Dosage guidance:
Safety: Reduce dose or avoid use in patients receiving opioids. Avoid use in patients with a history of substance use, misuse of medications, or depression (Ref).
Insomnia, sleep onset or sleep maintenance (alternative agent):
Note: Due to risk of next day impairment, dependence, and habituation, benzodiazepines should be reserved for patients in whom alternative, safer therapies for insomnia have failed (Ref). When used, limit long-term use (>4 weeks) to cases for which nonpharmacologic treatments are not available or not effective and benefits are felt to outweigh risks (Ref).
Oral: Initial: 5 to 10 mg once daily at bedtime, as needed.
Discontinuation of therapy: Reduce by 25% of the original dose every 1 to 2 weeks until lowest available dose is reached, then discontinue. Patients on long-term therapy or in whom discontinuation has previously failed may benefit from a slower taper in conjunction with cognitive behavioral therapy for insomnia (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.
Mild-to-moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.
Severe impairment: Use is contraindicated.
Insomnia: Elderly or debilitated patients: Note: Avoid use (Ref). Oral: Initial: 2.5 mg once daily, as needed, at bedtime; may increase dose to 5 mg at bedtime if tolerated (maximum dose: 5 mg/day).
Myoclonic seizures: Infants and Children ≤30 kg: Oral: Usual dosage: 0.3 to 1 mg/kg/day in 3 equally divided doses; if doses are not divided equally, administer larger dose at bedtime. Note: Therapy should be initiated below the usual dosage range and titrated carefully based on response. If inadequate response to usual dosage, may gradually increase dose further. Manufacturer labeling does not specify a maximum dosage.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.
Mild-to-moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.
Severe impairment: Use is contraindicated.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Postmarketing:
Cardiovascular: Hypotension, palpitations
Dermatologic: Dermatological reaction
Endocrine & metabolic: Change in libido
Gastrointestinal: Constipation, diarrhea, dyspepsia, heartburn, nausea, sialorrhea (Jan 1971), vomiting
Hematologic & oncologic: Granulocytopenia, leukopenia
Hepatic: Abnormal hepatic function tests
Hypersensitivity: Anaphylaxis, angioedema
Nervous system: Abnormal dreams (depressed dreaming), abnormality in thinking, aggressive behavior, amnesia (including anterograde amnesia), apprehension, asthenia, ataxia (Jan 1971), behavioral changes (including disinhibition, inappropriate behavior), complex sleep-related disorder (including sleep driving), confusion, depersonalization, depression, disorientation, dizziness, drowsiness (Jan 1971), drug abuse, drug dependence (Clift 1972), emotional lability, falling, fatigue, hallucination, hangover effect (Charles 1987), headache, hypothermia (Impallomeni 1976), lethargy, nervousness, nightmares (Girwood 1973), paresthesia (MacLean 1973), sedated state, staggering, suicidal ideation, suicidal tendencies, withdrawal syndrome (including catatonia, delirium, muscle rigidity, rebound anxiety, rebound insomnia, tremor) (Adam 1976; Mackinnon 1982)
Ophthalmic: Blurred vision
Respiratory: Dyspnea, increased bronchial secretions (Jan 1971)
Miscellaneous: Paradoxical reaction (Nassr 1986)
Hypersensitivity to nitrazepam, benzodiazepines, or any component of the formulation; myasthenia gravis; severe respiratory insufficiency (eg, significant sleep apnea syndrome); severe hepatic insufficiency; use as hypnotic in children
Concerns related to adverse effects:
• Anaphylaxis/anaphylactoid reactions: Have been reported with use (rare); patients who develop angioedema should not be rechallenged with nitrazepam.
• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia (Nelson 1999). May also rarely induce transient global amnesia or traveler's amnesia (if taken to induce sleep while traveling); caution patients to ensure they have uninterrupted sleep of 7 to 8 hours after ingestion of dose.
• Aspiration pneumonia: Bronchial hypersecretion and excessive salivation/drooling leading to aspiration pneumonia in young and elderly patients may occur rarely.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines; risk may be increased in adolescent/pediatric patients, geriatric patients, or patients with a history of alcohol use disorder or psychiatric/personality disorders (Mancuso 2004).
• Rebound insomnia: Following withdrawal of therapy, transient insomnia may recur accompanied by other reactions including restlessness, anxiety, and mood changes.
