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.

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

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

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.

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.

1 week to 5 months

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

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.