diazepam (Rx)

Brand and Other Names:Valium, Diastat AcuDial, more...Valtoco
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

tablet: Schedule IV

  • 2mg
  • 5mg
  • 10mg

oral solution: Schedule IV

  • 1mg/1mL
  • 5mg/mL

rectal gel (Diastat Acudial): Schedule IV

  • 2.5mg/0.5mL
  • 10mg/2mL
  • 20mg/4mL

injectable solution: Schedule IV

  • 5mg/mL

intramuscular device: Schedule IV

  • 5mg/mL

intranasal spray (Valtoco): Schedule IV

  • 5mg/0.1mL
  • 7.5mg/0.1mL
  • 10mg/0.1mL

Anxiety

Indicated for management of anxiety disorders or for short-term relief of the symptoms of anxiety

2-10 mg PO q6-12hr, OR

2-5 mg IV/IM q3-4hr if necessary, for moderate anxiety disorders; 5-10 mg IV/IM q3-4hr for severe anxiety disorders

Alcohol Withdrawal

Aid in symptomatic relief of acute agitation, tremor, impending or acute delirium tremens, hallucinations

10 mg PO q6-8hr during first 24hr; reduce to 5 mg PO q6-8hr PRN OR

10 mg IV/IM, initially may give additional doses of 5-10 mg IV q6-8hr as needed

Endoscopic Precedures

Adjunct use, if apprehension, anxiety or acute stress reactions present prior to endoscopic procedures

≤10 mg adequate; may give up to 20 mg IV, particularly when concomitant narcotics omitted; if IV cannot be used, 5-10 mg IM approximately 30 min prior to procedure

Titrate IV dosage to desired sedative response, such as slurring of speech, with slow administration immediately prior to procedure

Dosage of narcotics should be reduced by at least a third and in some cases may be omitted

Preoperative Sedation

If atropine, scopolamine or other premedications desired, they must be administered in separate syringes

10 mg (IM preferred) before surgery

Sedation in the ICU

5-10 mg IV 1-2 hours before surgery; 0.03-0.1 mg/kg q30min to 6hr

Muscle Spasm

May be used adjunctively for relief of skeletal muscle spasm due to reflex spasm to local pathology (eg, inflammation of the muscles or joints, secondary to trauma); spasm associated with local pathology, cerebral palsy, athetosis, stiff-man syndrome, or tetanus

2-10 mg PO q6-8hr PRN, OR

5-10 mg, IV/IM initially, THEN 5-10 mg q3-3hr, if necessary; administer larger doses for tetanus

Seizure Disorder

Indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) distinct from a patient’s usual seizure pattern

Used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy

2-10 mg PO q6-12hr

Intranasal spray

  • 0.2 mg/kg intranasally as single dose
  • Adolescent or adult weight-based dosing
    • 14-27 kg: 5 mg (one 5-mg device); 1 spray in 1 nostril
    • 28-50 kg: 10 mg (one 10-mg device); 1 spray in 1 nostril
    • 51-75 kg: 15 mg (two 7.5-mg devices); 1 spray in each nostril
    • ≥76 kg: 20 mg (two 10-mg devices); 1 spray in each nostril
  • Second dose and maximum dose
    • Second dose: When required, may be administered after at least 4 hr after initial dose; if the second dose is administered, use a new blister pack of diazepam intranasal
    • Maximum dosage: Not to exceed 2 doses to treat a single episode
    • Treatment frequency: Do not use for more than 1 episode q5days and no more than 5 episodes/month

Diazepam gel (rectal)

  • 0.2 mg/kg PR or 10-20 mg as single dose
  • Rectal gel is measured in 2.5-mg increments from 2.5-20 mg/dose; calculate dose and round upward to next measurable dose
  • May prescribe second dose of diazepam rectal gel; when required, may be given 4-12 hr after first dose
  • Adolescent or adult weight-based dosing
    • 14-25 kg: 5 mg
    • 26-37 kg: 7.5 mg
    • 38-50 kg: 10 mg
    • 51-62 kg: 12.5 mg
    • 63-75 kg: 15 mg
    • 76-87 kg: 17.5 mg
    • 88-111 kg: 20 mg

Status Epilepticus

5-10 mg initially (IV preferred); injection may be repeated if necessary, at 10-15 minute intervals up to 30 mg maximum; may repeat in 2 to 4 hours if necessary; however, consider that residual active metabolites may persist

Use extreme caution in individuals with chronic lung disease or unstable cardiovascular status

Administer IV slowly; administer IM if IV administration impossible

OR

0.2-0.5 mg/kg PR; round up dose to nearest 2.5 mg increment; not to exceed 20 mg as single dose  

Cardioversion

5-15 mg IV within 5-10 min prior to procedure to relieve anxiety and tension and to reduce recall of procedure

Dosage Modifications

Renal impairment:

  • Oral: Data not available
  • No dose adjustment recommended unless administered for prolonged period; decrease dose in prolonged periods
  • Rectal gel: Not studied; use caution
  • Intranasal spray: Not studied

