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 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. 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) 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