• Sleep-related activities: Hazardous sleep-related activities such as sleep-driving, cooking and eating food, and making phone calls while asleep have been noted with benzodiazepines (Dolder 2008).
Disease-related concerns:
• Depression: Avoid use in patients with depression because of concerns about worsening mood symptoms, particularly if suicidal risk may be present, except for acute or emergency situations (eg, acute agitation, status epilepticus) (Craske 2022).
• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.
• Hepatic impairment: Use with caution in patients with hepatic impairment (contraindicated in severe hepatic impairment).
• Renal impairment: Use with caution in patients with renal impairment.
• Respiratory disease: Reduce dose or avoid use in patients with respiratory disease, including chronic obstructive pulmonary disease or sleep apnea. Benzodiazepines may cause significant respiratory depression. Use is contraindicated in severe respiratory insufficiency.
• Sleep apnea: Benzodiazepines can suppress respiratory drive in patients with obstructive sleep apnea; use caution when prescribing for insomnia in this population (Webster 2020). Nitrazepam is contraindicated in cases of clinically significant sleep apnea.
Special populations:
• Debilitated patients: Use with caution in debilitated patients
• Older adult: Use with caution in older adults. Older adult patients may be at an increased risk of death with use; risk has been found highest within the first 4 months of use in older adult dementia patients (Jennum 2015; Saarelainen 2018).
• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury (Nelson 1999).
• Pediatric: Associated with sudden death in children <5 years of age being treated for seizure disorders (Murphy 1987; Rintahaka 1999). Use should be restricted to children unresponsive to other antiseizure agents. Higher doses may cause excessive drowsiness and bronchial hypersecretion in infants and young children; evaluate infants prior to initiation of therapy to determine if upper airway is clear.
Other warnings/precautions:
• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties.
• Hypnotic: Appropriate use: Should be used only after evaluation of potential causes of sleep disturbance. Failure of sleep disturbance to resolve after 7 to 10 days may indicate psychiatric and/or medical illness. A worsening of insomnia or the emergence of new abnormalities of thought or behavior may represent unrecognized psychiatric or medical illness and requires immediate and careful evaluation. Reassess patient for appropriateness of continued use after 2 to 3 weeks of consecutive treatment.
• Rebound insomnia: Following withdrawal of therapy, transient insomnia may recur accompanied by other reactions, including restlessness, anxiety, and mood changes.
• Tolerance: Nitrazepam is a long half-life benzodiazepine; duration of action after a single dose is determined by redistribution rather than metabolism (Brunton 2011). Tolerance develops to the hypnotic and antiseizure effects (Vinkers 2012). Chronic use of this agent may increase the perioperative benzodiazepine dose needed to achieve desired effect.
• Withdrawal: A longer sleep-onset latency and increased awakenings during sleep may occur for 1 to 2 days following the discontinuation of GABA-mediated (GABAergic) medications. A more severe withdrawal syndrome may rarely occur following abrupt discontinuation or large decreases in dose after sustained use (>10 days), and is characterized by new-onset agitation, ataxia, depersonalization, dizziness, dysphoria, fatigue, headache, hypersensitivity to stimuli, irritability, muscle cramps or pain, nausea, sweating, twitching, vomiting, and weakness. This withdrawal syndrome generally resolves within weeks or upon reinitiation of the GABAergic medication. Intermittent dosing may reduce the risk of withdrawal symptoms (BAP [Wilson 2019]). Use caution when reducing dose or withdrawing therapy; avoid abrupt discontinuation; decrease slowly and monitor for withdrawal symptoms.
Not available in the US
May be product dependent
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Mogadon: 5 mg, 10 mg
CDSA IV
Oral: Tablets may be swallowed whole, crushed, or dissolved in liquid. For insomnia, administer at bedtime. For myoclonic seizures, administer in 3 equally divided doses, or if doses are not divided equally, give larger dose at bedtime.
Oral: Myoclonic seizures: Tablets may be swallowed whole, crushed, or dissolved in liquid. Administer in 3 equally divided doses, or if doses are not divided equally, give larger dose at bedtime.
Note: Not approved in the United States.
Insomnia, sleep onset or sleep maintenance: Short-term treatment and symptomatic relief of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings.
Limitations of use: Restrict use to insomnia that impairs normal daytime functioning. Treatment should typically not exceed 7 to 10 consecutive days. Reevaluation of the patient is required if treatment continues for >2 to 3 consecutive weeks. Prescriptions should be written for short-term use (7 to 10 days) and limited to ≤1 month supply.