Hepatic impairment

  • Rectal gel: Not studied; use caution
  • Intranasal spray: Not studied
  • Prescribing information describes literature review showing diazepam 0.1-0.15 mg/kg IV had prolonged half-life by 2- to 5-fold in patients with alcoholic cirrhosis
  • Oral administration
    • Mild to moderate: Use with caution and consider dose adjustment; average half-life is increased in mild and moderate cirrhosis; average increase has been variously reported from 2-fold to 5-fold, with individual half-lives over 500 hr reported
    • Severe: Contraindicated

Dosing Considerations

Adjust dose periodically to reflect changes in patient’s age or weight

May use 2.5-mg dose as a partial replacement dose for patients who may expel a portion of first dose

Long-term (>4 months) effectiveness of diazepam has not been assessed by systematic clinical studies

Periodically reassess the efficacy for each patient

Once acute symptomatology has been properly controlled with diazepam injection, the patient may be placed on oral therapy if further treatment required

Discontinuation or dosage reduction

  • Use a gradual taper to discontinue diazepam tablets or reduce dosage to avoid withdrawal reactions
  • If any withdrawal reaction develops, consider pausing taper or increasing dose to previous tapered dosage level; subsequently decrease dose more slowly

Seizures (Orphan)

Intermittent use to control bouts of increased seizure activity or Dravet syndrome by various administrative routes

Orphan sponsors

  • SC: Xeris Pharmaceuticals, Inc, .3208 Red River Street, Suite 300, Austin, Texas 78705
  • Autoinjector: Meridian Medical Technologies, Inc., 6350 Stevens Forest Rd, Suite 301, Columbia, Maryland 21046

Dosage Forms & Strengths

tablet: Schedule IV

  • 2mg
  • 5mg
  • 10mg

oral solution: Schedule IV

  • 1mg/1mL
  • 5mg/mL

rectal gel (Diastsat Acudial): Schedule IV

  • 2.5mg/0.5mL
  • 10mg/2mL
  • 20mg/4mL

injectable solution: Schedule IV

  • 5mg/mL

intramuscular device: Schedule IV

  • 5mg/mL

intranasal spray (Valtoco): Schedule IV

  • 5mg/0.1mL
  • 7.5mg/0.1mL
  • 10mg/0.1mL

Sedative/Muscle Relaxant

Indicated for spasm associated with local pathology, cerebral palsy, and tetanus

<6 months: Not recommended

Potentially toxic dose in patients <6 years: >0.5 mg/kg

>6 years

  • 1-2.5 mg PO q6-8hr; increase gradually as needed and tolerated
  • 0.12-0.8 mg/kg/day PO divided q6-8hr, not to exceed 10 mg/dose OR  
  • 5-10 mg or 0.04-0.2 mg/kg IV/IM q3-4hr; no more than 0.6 mg/kg within 8 hours; respiratory assistance should be available

Seizure Disorder

Indicated for treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) distinct from a patient’s usual seizure pattern in patients with epilepsy aged ≥2 years (rectal gel) or ≥6 years (intranasal)

<2 years: Safety and efficacy not established

Diazepam gel (rectal)

  • Rectal gel is measured in 2.5-mg increments from 2.5-20 mg/dose; calculate dose and round upward to next measurable dose
  • May prescribe second dose of diazepam rectal gel; when required, may be given 4-12 hr after first dose
  • 2-6 years (0.5 mg/kg PR) weight-based dosing
    • 6-10 kg: 5 mg
    • 11-15 kg: 7.5 mg
    • 16-20 kg: 10 mg
    • 21-25 kg: 12.5 mg
    • 26-30 kg: 15 mg
    • 31-35 kg: 17.5 mg
    • 36-44 kg: 20 mg
  • 6-12 years (0.3 mg/kg PR) weight-based dosing
    • 10-16 kg: 5 mg
    • 17-25 kg: 7.5 mg
    • 26-33 kg: 10 mg
    • 34-41 kg: 12.5 mg
    • 42-50 kg: 15 mg
    • 51-58 kg: 17.5 mg
    • 59-74 kg: 20 mg
  • ≥12 years (0.2 mg/kg PR) weight-based dosing
    • 14-25 kg: 5 mg
    • 26-37 kg: 7.5 mg
    • 38-50 kg: 10 mg
    • 51-62 kg: 12.5 mg
    • 63-75 kg: 15 mg
    • 76-87 kg: 17.5 mg
    • 88-111 kg: 20 mg

