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Diazepam

Pronunciation

Pronunciation

(dye AZ e pam)

Dosage Forms

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

Concentrate, Oral:

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

Generic: 5 mg/mL (30 mL)

Gel, Rectal:

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

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

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

Solution, Injection:

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

Solution, Oral:

Generic: 1 mg/mL (5 mL [DSC], 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

Brand Names: U.S.

  • Diastat AcuDial
  • Diastat Pediatric
  • Diazepam Intensol
  • Valium

Pharmacologic Category

  • Benzodiazepine

Pharmacology

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.

Absorption

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

Rectal: Well absorbed

Distribution

Vd: 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

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.

Excretion

Urine (predominantly as glucuronide conjugates)

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

Time to Peak

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

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

Duration of Action

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

Status epilepticus: 15 to 30 minutes

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)

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)

Protein Binding

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

Rectal: 95% to 98%

Special Populations: Hepatic Function Impairment

The half-life is prolonged and clearance is decreased.

Special Populations: Elderly

The half-life is increased and clearance is decreased.

Special Populations: Children

The half-life is longer in infants; half-life is shorter in children ≥ 3 years.

Use: Labeled Indications

Acute ethanol withdrawal (oral and injection): May be useful in symptomatic relief of acute agitation, tremor, impending or acute delirium, tremens, and hallucinosis.

Anxiety (oral and injection): Management of anxiety disorders; short-term relief of the symptoms of anxiety.

Muscle spasm (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; tetanus.

Preoperative (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: 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); adjunct in severe recurrent convulsive seizures (injection).

Status epilepticus (injection): Adjunct in status epilepticus.

Use: Unlabeled

Panic disorders; short-term treatment of spasticity in children with cerebral palsy; sedation for mechanically-ventilated patients in the intensive care unit

Contraindications

Hypersensitivity to diazepam or any component of the formulation; acute narrow-angle glaucoma; untreated open-angle glaucoma; infants <6 months of age (oral); myasthenia gravis, severe respiratory impairment, severe hepatic impairment, sleep apnea syndrome (oral tablet).

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.

Dosing: Adult

Note: Oral absorption is more reliable than IM

Acute ethanol withdrawal:

IV, IM: 10 mg initially; may administer 5 to 10 mg 3 to 4 hours later, if needed

Oral: 10 mg 3 to 4 times during first 24 hours, then decrease to 5 mg 3 to 4 times daily as needed

Anxiety (symptoms/disorders):

Oral: 2 to 10 mg 2 to 4 times daily if needed

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

Muscle spasm:

Oral: 2 to 10 mg 3 or 4 times daily

IV, IM: Initial: 5 to 10 mg; then 5 to 10 mg in 3 to 4 hours, if necessary. Larger doses may be required if associated with tetanus.

Preoperative: Anxiety: IM: 10 mg prior to surgery

Sedation in the ICU patient: IV: Loading dose: 5 to 10 mg; Maintenance dose: 0.03 to 0.1 mg/kg every 30 minutes to 6 hours (Barr 2013)

Seizures:

Adjunctive maintenance therapy: Oral: 2 to 10 mg 2 to 4 times daily.

Intermittent management of seizures: Rectal gel (Diastat): 0.2 mg/kg; may be repeated in 4 to 12 hours if needed; do not use for more than 5 episodes per month or more than one episode every 5 days. Note: Round dose to the nearest 2.5 mg increment.

Status epilepticus:

IV:

Manufacturer's labeling: 5 to 10 mg; may repeat every 10 to 15 minutes (maximum total dose: 30 mg). If necessary, may repeat in 2 to 4 hours.

Neurocritical Care Society recommendations: 0.15 mg/kg (maximum dose: 10 mg) given at a rate of ≤5 mg/minute; may repeat in 5 minutes (NCS [Brophy 2012]).

Rectal (formulation not specified): Note: Diazepam may be administered rectally when there is no IV access and IM administration of midazolam (drug of choice for IM administration during status epilepticus) is contraindicated (NCS [Brophy 2012]). The parenteral formulation of diazepam may be given rectally if rectal gel (Diastat) is not available (Arif 2008).

Premonitory/Out-of-hospital treatment: 10 mg once; may repeat once if necessary (Kälviäinen 2007)

Skeletal muscle relaxant (adjunct therapy): Oral: 2 to 10 mg 3 to 4 times daily

Dosing: Geriatric

Oral absorption is more reliable than IM Elderly and/or debilitated patients:

Oral: 2 to 2.5 mg 1 to 2 times daily initially; increase gradually as needed and tolerated.