Seizures: Management of myoclonic seizures in children.
Beers Criteria: Benzodiazepines (nitrazepam) are identified in the Beers Criteria as potentially inappropriate medications to be avoided in patients 65 years and older due to risk of abuse, misuse, physical dependence and addiction. In addition, older adults have increased risk of impaired cognition, delirium, falls, fractures, and motor vehicle accidents with benzodiazepine use (Beers Criteria [AGS 2023]).
Substrate of CYP3A4 (Major with inducers), CYP3A4 (Minor with inhibitors); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential;
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Alcohol (Ethyl): CNS Depressants may increase CNS depressant effects of Alcohol (Ethyl). Risk C: Monitor
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
ARIPiprazole Lauroxil: May increase CNS depressant effects of Benzodiazepines. ARIPiprazole Lauroxil may increase hypotensive effects of Benzodiazepines. Specifically, the risk of orthostatic hypotension may be increased. Risk C: Monitor
ARIPiprazole: May increase CNS depressant effects of Benzodiazepines. ARIPiprazole may increase hypotensive effects of Benzodiazepines. Specifically, orthostatic hypotension may be increased. Risk C: Monitor
Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Beta-Acetyldigoxin: Benzodiazepines may increase serum concentration of Beta-Acetyldigoxin. Risk C: Monitor
Blonanserin: CNS Depressants may increase CNS depressant effects of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider Therapy Modification
Brexanolone: CNS Depressants may increase CNS depressant effects of Brexanolone. Risk C: Monitor
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Buprenorphine: CNS Depressants may increase CNS depressant effects 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 at lower doses in patients already receiving CNS depressants. Risk D: Consider Therapy Modification
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
Certoparin: May increase serum concentration of Benzodiazepines. Risk C: Monitor
Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification
Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification
Chlormethiazole: May increase CNS depressant effects of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider Therapy Modification
Chlorphenesin Carbamate: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
CloZAPine: Benzodiazepines may increase adverse/toxic effects of CloZAPine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Monitor for respiratory depression, hypotension, and other toxicities if these agents are combined. Risk D: Consider Therapy Modification
CNS Depressants: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Corticosteroids (Orally Inhaled): Benzodiazepines may increase adverse/toxic effects of Corticosteroids (Orally Inhaled). Specifically, the risk of pneumonia may be increased. Risk C: Monitor
CYP3A4 Inducers (Strong): May decrease serum concentration of Nitrazepam. Risk C: Monitor
Dantrolene: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Daridorexant: May increase CNS depressant effects of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification
Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Difenoxin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dothiepin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Doxylamine: CNS Depressants may increase CNS depressant effects of Doxylamine. Risk C: Monitor
DroPERidol: May increase CNS depressant effects of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider Therapy Modification
Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Esketamine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid
Flunitrazepam: CNS Depressants may increase CNS depressant effects of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider Therapy Modification
HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification
Ilaprazole: May increase serum concentration of Benzodiazepines. Risk C: Monitor
Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Lemborexant: May increase CNS depressant effects of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider Therapy Modification
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofepramine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Melatonin: May increase sedative effects of Benzodiazepines. Risk C: Monitor
Melitracen [INT]: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methadone: Benzodiazepines may increase CNS depressant effects of Methadone. Management: Clinicians should generally avoid concurrent use of methadone and benzodiazepines when possible; any combined use should be undertaken with extra caution. Risk D: Consider Therapy Modification
Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider Therapy Modification
Methoxyflurane: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
OLANZapine: Benzodiazepines may increase adverse/toxic effects of OLANZapine. Management: Monitor closely for hypotension, respiratory or central nervous system depression, and bradycardia if olanzapine is combined with benzodiazepines. Use of parenteral benzodiazepines with IM olanzapine is not recommended. Risk C: Monitor
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: CNS Depressants may increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Oxybate Salt Products: Benzodiazepines may increase CNS depressant effects of Oxybate Salt Products. Risk X: Avoid
OxyCODONE: CNS Depressants may increase CNS depressant effects of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Paliperidone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
Perampanel: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Pipamperone: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor
Pizotifen: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider Therapy Modification
ROPINIRole: CNS Depressants may increase sedative effects of ROPINIRole. Risk C: Monitor
Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor
Suvorexant: CNS Depressants may increase CNS depressant effects 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. Risk D: Consider Therapy Modification
Teduglutide: May increase serum concentration of Benzodiazepines. Risk C: Monitor
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Theophylline Derivatives: May decrease therapeutic effects of Benzodiazepines. Risk C: Monitor
Trimeprazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Yohimbine: May decrease therapeutic effects of Antianxiety Agents. Risk C: Monitor
Zolpidem: CNS Depressants may increase CNS depressant effects 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. Risk D: Consider Therapy Modification
Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification
Manage epilepsy in patients who could become pregnant based on a shared decision-making process that optimizes seizure control and considers the possibility of pregnancy during treatment (Pack 2024). Regularly discuss age-specific and developmental needs, including pregnancy planning and contraceptive options during the patient's reproductive lifespan (ACOG 2020; NICE 2022).