Intranasal spray

  • <6 years: Safety and efficacy not established
  • Administer intranasally as a single dose
  • 6-11 years (0.3 mg/kg) weight-based dosing
    • 10-18 kg: 5 mg (one 5-mg device); 1 spray in 1 nostril
    • 19-37 kg: 10 mg (one 10-mg device); 1 spray in 1 nostril
    • 38-55 kg: 15 mg (two 7.5-mg devices); 1 spray in each nostril
    • 56-74 kg: 20 mg (two 10-mg devices); 1 spray in each nostril
  • ≥12 years (0.2 mg/kg) weight-based dosing
    • 14-27 kg: 5 mg (one 5-mg device); 1 spray in 1 nostril
    • 28-50 kg: 10 mg (one 10-mg device); 1 spray in 1 nostril
    • 51-75 kg: 15 mg (two 7.5-mg devices); 1 spray in each nostril
    • ≥76 kg: 20 mg (two 10-mg devices); 1 spray in each nostril
  • Second dose and maximum dose
    • Second dose: When required, may be administered after at least 4 hr after initial dose; if the second dose is administered, use a new blister pack of diazepam intranasal
    • Maximum dosage: Not to exceed 2 doses to treat a single episode
    • Treatment frequency: Do not use for more than 1 episode q5days and no more than 5 episodes/month

Status Epilepticus

Potentially toxic dose in patients <6 years: >0.5 mg/kg  

PR

  • 2-6 years: 0.5 mg/kg; may repeat in 4-12 hours PRN  
  • 6-12 years: 0.3 mg/kg; may repeat in 4-12 hours PRN
  • >12 years: 0.2 mg/kg; may repeat in 4-12 hours PRN

IV

  • >30 days – 5 years: 0.2-0.5 mg slowly q2-5 min up to 5 mg maximum (IV preferred); children ≥5 years, 1 mg q2-5 min up to a maximum of 10 mg (slow IV administration preferred); repeat in 2 to 4 hr if necessary; EEG monitoring of the seizure may be helpful
  • >5 years: 1 mg IV given slowly every 2-5 min; not to exceed 10 mg total dose; may repeat in 2-4 hours if necessary

Dosage Modifications

Renal impairment

Rectal gel: Not studied; use caution

Intranasal spray: Not studied

Oral: Data not available

Hepatic impairment

Rectal gel: Not studied; use caution

Intranasal spray: Not studied

Prescribing information describes literature review showing diazepam 0.1-0.15 mg/kg IV had prolonged half-life by 2- to 5-fold in patients with alcoholic cirrhosis

  • Oral administration
    • Mild to moderate: Use with caution; average half-life increased in mild and moderate cirrhosis; average increase has been reported from 2-fold to 5-fold, with individual half-lives over 500 hr
    • Severe: Contraindicated

Dosing Considerations

Long-term (>4 months) effectiveness of diazepam has not been assessed by systematic clinical studies

Periodically reassess the efficacy of each patient

Intranasal spray

  • Not approved for use in neonates or infants
  • Prolonged CNS depression observed with neonates treated with diazepam
  • Serious adverse reactions including fatal reactions and gasping syndrome occurred in premature neonates and low-birth-weight infants who received drugs containing benzyl alcohol as a preservative (diazepam intranasal contains benzyl alcohol 10.5 mg/0.1mL)

Reduce hazardous risks in children with slow IV dosing

  • Administer drug slowing to obtain maximal clinical effect with minimum dose, and thereby, reduced risk of hazardous side effects (eg, apnea, prolonged somnolence)
  • Administer slowly over 3-min period (not to exceed 0.25 mg/kg)
  • May repeat dose after 15-30 minutes
  • If symptom relief not obtained after 3rd administration, adjunctive therapy appropriate for the condition is recommended

Discontinuation or dosage reduction

  • Use a gradual taper to discontinue diazepam tablets or reduce dosage to avoid withdrawal reactions
  • If any withdrawal reaction develops, consider pausing taper or increasing dose to previous tapered dosage level; subsequently decrease dose more slowly

Dosing Considerations

Due to long-acting metabolite, not considered a drug of choice in the elderly; associated with falls

Rectal gel: Use lower dose

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Interactions

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            Adverse Effects

            1-10%

            Ataxia (3%)

            Somnolence (>1%)

            Rectal gel

            • Diarrhea (4%)
            • Rash (3%)
            • Incoordination (3%)
            • Euphoria (3%)
            • Dizziness (3%)
            • Asthma (2%l)

            Intranasal

            • Nasal discomfort (6%)
            • Nasal congestion (3%)
            • Epistaxis (3%)
            • Dysgeusia (2%)

            Frequency Not Defined

            Hypotension

            Fatigue

            Muscle weakness

            Respiratory depression

            Urinary retention

            Depression

            Incontinence

            Blurred vision

            Dysarthria

            Headache

            Skin rash

            Changes in salivation

            Drowsiness

            Venous thrombosis

            Confusion

            Hypoactivity

            Slurred speech

            Syncope

            Tremor

            Vertigo

            Constipation

            Nausea

            Changes in libido

            Bradycardia

            Cardiovascular collapse

            Diplopia

            Nystagmus

            Urticaria

            Paradoxical reactions, including acute hyperexcited states, anxiety, hallucinations, increased muscle spasticity, insomnia, rage, sleep disturbances and stimulation

            Peroral endoscopic procedures: Coughing, depressed respiration, dyspnea, hyperventilation, laryngospasm, and pain in throat or chest

