Note: Reduce dose or avoid use in patients receiving opioids, with significant chronic disease (eg, respiratory compromise), or at increased risk for accumulation (eg, advanced cirrhosis). Use is contraindicated in severe respiratory disease or severe hepatic impairment. Avoid use in patients with a history of substance use, misuse of medications, or depression (Craske 2022).
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 (Neubauer 2021). 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 (ACP [Qaseem 2016]; ESRS [Riemann 2017]).
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 (Bélanger 2009).
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.
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.
Insomnia: Elderly or debilitated patients: 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). Avoid use (Beers Criteria [AGS 2019]).
May be product dependent
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Mogadon: 5 mg, 10 mg
Not available in the US
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: Based on pharmacologic class concerns for benzodiazepines in the Beers Criteria, nitrazepam may be a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) due to increased risk of impaired cognition, delirium, falls, fractures, and motor vehicle accidents with benzodiazepine use. However, use may be appropriate in the elderly when used for seizure disorders, rapid eye movement sleep behavior disorders, benzodiazepine or ethanol withdrawal, severe generalized anxiety disorder, or periprocedural anesthesia (Beers Criteria [AGS 2019]).
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.
Substrate of CYP3A4 (major); 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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect 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 enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect 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 enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
CloZAPine: Benzodiazepines may enhance the adverse/toxic effect of CloZAPine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Monitor for respiratory depression, hypotension, and other toxicities if these agents are combined. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Cosyntropin: May enhance the hepatotoxic effect of Nitrazepam. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Nitrazepam. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect 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 enhance the CNS depressant effect 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 enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect 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
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect 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 enhance the CNS depressant effect 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
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect 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
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Melatonin: May enhance the sedative effect of Benzodiazepines. Risk C: Monitor therapy
Methadone: Benzodiazepines may enhance the CNS depressant effect 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 enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect 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
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
OLANZapine: Benzodiazepines may enhance the adverse/toxic effect 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 therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect 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
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: Benzodiazepines may enhance the CNS depressant effect of Oxybate Salt Products. Risk X: Avoid combination
OxyCODONE: CNS Depressants may enhance the CNS depressant effect 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
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect 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 enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Teduglutide: May increase the serum concentration of Benzodiazepines. Risk C: Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk C: Monitor therapy
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
Nitrazepam crosses the placenta.
Teratogenic effects have been observed with some benzodiazepines; however, additional studies are needed. The incidence of premature birth and low birth weights may be increased following maternal use of benzodiazepines; hypoglycemia and respiratory problems in the neonate may occur following exposure late in pregnancy. Neonatal withdrawal symptoms may occur within days to weeks after birth and “floppy infant syndrome” (which also includes withdrawal symptoms) have been reported with some benzodiazepines (Bergman 1992; Iqbal 2002; Wikner 2007). Symptoms may include hypoactivity, hypotonia, hypothermia, respiratory depression, apnea, feeding problems, and impaired metabolic response to cold stress. Use during pregnancy is not recommended.
Nitrazepam is present in breast milk.
Drowsiness, lethargy, or weight loss in nursing infants have been observed in case reports following maternal use of some benzodiazepines (Iqbal 2002). Breastfeeding is not recommended by the manufacturer. Infants exposed to nitrazepam via breast milk should be monitored for adverse events, including irritability and sedation.
Respiratory, cardiovascular, and mental status
Steady state levels after 4 days: 40 ng/mL
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
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%)
