Version May 2024
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.
The use of benzodiazepines, including chlordiazepoxide, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or 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 chlordiazepoxide and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction.
The continued use of benzodiazepines, including chlordiazepoxide, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of chlordiazepoxide after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue chlordiazepoxide or reduce the dosage.
Dosage guidance:
Safety: Reduce dose or avoid use in patients receiving opioids or with significant chronic disease (eg, respiratory compromise) (Ref). Avoid use in patients with a history of substance use, misuse of medications, or depression (Ref).
Alcohol withdrawal syndrome, treatment:
Note: Withdrawal will progress at different rates in some patients; flexibility in dosing and duration is warranted (Ref). Regimens vary and depend on withdrawal history, degree of current withdrawal symptoms, blood alcohol concentration, and whether the patient is treated inpatient or in the ambulatory setting. Many facilities only treat alcohol withdrawal in the ambulatory setting if Clinical Institute Withdrawal Assessment for Alcohol (CIWA-AR) score is ≤15 and there is no history of withdrawal seizures or delirium tremens (Ref). The following are 2 suggested regimens.
Symptom-triggered regimen:
Note: Some experts recommend symptom-triggered dosing for patients who score >15 on the CIWA-AR, revised scale (Ref).
Oral: 25 to 100 mg as needed per institution-specific protocol until appropriate sedation achieved; dose and frequency determined by withdrawal symptom severity using a validated severity assessment scale, such as the CIWA-AR (Ref).
Example regimen (Holt 2023):
Day 1: Oral: 50 mg every 6 hours.
Day 2: Oral: 50 mg every 8 hours.
Day 3: Oral: 50 mg every 12 hours.
Day 4: Oral: 50 mg once at bedtime.
Fixed regimen:
Note: Some experts recommend fixed-dose regimens for patients at risk for mild withdrawal (CIWA-AR ≤15), particularly in an ambulatory setting where CIWA-AR scores cannot be reliably administered (Ref). In addition to scheduled doses shown in the example regimen below, provide up to 5 additional as-needed 50 mg doses to be used over the 4-day treatment period for breakthrough symptoms (Ref).
Day 1: Oral: 50 mg every 4 to 6 hours.
Day 2: Oral: 50 mg every 8 to 12 hours.
Day 3: Oral: 50 mg every 12 to 24 hours.
Day 4: Oral: 25 mg every 12 to 24 hours, then discontinue chlordiazepoxide (Ref).
Anxiety disorders (adjunctive therapy or monotherapy) (alternative agent):
Note: Generally used short-term for symptom relief until preferred therapy (eg, serotonin reuptake inhibitor) is effective (eg, 4 to 6 weeks, followed by tapering). Long-term low-dose therapy (eg, 5 mg/day) may be considered in select patients when other treatments are ineffective or poorly tolerated (Ref). Use with caution in patients with posttraumatic stress disorder; benzodiazepines may worsen symptoms (Ref).
Usual range: Oral: 5 to 25 mg 2 to 4 times daily; increase gradually based on response and tolerability; patients with mild to moderate symptoms generally respond to total daily doses ≤40 mg. Maximum dose: 100 mg/day in divided doses.
Discontinuation of therapy: Unless safety concerns require a more rapid withdrawal, gradually taper to detect reemerging symptoms and minimize rebound and withdrawal symptoms (Ref).
Low or moderate dose, no concerns for benzodiazepine use disorder : Taper total daily dose by 20% to 25% every week based on response and tolerability (taper increments will be limited by available dosage forms) (Ref).
Extended or high-dose therapy, or suspected benzodiazepine use disorder: Taper total daily dose by approximately 25% every 1 to 2 weeks based on response, tolerability, and individual patient factors (taper increments will be limited by available dosage forms) (Ref). Reduce dose more rapidly in the beginning, and slow the dose reduction as the taper progresses because earlier stages of withdrawal are easier to tolerate (Ref). The optimal duration and taper increment will vary; up to 6 months may be necessary for some patients on higher doses, and a taper rate of 50% every week may be tolerated in some patients (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; however, the following recommendations have been used by some clinicians:
Adults:
CrCl ≥10 mL/minute: No dosage adjustment necessary (Ref).
CrCl <10 mL/minute: Administer 50% of dose (Ref).
Peritoneal dialysis: Administer 50% of dose (Ref).
There are no dosage adjustments provided in the manufacturer’s labeling; however, chlordiazepoxide undergoes hepatic metabolism and should be used with caution.
Alcohol withdrawal syndrome: Refer to adult dosing.
Anxiety disorders: Oral: Use lower initial doses of 5 mg 2 to 4 times daily and titrate slowly; refer to adult dosing.
Discontinuation of therapy: Refer to adult dosing.
(For additional information see "Chlordiazepoxide: Pediatric drug information")
Anxiety: Note: Use of chlordiazepoxide as an anxiolytic has been replaced by newer agents (Ref). Children ≥6 years and Adolescents: Oral: Usual dose: 5 mg 2 to 4 times daily; may increase to 10 mg 2 to 3 times daily in some patients. Pediatric patients may have variable response; begin with the lowest dose and slowly titrate.
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 pediatric-specific dosage adjustments provided in the manufacturer’s labeling; in adult patients, dosage adjustment suggested.