            Serious

            • Neutropenia
            • Jaundice
            • Local effects: Pain, swelling, thrombophlebitis, carpal tunnel syndrome, tissue necrosis
            • Phlebitis if too rapid IV push

            Oral

            • Central nervous system: Confusion, depression, dysarthria, headache, slurred speech, tremor, vertigo
            • Gastrointestinal system: Constipation, nausea, gastrointestinal disturbances
            • Special senses: Blurred vision, diplopia, dizziness
            • Cardiovascular system: Hypotension
            • Psychiatric and paradoxical reactions: Stimulation, restlessness, acute hyperexcited states, anxiety, agitation, aggressiveness, irritability, rage, hallucinations, psychoses, delusions, increased muscle spasticity, insomnia, sleep disturbances, and nightmares. Inappropriate behavior and other adverse behavioral effects have been reported when using benzodiazepines.
            • Urogenital system: Incontinence, changes in libido, urinary retention
            • Skin and appendages: Skin reactions
            • Laboratories: Elevated transaminases and alkaline phosphatase
            • Other: Changes in salivation, including dry mouth, hypersalivation
            • Antegrade amnesia may occur using therapeutic dosages, the risk increasing at higher dosages; amnestic effects may be associated with inappropriate behavior
            • Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during and after diazepam therapy and are of no known significance
            • Because of isolated reports of neutropenia and jaundice, periodic blood counts and liver function tests are advisable during long-term therapy

            Postmarketing Reports

            Injury, poisoning, and procedural complications: Falls and fractures in benzodiazepine users; risk is increased in those taking concomitant sedatives (including alcohol), and in the elderly

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            Warnings

            Black Box Warnings

            Risks from concomitant use with opioids

            • Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death
            • Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate
            • Limit dosages and durations to the minimum required
            • Follow patients for signs and symptoms of respiratory depression and sedation
            • Inform patients and caregivers that potentially fatal additive effects may occur if diazepam is used with opioids and that such drugs should not be used concomitantly unless supervised by a health care provider
            • Prescribers are strongly advised to take all reasonable steps to ensure that caregivers fully understand their role and obligations vis a vis the administration of diazepam rectal gel to individuals in their care
            • Prescribers should advise caregivers that they expect to be informed immediately if a patient develops any new findings which are not typical of the patient’s characteristic seizure episode

            Addiction, abuse, and misuse

            • On September 2020, FDA addressed serious risks of benzodiazepine addiction, abuse, and misuse, which can lead to overdose and death
            • Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes; before prescribing and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction
            • Physical dependence can occur when taken steadily for several days to weeks, even as prescribed
            • Risks of dependence and withdrawal increase with longer treatment duration and higher daily dose; although injection is indicated only for intermittent use, if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction may precipitate acute
            • withdrawal reactions, including seizures, which can be life-threatening; use gradual taper when discontinuing therapy to reduce withdrawal reactions risk
            • Assess each patient’s risk prior to prescribing and monitor regularly for the development of these conditions

            Contraindications

            Documented hypersensitivity

            Acute narrow-angle glaucoma and open-angle glaucoma unless patients receiving appropriate therapy

            Cautions

            Efficacy and safety of parenteral diazepam has not been established in neonate (30 days or less of age); prolonged central nervous system depression has been observed in neonates, apparently due to inability to biotransform diazepam into inactive metabolites; benzyl alcohol has been reported to be associated with a fatal gasping syndrome in premature infants

            Not recommended for chronic, daily use as an anticonvulsant because of potential for development of tolerance to diazepam; chronic daily use of diazepam may increase frequency and/or severity of tonic-clonic seizures, requiring an increase in dosage of standard anticonvulsant medication; in such cases, abrupt withdrawal of chronic diazepam may also be associated with a temporary increase in the frequency and/or severity of seizures

            Concomitant use of benzodiazepines, including diazepam, and opioids may result in profound sedation, respiratory depression, coma, and death; reserve concomitant prescribing of benzodiazepines and opioids for use in patients for whom alternative treatment options are inadequate; reduce opiate dose one-third when diazepam is added

            Advise both patients and caregivers about risks of respiratory depression and sedation when diazepam is used with opioids; advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined

            Use caution in COPD, sleep apnea, renal/hepatic disease, open-angle glaucoma (questionable), depression, suicide ideation, impaired gag reflex, history of drug abuse, or obese patients (prolonged action when discontinued)

            Use of benzodiazepines, including diazepam, both used alone and in combination with other CNS depressants, may lead to potentially fatal respiratory depression

            May impair ability to perform hazardous tasks

            For patients using treated more frequently than recommended, to reduce risk of withdrawal reactions, use a gradual taper to discontinue therapy (a patient-specific plan should be used to taper the dose)

            Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use

            In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months

            Anterograde amnesia reported with benzodiazepine use

            Avoid extravasation with IV dosing

            Paradoxical reactions may occur including hallucinations, aggressive behavior, and psychoses; dinscontinue use if reactions occur