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

Dosing: Pediatric

Conscious sedation for procedures:

Oral:

Children: 0.2 to 0.3 mg/kg (maximum dose: 10 mg) 45 to 60 minutes prior to procedure

Adolescents: 10 mg

IV: Adolescents: 5 mg; may repeat with 2.5 mg if needed

Febrile seizure prophylaxis: Oral: Children: 1 mg/kg/day divided every 8 hours; initiate therapy at first sign of fever and continue for 24 hours after fever is gone

Muscle spasm associated with tetanus: IV, IM:

Infants >30 days and Children <5 years: 1 to 2 mg/dose every 3 to 4 hours as needed

Children ≥5 years: 5 to 10 mg/dose every 3 to 4 hours as needed

Sedation or muscle relaxation or anxiety:

Oral: Children: 0.12 to 0.8 mg/kg/day in divided doses every 6 to 8 hours

IM, IV: Children: 0.04 to 0.3 mg/kg/dose every 2 to 4 hours to a maximum of 0.6 mg/kg within an 8-hour period if needed

Seizures: Rectal gel (Diastat): Round dose to the nearest 2.5 mg increment; dose may be repeated in 4 to 12 hours if needed; do not use for more than 5 episodes per month or more than one episode every 5 days.

Children 2 to 5 years: 0.5 mg/kg (maximum dose: 20 mg)

Children 6 to 11 years: 0.3 mg/kg (maximum dose: 20 mg)

Children ≥12 years and Adolescents: 0.2 mg/kg (maximum dose: 20 mg)

Status epilepticus:

IV: American Academy of Pediatrics and Neurocritical Care Society recommendations: 0.1 to 0.3 mg/kg (maximum dose: 10 mg) given over ~2 minutes; may repeat dose after 5 to 10 minutes (AAP [Hegenbarth 2008]) or 0.15 mg/kg (maximum dose: 10 mg) given at a rate of ≤5 mg/minute; may repeat in 5 minutes (NCS [Brophy 2012])

Rectal (formulation not specified): Note: According to the Neurocritical Care Society, diazepam may be administered rectally when there is no IV access and IM administration of midazolam (drug of choice for IM administration during status epilepticus) is contraindicated (NCS [Brophy 2012]). The parenteral formulation of diazepam may be given rectally if rectal gel (Diastat) is not available (Arif 2008; Dieckmann 1994). Maximum recommended dose according to the manufacturer: 20 mg/dose

Children 2 to 5 years: 0.5 mg/kg

Children 6 to 11 years: 0.3 mg/kg

Children >12 years and Adolescents: 0.2 mg/kg

American Academy of Pediatrics recommendations (AAP [Hegenbarth 2008]): Initial: 0.5 mg/kg (maximum dose: 20 mg).

Spasticity in cerebral palsy (off-label use): Oral: Dose should be individualized:

Children ≤5 years: <8.5 kg: 0.5 to 1 mg at bedtime; 8.5 to 15 kg: 1 to 2 mg at bedtime (Mathew 2005)

Children 5 to 16 years: 1.25 mg 3 times daily to 5 mg 4 times daily (Engle 1966)

Dosing: Renal Impairment

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

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

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.

IV: Administer undiluted by slow IV push; do not mix with other solutions or medications. Rapid injection may cause respiratory depression or hypotension. In infants and children, do not exceed 1 to 2 mg/minute IV push; 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).

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 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; do not reuse; see manufacturer’s Administration and Disposal Instructions.

Compatibility

Per manufacturer, do not mix IV product with other solutions or drugs in syringe or infusion. Variable stability (consult detailed reference) in D5W, LR, NS, R.

Y-site administration: Incompatible with amphotericin B cholesteryl sulfate complex, atracurium, bivalirudin, cefepime, ceftaroline, dexmedetomidine, diltiazem, doripenem, fenoldopam, fluconazole, foscarnet, heparin, hetastarch in lactate electrolyte injection (Hextend), ketamine, linezolid, meropenem, oxaliplatin, pancuronium, pantoprazole, potassium chloride, propofol, tigecycline, tirofiban, vecuronium, vitamin B complex with C. Variable (consult detailed reference): Cisatracurium, dobutamine, hydromorphone, morphine, nafcillin, quinidine gluconate, sufentanil.

