (≥1%), pain (≥1%), speech disturbance (≥1%)

Neuromuscular & skeletal: Asthenia (1% to 2%)

Respiratory: Asthma (2%), epistaxis (3%), nasal congestion (3%), 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: Cough

Frequency not defined:

Cardiovascular: ECG changes, localized phlebitis, venous thrombosis

Endocrine & metabolic: Change in libido

Gastrointestinal: Altered salivation, constipation, gastrointestinal distress, hiccups, 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 dependence, drug withdrawal, dysarthria, fatigue, hypoactivity, myasthenia, paradoxical central nervous system stimulation, psychiatric signs and symptoms, slurred speech, vertigo

Neuromuscular & skeletal: Tremor

Ophthalmic: Blurred vision, diplopia

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Benzodiazepine Allergy

Toxicology

• Benzodiazepines

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 Open Interactions

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

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

Alfentanil: DiazePAM may enhance the CNS depressant effect of Alfentanil. Hypotension may also occur. Risk C: Monitor therapy

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

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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

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

Cannabis: May enhance the CNS depressant effect of CNS Depressants. 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. Risk D: Consider therapy modification

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

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

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 CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination. Some combinations are specifically contraindicated by manufacturers; others may have recommended dose adjustments. If combined, monitor for increased substrate effects. Risk D: Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Risk D: Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C19 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Risk D: Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

Disulfiram: May increase the serum concentration of DiazePAM. Risk C: Monitor therapy

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

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. 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. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk D: Consider therapy modification

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

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Risk D: Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

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

Fexinidazole [INT]: May increase the serum concentration of Products Containing Propylene Glycol. 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

Fosamprenavir: May increase the serum concentration of DiazePAM. Risk C: Monitor therapy

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

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

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

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

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

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. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. 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

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

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Risk D: Consider therapy modification

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

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Risk D: Consider therapy modification

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

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

OLANZapine: May enhance the adverse/toxic effect of Benzodiazepines. Management: Avoid concomitant use of parenteral benzodiazepines and IM olanzapine due to risks of additive adverse events (e.g., cardiorespiratory depression). Olanzapine prescribing information provides no specific recommendations regarding oral administration. 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

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

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

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. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Risk D: Consider therapy modification

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

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

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

Saquinavir: May increase the serum concentration of DiazePAM. Risk C: Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Risk D: Consider therapy modification

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

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

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. 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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Trimeprazine: 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

Test Interactions

False-negative urinary glucose determinations when using Clinistix® or Diastix®

Genes of Interest

• CYP2C19 - Diazepam
• Cytochrome P450 2C19
• Cytochrome P450 3A4

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).

Advanced Practitioners Physical Assessment/Monitoring

Assess for history of addiction; long-term use can result in dependence, abuse, or tolerance; periodically evaluate need for continued use. Monitor blood pressure and CNS status. For inpatient use, institute safety measures to prevent falls. Taper dosage slowly when discontinuing. Teach patient seizure precautions (if administered for seizures).

Nursing Physical Assessment/Monitoring

Assess for history of addiction; long-term use can result in dependence, abuse, or tolerance; periodically evaluate need for continued use. Monitor blood pressure and CNS status. For inpatient use, institute safety measures to prevent falls. Taper dosage slowly when discontinuing. Teach patient seizure precautions (if administered for seizures).

Controlled Substance

C-IV

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

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 (500 mL)

Solution Auto-injector, Intramuscular:

Generic: 10 mg/2 mL (2 mL)

Tablet, Oral:

Valium: 2 mg, 5 mg, 10 mg [scored]

Generic: 2 mg, 5 mg, 10 mg

Dosage Forms: Canada

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

Gel, Rectal:

Diastat: 5 mg/mL (0.5 mL, 1 mL, 2 mL, 3 mL, 4 mL) [contains benzoic acid, benzyl alcohol, sodium benzoate]

Solution, Injection:

Generic: 5 mg/mL (2 mL)

Solution, Oral:

Generic: 1 mg/mL (500 mL)

Solution Auto-injector, Intramuscular:

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

Tablet, Oral:

Valium: 5 mg

Generic: 2 mg, 5 mg, 10 mg

Anatomic Therapeutic Chemical (ATC) Classification

• N05BA01

Generic Available (US)

May be product dependent

Pricing: US

Concentrate (diazePAM Intensol Oral)

5 mg/mL (per mL): $1.43

Concentrate (diazePAM Oral)

5 mg/mL (per mL): $1.25

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): $336.00

Liquid (Valtoco 5 MG Dose Nasal)

5MG/0.1ML (per each): $336.00

Liquid Therapy Pack (Valtoco 15 MG Dose Nasal)

7.5MG/0.1ML (per each): $336.00

Liquid Therapy Pack (Valtoco 20 MG Dose Nasal)

10MG/0.1ML (per each): $336.00

Solution (diazePAM Injection)

5 mg/mL (per mL): $11.18 - $16.41

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): $4.08

5 mg (per each): $6.31

10 mg (per each): $10.65

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.

Mechanism of Action

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.

Pharmacodynamics/Kinetics

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:

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

Status epilepticus: 15 to 30 minutes.

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).

Pharmacodynamics/Kinetics: 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.

Geriatric: 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.

Dental Use

Oral medication for preoperative dental anxiety; sedative component in IV conscious sedation in oral surgery patients; skeletal muscle relaxant

* See Uses in AHFS Essentials for additional information.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Dental Health Professional Considerations

An adult companion should accompany the patient to and from dental office.

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia and changes in salivation (normal salivary flow resumes upon discontinuation) (see Dental Health Professional Considerations)

Effects on Bleeding

No information available to require special precautions

Dental Usual Dosing

Anxiety/sedation/skeletal muscle relaxant: Adults:

Oral: 2 to 10 mg 2 to 4 times daily

IM, IV: 2 to 10 mg, may repeat in 3 to 4 hours if needed

Anxiety: Elderly: Oral: Initial: 1 to 2 mg 1 to 2 times daily; increase gradually as needed, rarely need to use >10 mg daily (watch for hypotension and excessive sedation)

Skeletal muscle relaxant: Elderly: Oral: Initial: 2 to 5 mg 2 to 4 times daily

Related Information

• Anesthetic Agents
• Beers Criteria 2019: Potentially Inappropriate Medication Use in Older Adults ≥65 Years of Age
• Benzodiazepine Comparison Table
• Management of Drug Extravasations
• Moderate Sedation
• Patient Information for Disposal of Unused Medications
• Relative Infant Dose

Pharmacotherapy Pearls

Diastat AcuDial: When dispensing, consult package information for directions on setting patient's dose; confirm green "ready" band is visible prior to dispensing product.

FDA Approval Date

November 15, 1963

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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); D-Pam (NZ); 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); Propam (NZ); 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, OM, SA, SE, SY, TW, 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)

Last Updated 10/14/20