            Risk of abuse, misuse, and addiction

            • Use with caution in patients with a history of drug abuse or acute alcoholism; tolerance, psychological, and physical dependence may occur with prolonged use (>10 days)
            • Benzodiazepines may increase risks of abuse, misuse, and addiction, which can lead to overdose or death
            • Abuse and misuse of benzodiazepines often (but not always) involve use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death
            • Avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (eg, opioid analgesics, stimulants); advise patients on proper disposal of unused drug; if a substance use disorder is suspected, evaluate patient and institute (or refer them for) early treatment, as appropriate
            • Counsel about risks and proper use along with monitoring for signs and symptoms of abuse, misuse, and addiction, particularly in patients at elevated risk of abuse; do not exceed recommended dosing frequency

            Propylene glycol toxicity

            • Propylene glycol toxicity reported in patients treated with diazepam injection at doses significantly greater than recommended when it was being used to treat alcohol withdrawal symptoms at doses >900 mg/day
            • Propylene glycol toxicity is associated with an anion gap metabolic acidosis, serum hyperosmolality, and increased lactate
            • Can cause acute tubular necrosis (which can progress to multiorgan failure), mental status changes, hypotension, seizures, and cardiac arrhythmias
            • Patients at high risk for propylene glycol toxicity include those with renal dysfunction, hepatic dysfunction, impaired alcohol dehydrogenase enzymes, or other comorbidities (eg, history of alcoholism)

            Drug interactions overview

            • Substrate of CYP2C19 and CYP3A4
            • Opioids
              • Limit dosage and duration if concomitantly used; monitor closely for respiratory depression and sedation
              • Coadministration of benzodiazepines and opioids increases risk of respiratory depression
            • CNS depressants or alcohol
              • Coadministration of other CNS depressants or alcohol consumption may potentiate CNS-depressant effects of diazepam
            • CYP2C19 or CYP3A4 inhibitors
              • May decrease rate of diazepam elimination, thereby increasing adverse reactions to diazepam
            • CYP2C19 or CYP3A4 inducers
              • May increase rate of diazepam elimination; therefore, efficacy of diazepam may be decreased
            • CYP2C19 or CYP3A4 substrates
              • Diazepam may interfere with metabolism of substrates for CYP2C19 and CYP3A4 leading to a potential drug-drug interaction
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            Pregnancy & Lactation

            Pregnancy

            There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as diazepam injection, during pregnancy; healthcare providers are encouraged to recommend that pregnant patient receiving therapy enroll in North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888- 233-2334 or online at http://www.aedpregnancyregistry.org/

            Infants born to mothers using benzodiazepines late in pregnancy reported to experience symptoms of sedation and/or neonatal withdrawal

            Advise pregnant females that use of this medication late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns

            Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects

            Neonatal withdrawal and floppy infant syndrome

            • Neonatal withdrawal syndrome and symptoms suggestive of floppy infant syndrome associated with administration of benzodiazepines during the later stages of pregnancy and peripartum period have been reported
            • Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates; monitor neonates exposed to therapy during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems; monitor neonates exposed to therapy during pregnancy for signs of withdrawal; manage these neonates accordingly

            Animal data

            • Produced increased incidences of fetal malformations in mice and hamsters when given orally at single doses ≥100 mg/kg (approximately 20 times maximum recommended adult dose [0.4 mg/kg/day] or greater on mg/m2 basis)
            • Cleft palate and exencephaly are the most common and consistently reported malformations produced in these species by administration of high, maternally-toxic doses of diazepam during organogenesis
            • Administration of benzodiazepines or other drugs that enhance GABAergic inhibition to neonatal rats has been reported to result in widespread apoptotic neurodegeneration in the developing brain at plasma concentrations relevant for seizure control in humans
            • The window of vulnerability to these changes in rats (postnatal days 0-14) includes a period of brain development that takes place during the third trimester of pregnancy in humans

            Lactation

            Present in breastmilk

            Because diazepam and its metabolites may be present in human breast milk for prolonged periods of time after acute use, patients should be advised not to breastfeed for an appropriate period of time after receiving treatment

            There are no data specifically for diazepam intranasal

            Reports of sedation, poor feeding and poor weight gain in infants exposed to diazepam through breast milk; there are no data on effects of diazepam on milk production

            Instruct patients to inform their healthcare provider if they are breastfeeding or plan to breastfeed; instruct breastfeeding patients to monitor their infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs

            Consider developmental and health benefits of breastfeeding along with the mother's clinical need for therapy and any potential adverse effects on breastfed infant therapy or from the underlying maternal condition

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Although precise mechanism in antiseizure effects is unknown, animal and in vitro studies suggest that it acts to suppress seizures through interaction with γ-aminobutyric acid (GABA) receptors of the A-type (GABAA ); GABA, the major inhibitory neurotransmitter in central nervous system (CNS), acts at this receptor to open membrane channel allowing chloride ions to flow into neurons; entry of chloride ions causes an inhibitory potential that reduces ability of neurons to depolarize to threshold potential necessary to produce action potentials; excessive depolarization of neurons is implicated in the generation and spread of seizures; it is believed that diazepam enhances the actions of GABA by causing GABA to bind more tightly to the GABAA receptor.