Compatibility in syringe: Incompatible with dimenhydrinate, doxapram, glycopyrrolate, heparin, hydromorphone, pantoprazole, sufentanil. Variable (consult detailed reference): Ketorolac, nalbuphine, ranitidine.

Storage

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

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).

Drug Interactions

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

Alfentanil: Diazepam may enhance the CNS depressant effect of Alfentanil. Hypotension may also occur. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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 patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

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

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Cosyntropin: May enhance the hepatotoxic effect of Diazepam. Monitor therapy

CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C19 Inhibitors (Moderate): May decrease the metabolism of CYP2C19 Substrates. Monitor therapy

CYP2C19 Inhibitors (Strong): May decrease the metabolism of CYP2C19 Substrates. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C19 Substrates. 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). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Disulfiram: May increase the serum concentration of Diazepam. 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. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. 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. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP2C19 Substrates. Conversely, concentrations of active metabolites may be increased for those drugs activated by CYP2C19. Management: Concurrent use of enzalutamide with CYP2C19 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C19 substrate should be performed with caution and close monitoring. Consider therapy modification

Etravirine: May decrease the serum concentration of Diazepam. Etravirine may increase the serum concentration of Diazepam. Monitor therapy

Fosamprenavir: May increase the serum concentration of Diazepam. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Hydrocodone: CNS Depressants may enhance the CNS depressant effect of Hydrocodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Luliconazole: May increase the serum concentration of CYP2C19 Substrates. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Methadone: Benzodiazepines may enhance the CNS depressant effect of Methadone. Avoid combination

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Metyrosine: CNS Depressants may enhance the sedative effect of Metyrosine. Monitor therapy

Mifepristone: May increase the serum concentration of CYP3A4 Substrates. 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. Consider therapy modification

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

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

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

Netupitant: May increase the serum concentration of CYP3A4 Substrates. 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. Avoid combination

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

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. 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. Consider therapy modification

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

Ritonavir: May increase the serum concentration of Diazepam. Monitor therapy

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

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

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

Saquinavir: May increase the serum concentration of Diazepam. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Oxybate: Benzodiazepines may enhance the CNS depressant effect of Sodium Oxybate. Avoid combination

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. 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. 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. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

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

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

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

Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. 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. Consider therapy modification

Test Interactions

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

Adverse Reactions

Frequency not defined. Adverse reactions may vary by route of administration.

Cardiovascular: Hypotension, localized phlebitis, vasodilatation

Central nervous system: Amnesia, ataxia, confusion, depression, drowsiness, dysarthria, fatigue, headache, slurred speech, vertigo

Dermatologic: Skin rash

Endocrine & metabolic: Change in libido

Gastrointestinal: Altered salivation (dry mouth or hypersalivation), constipation, diarrhea, nausea

Genitourinary: Urinary incontinence, urinary retention

Hepatic: Jaundice

Local: Pain at injection site

Neuromuscular & skeletal: Tremor, weakness

Ophthalmic: Blurred vision, diplopia

Respiratory: Apnea, asthma, bradypnea

Miscellaneous: Paradoxical reaction (eg, aggressiveness, agitation, anxiety, delusions, hallucinations, inappropriate behavior, increased muscle spasms, insomnia, irritability, psychoses, rage, restlessness, sleep disturbances, stimulation)

Warnings/Precautions

Concerns related to adverse effects:

• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia.

• 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, hallucinations, and psychoses, have been reported with benzodiazepines, particularly in pediatric or elderly patients. Discontinue if such reactions 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.

• Impaired gag reflex: Use benzodiazepines with caution in patients with an impaired gag reflex.

• 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:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Debilitated/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.

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

• 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]; 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.

Monitoring Parameters

Heart rate, respiratory rate, blood pressure, and mental status; liver enzymes and CBC with long-term therapy.

Critically-ill mechanically-ventilated patients: Monitor depth of sedation with either the Richmond Agitation-Sedation Scale (RASS) or Sedation-Agitation Scale (SAS) (Barr 2013)

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. In humans, 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).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), shortness of breath, change in balance, confusion, hallucinations, memory impairment, severe dizziness, passing out, severe loss of strength and energy, muscle spasms, twitching, insomnia, vision changes, or severe injection site redness, burning, pain or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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