Nitrazepam crosses the placenta (Kangas 1977).
In-utero exposure to benzodiazepines has the potential to cause harm to the fetus. Teratogenic effects have been observed in some studies; however, a clear association has not been reported and additional data are needed (Bellantuono 2013; Chuang 2024; Freeman 2018; Grigoriadis 2019; Tinker 2019; Wu 2024). Data are insufficient to evaluate the risk of specific major congenital malformations following in utero exposure to nitrazepam (Pack 2024). Exposure to a benzodiazepine late in pregnancy may cause neonatal sedation (hypotonia, lethargy, respiratory depression) and/or symptoms of neonatal withdrawal (feeding difficulties, hyperreflexia, inconsolable crying, irritability, restlessness, tremors) (Iqbal 2002). Monitor newborns exposed to nitrazepam in utero for adverse events. Data related to long-term effects on neurodevelopment following maternal use of benzodiazepines are inconclusive (Andrade 2024; Radojčić 2017; Sundbakk 2025; Wang 2022) and data are insufficient to evaluate the risk of neurodevelopmental outcomes (IQ scores or autism spectrum disorder) in children following in utero exposure to nitrazepam (Pack 2024). Screen for major congenital malformations and monitor fetal growth when antiseizure medications are used during pregnancy. Conduct age-appropriate developmental screening in children with previous in utero exposure to antiseizure medications (Pack 2024).
Epilepsy is associated with adverse maternal and fetal outcomes (Kuang 2024; Mazzone 2023). Convulsive seizures should be minimized to reduce risks to the fetus and pregnant patient. Use caution if removing or replacing an effective seizure medication in patients who become pregnant during therapy. Folic acid supplementation prior to and during pregnancy minimizes the risk of congenital malformations and poor neurodevelopment (Pack 2024).
Treatment for insomnia in pregnant patients should be individualized. Untreated insomnia may lead to adverse pregnancy outcomes. Although recommendations vary, nonpharmacologic therapy is preferred as an initial treatment of insomnia during pregnancy (BAP [McAllister-Williams 2017]; BAP [Wilson 2019]; Palagini 2022).
Nitrazepam is present in breast milk (Kangas 1981; Matheson 1990).
Drowsiness, lethargy, or weight loss in nursing infants have been observed in case reports following maternal use of some benzodiazepines, including nitrazepam (Iqbal 2002; Speight 1977).
Breastfeeding is not recommended by the manufacturer. Infants exposed to nitrazepam via breast milk should be monitored for adverse events, including irritability and sedation. Consider the long half-life of nitrazepam and the potential for accumulation.
Respiratory, cardiovascular, and mental status
Steady state levels after 4 days: 40 ng/mL (SI: 142.4 nmol/L).
Intermediate-acting benzodiazepine (based on half-life) (Griffin 2013). Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the CNS, 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.
Onset of action: 20 to 50 minutes.
Absorption: Rapid.
Duration of action: Classified as an intermediate-acting benzodiazepine; classification based on benzodiazepines with half-life of 12 to 40 hours (Griffin 2013).
Distribution: Vd: 2.4 L/kg (range: 1.6 to 3.2 L/kg), Elderly: 4.8 L/kg (range: 3.1 to 6.5 L/kg); also distributes into CSF, saliva (Kangas 1979).
Protein binding: 87%.
Metabolism: Hepatic: Nitroreduction, acetylation; no active metabolites.
Bioavailability: ~80%.
Half-life elimination: 30 hours (range: 18 to 57 hours), Elderly/ill patients: 40 hours.
Time to peak, plasma: ~3 hours.
Excretion: Urine (65% to 71%, ~1% as unchanged drug); feces (14% to 20%).