            Absorption

            Bioavailability: 90% (PR); 97% (intranasal)

            Duration: Variable, dependent on dose and frequency (PO [hypnotic action]); 15-60 min (IV [sedative action])

            Peak plasma time: 1-1.5 hr (PO), 5-90 min (PR); 1.5 hr (intranasal)

            Peak plasma concentration: 373 ng/mL (initial at 45 min); 447 ng/mL (second peak at 70 min)

            Effect of food (Oral)

            • With presence of food: Increased peak plasma time by 1.25 hr; average decrease in Cmax of 20% and 27% decreased in AUC

            Distribution

            Protein bound: 98% (PO); 95-98% (intranasal)

            Vd (steady state): 0.8-1 L/kg

            Metabolism

            Metabolized by hepatic P450 enzymes CYP2C19, CYP3A4

            Metabolites: N-desmethyldiazepam, 3-hydroxdiazepam, oxazepam

            Active metabolites: N-desmethyldiazepam and temazepam, which are both further metabolized to oxazepam; largely eliminated by glucuronidation

            Elimination

            Half-life

            • 20-70 hr (active metabolite); 49.2 hr (10-mg intranasal dose)
            • N-desmethyldiazepam: Up to 100 hr

            Renal clearance: 20-30 mL/min

            Excretion: Urine

            Pharmacogenomics

            Clearance: 20-30 mL/min (young adults)

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            Administration

            IV Incompatibilities

            Solution: D5W(?), Ringer's(?), LR(?), NS(?) (See IV Preparation)

            Additive: Bleomycin, dobutamine, doxorubicin, floxacillin, fluorouracil, furosemide

            Syringe: Doxapram, glycopyrrolate, heparin, hydromorphone, ketorolac(?), nalbuphine(?), ranitidine(?), sufentanil

            Y-site: Amphotericin B cholesteryl SO4, atracurium, bivalirudin, cefepime, dexmedetomidine, diltiazem, fenoldopam, fluconazole, foscarnet, gatifloxacin, heparin, heparin/hydrocortisone, Hextend, hydromorphone, linezolid, meropenem, pancuronium, KCl, propofol, remifentanil(?), tirofiban, vecuronium, vitamin B/C

            Not specified: Atropine, epinephrine, hydroxyzine, lidocaine, meperidine, morphine, norepinephrine, pentobarbital, Na bicarbonate

            IV Compatibilities

            Additive: Netilmicin, verapamil

            Syringe: Cimetidine

            Y-site: Cisatracurium (may be incompatible at higher concentration), dobutamine, fentanyl, hydromorphone (may be incompatible at higher concentration), methadone, morphine sulfate, nafcillin, quinidine, remifentanil (may be incompatible at higher concentration), sufentanil

            Not specified: Aminophylline, cefazolin

            IV Preparation

            Compatibility with D5W, NS, and Ringer's controversial. If infusion is selected, adding the infusion solution to the diazepam injection (and not the other way around) may prevent precipitate formation

            IV Administration

            Administer over 3 min; no more than 5 mg/min

            Monitor respiration q5-15min and before each IV dose

            Have airway support ready until effects of IV administration are known

            Thrombosis prevention

            • Administer directly into a large vein to avoid thrombosis
            • If this is not feasible, give drug into tubing of a flowing IV solution as close as possible to vein insertion
            • Do not use small veins such as those of wrist or dorsum of hand

            IM Administration

            Inject deeply into the muscle

            Oral Administration

            Dilute oral concentrate with water/juice/carbonated beverages or mix with semisolid foods

            Take tablets as prescribed

            Advise patients to avoid driving or operating heavy machinery until patient is aware of the effects of the drug

            Oral solution: Dilute oral concentrate with water/juice/carbonated beverages or mix with semisolid foods

            Rectal Administration

            Place patient on side facing you with upper leg bent forward, lubricate rectal applicator tip, gently insert syringe tip in rectum and slowly push plunger

            Rectal gel should not be used more than 5 episodes/month and no more than one episode q5days

            Intranasal Administration

            For intranasal use only

            No device assembly required; ready-to-use nasal spray device; do not open individual blister packs or test nasal spray devices before use

            Do not use if nasal spray unit appears damaged

            Each single-dose nasal spray device sprays 1 time and cannot be reused

            Nasal spray delivers its entire contents upon activation

            Before use, instruct individual administering diazepam intranasal on how to identify seizure clusters and how to appropriately administer the product

