diazepam intranasal (Rx)

Adverse effects reported in prescribing information based on data from diazepam rectal gel unless otherwise specified

>10%

Somnolence (23%)

1-10%

Headache (5%)

Diarrhea (4%)

Ataxia (3%)

Dizziness (3%)

Euphoria (3%)

Incoordination (3%)

Rash (3%)

Asthma (2%)

Vasodilation (2%)

Asthenia (≥1%)

Hypotension, vasodilatation (≥1%)

Agitation, confusion, convulsion, dysarthria, emotional lability, speech disorder, thinking abnormal, vertigo (≥1%)

Hiccup (≥1%)

Diazepam intranasal

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

Frequency Not Defined

The following infrequent adverse events have been reported previously with diazepam use: Depression, slurred speech, syncope, changes in libido, urinary retention, bradycardia, cardiovascular collapse, nystagmus, urticaria, neutropenia, and jaundice

Paradoxical reactions such as acute hyperexcited states, anxiety, hallucinations, increased muscle spasticity, insomnia, rage, sleep disturbances, and stimulation have been reported with other diazepam products

Contraindications

Hypersensitivity

Acute narrow-angle glaucoma

Cautions

Benzodiazepines expose users to 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

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death; because of these risks, reserve concomitant prescribing of benzodiazepines and opioids for use in patients for whom alternative treatment options are inadequate

Use of drug, particularly in patients at elevated risk of abuse, necessitates counseling about risks and proper use of drug along with monitoring for signs and symptoms of abuse, misuse, and addiction; do not exceed recommended dosing frequency

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

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

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

May produce CNS depression; caution patients against engaging in hazardous activities requiring mental alertness until effects of the drug, such as drowsiness, have subsided, and as their medical condition permits

Caution in patients with compromised respiratory function related to a concurrent disease process (eg, asthma, pneumonia) or neurologic damage

Antiepileptic drugs (AEDs) increase risk of suicidal thoughts or behavior in patients taking these drugs for any indication; monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior

Benzodiazepines can increase intraocular pressure in patients with glaucoma; may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy; diazepam is contraindicated in patients with narrow-angle glaucoma

Not approved for use in neonates or infants; diazepam intranasal contains benzyl alcohol, which can cause serious and fatal adverse reactions, including gasping syndrome, in neonates and low-birth-weight infants

Drug interaction overview

• Diazepam is a CYP2C19 and CYP3A4 substrate
• Coadministration of benzodiazepines and opioids increases risk of respiratory depression; limit dosage and duration if concomitantly used; monitor closely for respiratory depression and sedation
• 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

Pregnancy

North American Antiepileptic Drug (NAAED) Pregnancy Registry: 1-888-233-2334; http://www.aedpregnancyregistry.org

There are no adequate data on the use of diazepam intranasal in pregnant women

Available data suggest that the class of benzodiazepines is not associated with marked increases in risk for congenital anomalies

Although some early epidemiological studies suggested a relationship between benzodiazepine use in pregnancy and congenital anomalies such as cleft lip and or palate, these studies had considerable limitations

More recently completed studies of benzodiazepine use in pregnancy have not consistently documented elevated risks for specific congenital anomalies

There is insufficient evidence to assess the effect of benzodiazepine pregnancy exposure on neurodevelopment

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

Animal data

• Increased incidences of fetal malformations in mice and hamsters when given PO at single doses of ≥100 mg/kg or greater (∼13 times the maximum recommended human dose [MRHD = 0.6mg/kg/day] or greater on a 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

Lactation

Diazepam is excreted in human milk

There are no data specifically for diazepam intranasal

Postmarketing experience suggests that breastfed infants of mothers taking benzodiazepines may have effects of lethargy, somnolence, and poor sucking

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.

Mechanism of Action

The exact mechanism of action for diazepam is not fully understood, but it is thought to involve potentiation of gamma aminobutyric acid (GABA) neurotransmission resulting from binding at the benzodiazepine site of the GABA-A receptor

Absorption

Peak plasma concentration: 1.5 hr

Absolute bioavailability: 97%

Distribution

Protein bound: 95-98% (including active desmethyldiazepam metabolite)

Vd: 0.8-1 L/kg

Metabolism

Metabolism of diazepam is primarily hepatic and involves demethylation (primarily by CYP2C19 and CYP3A4) and 3-hydroxylation (primarily by CYP3A4), followed by glucuronidation

Elimination

Half-life: 49.2 hr (10-mg intranasal dose)

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

Storage

Store at 20-25ºC (68-77ºF); excursions permitted from 15-30ºC (59-86ºF)

Do not freeze

Protect from light