            Prescribing the drug

            • A decision to prescribe diazepam rectal gel involves more than the diagnosis and selection of correct dose
            • The prescriber must be convinced from historical reports and/or personal observations that the patient exhibits identifiable characteristics of seizure cluster that can be distinguished from the patient’s usual seizure activity by the caregiver who will be responsible for administering diazepam rectal gel
            • As diazepam rectal gel is only intended for adjunctive use, the prescriber must ensure that the patient is receiving an optimal regimen of standard anti-epileptic drug treatment and is, nevertheless, continuing to experience these characteristic episodes
            • Since a non-health professional will be obliged to identify episodes suitable for treatment, make the decision to administer treatment upon that identification, administer the drug, monitor the patient, and assess the adequacy of the response to treatment; a major component of the prescribing process involves the necessary instruction of this individual
            • The prescriber and caregiver must have a common understanding of what is and is not an episode of seizures that is appropriate for treatment, the timing of administration in relation to the onset of the episode, the mechanics of administering the drug, how and what to observe following administration, and what would constitute an outcome requiring immediate and direct medical attention

            Storage

            Tablets

            • Store in tightly closed container between 68-77ºF (20-25ºC) and out of the light
            • Keep diazepam tablets and all medicines out of reach of children

            Injection solution

            • Store at 20-25ºC (68-77ºF); protect from light

            Rectal gel

            • Store at 25ºC (77ºF)

            Intranasal spray

            • Store at 20-25ºC (68-77ºF); excursions permitted from 15-30ºC (59-86ºF)
            • Do not freeze
            • Protect from light
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            Images

            BRAND FORM. UNIT PRICE PILL IMAGE
            diazepam injection
            -
            5 mg/mL solution
            diazepam injection
            -
            5 mg/mL solution
            diazepam injection
            -
            5 mg/mL vial
            diazepam injection
            -
            5 mg/mL solution
            diazepam injection
            -
            5 mg/mL solution
            diazepam injection
            -
            5 mg/mL solution
            diazepam oral
            -
            10 mg tablet
            diazepam oral
            -
            5 mg tablet
            diazepam oral
            -
            10 mg tablet
            diazepam oral
            -
            10 mg tablet
            diazepam oral
            -
            5 mg tablet
            diazepam oral
            -
            2 mg tablet
            diazepam oral
            -
            5 mg tablet
            diazepam oral
            -
            10 mg tablet
            diazepam oral
            -
            10 mg tablet
            diazepam oral
            -
            5 mg tablet
            diazepam oral
            -
            5 mg tablet
            diazepam oral
            -
            2 mg tablet
            diazepam oral
            -
            2 mg tablet
            diazepam oral
            -
            2 mg tablet
            diazepam oral
            -
            5 mg/mL liquid
            diazepam oral
            -
            2 mg tablet
            diazepam oral
            -
            5 mg/5 mL (1 mg/mL) solution
            Diazepam Intensol oral
            -
            5 mg/mL liquid
            Valium oral
            -
            5 mg tablet
            Valium oral
            -
            10 mg tablet
            Valium oral
            -
            2 mg tablet
            Diastat rectal
            -
            2.5 mg kit
            diazepam rectal
            -
            12.5-15-17.5-20 mg kit
            diazepam rectal
            -
            5-7.5-10 mg kit
            Diastat AcuDial rectal
            -
            12.5-15-17.5-20 mg kit
            Diastat AcuDial rectal
            -
            5-7.5-10 mg kit

            Copyright © 2010 First DataBank, Inc.

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            Patient Handout

            Select a drug:
            Patient Education
            diazepam oral

            DIAZEPAM - ORAL

            (dye-AZ-e-pam)

            COMMON BRAND NAME(S): Valium

            WARNING: Diazepam has a risk for abuse and addiction, which can lead to overdose and death. Taking this medication with alcohol or other drugs that can cause drowsiness or breathing problems (especially opioid medications such as codeine, hydrocodone) may cause very serious side effects, including death. To lower your risk, your doctor should have you take the smallest dose of diazepam that works, and take it for the shortest possible time. Be sure you know how to take diazepam and what other drugs you should avoid taking with it. See also Drug Interactions section. Get medical help right away if any of these very serious side effects occur: slow/shallow breathing, unusual lightheadedness, severe drowsiness/dizziness, difficulty waking up.Suddenly stopping this medication may cause serious (possibly fatal) withdrawal, especially if you have used it for a long time or in high doses. To prevent withdrawal, your doctor may lower your dose slowly. Tell your doctor or pharmacist right away if you have any withdrawal symptoms such as headaches, trouble sleeping, restlessness, hallucinations/confusion, depression, nausea, or seizures. Withdrawal symptoms may sometimes last weeks to months.

            USES: Diazepam is used to treat anxiety, alcohol withdrawal, and seizures. It is also used to relieve muscle spasms and to provide sedation before medical procedures. This medication works by calming the brain and nerves. Diazepam belongs to a class of drugs known as benzodiazepines.

            HOW TO USE: See also Warning section.Read the Medication Guide provided by your pharmacist before you start taking diazepam and each time you get a refill. If you have any questions, ask your doctor or pharmacist.Take this medication by mouth with or without food as directed by your doctor. If you are using the liquid form of this medication, carefully measure the dose using a special measuring device/spoon. Do not use a household spoon because you may not get the correct dose.If you are using the concentrated solution, use the medicine dropper provided and mix the measured dose with a small amount of liquid or soft food (such as applesauce, pudding). Take all of the mixture right away. Do not store the mixture for later use.The dosage is based on your medical condition, age, and response to treatment. Do not increase your dose or use this drug more often or for longer than prescribed. Your condition will not improve any faster, and your risk of side effects will increase. Properly stop the medication when so directed.When this medication is used for a long time, it may not work as well. Talk with your doctor if this medication stops working well.Though it helps many people, this medication may sometimes cause addiction. This risk may be higher if you have a substance use disorder (such as overuse of or addiction to drugs/alcohol). Take this medication exactly as prescribed to lower the risk of addiction. Ask your doctor or pharmacist for more details.Avoid eating grapefruit or drinking grapefruit juice while using this medication unless your doctor or pharmacist says you may do so safely. Grapefruit can increase the chance of side effects with this medicine. Ask your doctor or pharmacist for more details.If directed by your doctor, take this medication regularly to get the most benefit from it. To help you remember, take it at the same time(s) each day.Tell your doctor if your condition lasts or gets worse.

            SIDE EFFECTS: See also Warning section.Drowsiness, dizziness, tiredness, blurred vision, or unsteadiness may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly.Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.Tell your doctor right away if you have any serious side effects, including: mental/mood changes (such as memory problems, agitation, hallucinations, confusion, restlessness, depression), trouble speaking, trouble walking, muscle weakness, shaking (tremors), trouble urinating, yellowing eyes/skin, signs of infection (such as sore throat that doesn't go away, fever, chills).Get medical help right away if you have any very serious side effects, including: slow/shallow breathing.A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

            PRECAUTIONS: Before taking diazepam, tell your doctor or pharmacist if you are allergic to it; or to other benzodiazepines (such as oxazepam, temazepam); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your doctor or pharmacist your medical history, especially of: a certain muscle disease (myasthenia gravis), lung/breathing problems (such as COPD, sleep apnea), mental/mood disorders (such as depression, thoughts of suicide, psychosis), personal or family history of a substance use disorder (such as overuse of or addiction to drugs/alcohol), glaucoma, liver disease, kidney disease.This drug may make you dizzy or drowsy or blur your vision. Alcohol or marijuana (cannabis) can make you more dizzy or drowsy. Do not drive, use machinery, or do anything that needs alertness or clear vision until you can do it safely. Avoid alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).Some liquid products may contain alcohol. Ask your doctor or pharmacist about using this product safely.Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).For some children, instead of having a calming effect, diazepam may have the opposite effect, causing mental/mood changes (such as agitation, hallucinations, restlessness).Older adults may be more sensitive to the side effects of this drug, especially drowsiness and loss of coordination. These side effects can increase the risk of falling. For some older adults, instead of having a calming effect, diazepam may have the opposite effect, causing mental/mood changes (such as agitation, hallucinations, restlessness).Tell your doctor if you are pregnant or plan to become pregnant. You should not become pregnant while using diazepam. Diazepam may harm an unborn baby. If you become pregnant or think you may be pregnant, talk to your doctor right away about the risks and benefits of this medication. Consult your doctor for more details.This drug passes into breast milk and may have undesirable effects on a nursing infant. Breast-feeding while using this medication is not recommended. Consult your doctor before breast-feeding.

            DRUG INTERACTIONS: See also Warning and How to Use sections.Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.Some products that may interact with this drug include: clozapine, fluvoxamine, orlistat, sodium oxybate.The risk of serious side effects (such as slow/shallow breathing, severe drowsiness/dizziness) may be increased if this medication is taken with other products that may also cause drowsiness or breathing problems. Tell your doctor or pharmacist if you are taking other products such as opioid pain or cough relievers (such as codeine, hydrocodone), alcohol, marijuana (cannabis), other drugs for sleep or anxiety (such as alprazolam, lorazepam, zolpidem), muscle relaxants (such as carisoprodol, cyclobenzaprine), or antihistamines (such as cetirizine, diphenhydramine).Check the labels on all your medicines (such as allergy or cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about using those products safely.This medication may interfere with certain lab tests, possibly causing false test results. Make sure lab personnel and all your doctors know you use this drug.

            OVERDOSE: If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe drowsiness, slow reflexes, slow/shallow breathing, fainting, loss of consciousness.

            NOTES: Do not share this medication with others. Sharing it is against the law.If this drug is used for a long period of time, lab and/or medical tests (such as liver function tests, complete blood count) may be done while you are taking this medication. Keep all medical and lab appointments.

            MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.

            STORAGE: Store at room temperature away from light and moisture. Do not store in the bathroom. If you are using the concentrated solution, discard the opened bottle after 90 days. Keep all medications away from children and pets.Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

            MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-888-633-4298 (US) or 1-800-668-1507 (Canada).

            Information last revised February 2022. Copyright(c) 2022 First Databank, Inc.

            IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.