There are no dosage adjustments provided in the manufacturer’s labeling; however, chlordiazepoxide undergoes hepatic metabolism and should be used with caution.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Frequency not defined
Cardiovascular: Edema, syncope
Central nervous system: Abnormal electroencephalogram, ataxia, confusion, drowsiness, drug-induced extrapyramidal reaction
Dermatologic: Skin rash
Endocrine & metabolic: Change in libido, menstrual disease
Gastrointestinal: Constipation, nausea
Hematologic & oncologic: Agranulocytosis, bone marrow depression
Hepatic: Hepatic insufficiency, jaundice
Miscellaneous: Paradoxical reaction
Hypersensitivity to chlordiazepoxide or any component of the formulation.
Concerns related to adverse effects:
• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia (Nelson 1999).
• 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).
• 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).
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Porphyria: Use with caution in patients with porphyria.
• 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.
Special populations:
• Debilitated patients: Use with caution in debilitated patients; active metabolites with extended half-lives may lead to delayed accumulation and adverse effects, including ataxia and over-sedation.
• Older adult: Avoid use; if used, use with caution in older adults; active metabolites with extended half-lives may lead to delayed accumulation and adverse effects, including ataxia and over-sedation. 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: Use with caution in children; active metabolites with extended half-lives may lead to delayed accumulation and adverse effects, including ataxia and over-sedation.
Other warnings/precautions:
• Abuse, misuse, and substance use disorder: Counsel patients at increased risk on proper use and monitor for signs and symptoms of abuse, misuse, and substance use disorder. Institute early treatment or refer patients in whom substance use disorder is suspected. Limit dosages and durations to the minimum required.
• Dependence and withdrawal reactions: Some patients may develop a protracted withdrawal syndrome lasting >12 months; may be difficult to differentiate withdrawal symptoms from reemergence or continuation of symptoms for which benzodiazepines were prescribed. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.
• Tolerance: Chlordiazepoxide is a long half-life benzodiazepine. Duration of action after a single dose is determined by redistribution rather than metabolism. Tolerance does not develop to the anxiolytic effects (Vinkers 2012). Chronic use of this agent may increase the perioperative benzodiazepine dose needed to achieve desired sedative effect.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral, as hydrochloride:
Generic: 5 mg, 10 mg, 25 mg
Yes
Capsules (chlordiazePOXIDE HCl Oral)
5 mg (per each): $0.35 - $19.90
10 mg (per each): $0.40 - $21.08
25 mg (per each): $0.43 - $22.33
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral, as hydrochloride:
Generic: 5 mg, 10 mg, 25 mg
C-IV
An FDA-approved patient medication guide, which is available with the product information and at http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf#page=8, must be dispensed with this medication.
Alcohol withdrawal syndrome: Management of acute alcohol withdrawal symptoms.
Anxiety disorders: Management of anxiety disorders or short-term relief of anxiety symptoms.
ChlordiazePOXIDE may be confused with chlorproMAZINE or chlorothiazide
Librium may be confused with Librax
Beers Criteria: Chlordiazepoxide is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older due to risk of abuse, misuse, physical dependence, and addiction. In addition, older adults have an increased risk of impaired cognition, delirium, falls, fractures, and motor vehicle accidents with benzodiazepine use and slower metabolism of long-acting benzodiazepines (eg, chlordiazepoxide). However, benzodiazepines may be appropriate in the elderly when used for seizure disorders, rapid eye movement sleep behavior disorder, benzodiazepine or ethanol withdrawal, severe generalized anxiety disorder, or periprocedural anesthesia (Beers Criteria [AGS 2023]).
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
Cimetidine: May increase the serum concentration of ChlordiazePOXIDE. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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
CYP3A4 Inhibitors (Strong): May increase the serum concentration of ChlordiazePOXIDE. 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
Disulfiram: May increase the serum concentration of ChlordiazePOXIDE. Risk C: Monitor therapy
Doxylamine: CNS Depressants may enhance the CNS depressant effect of Doxylamine. 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
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
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
Fosphenytoin-Phenytoin: ChlordiazePOXIDE may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
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
Ilaprazole: May increase the serum concentration of Benzodiazepines. Risk C: Monitor therapy
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
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
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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
Zuranolone: May enhance the CNS depressant effect 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
Evaluate pregnancy status prior to use. Pregnancy testing is recommended before treating acute alcohol withdrawal symptoms (ASAM 2020).
Therapy for anxiety should be individualized (BAP [McAllister-Williams 2017]); avoid the use of benzodiazepines for the treatment of anxiety disorders in patients planning to become pregnant (Larsen 2015).
Chlordiazepoxide crosses the human placenta and fetal serum concentrations are similar to those in the mother (Stirrat 1974).
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; Freeman 2018; Grigoriadis 2019; Noh 2022; Szpunar 2022; Tinker 2019; Wikner 2007). 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). Data related to long-term effects on neurodevelopment are inconclusive (Chen 2022; Radojčić 2017; Sundbakk 2022; Wang 2022). Newborns exposed to chlordiazepoxide in utero should be monitored for feeding problems, respiratory depression, sedation, and withdrawal.
Treatment for alcohol withdrawal may be considered for pregnant patients with at least moderate symptoms (CIWA-Ar scores ≥10) (ASAM 2020). The short-term use of a long-acting benzodiazepine may be used in pregnant patients requiring treatment of acute alcohol withdrawal symptoms (WHO 2014); however, the use of shorter-acting benzodiazepines is preferred in patients at risk for preterm delivery or when treatment is needed during the third trimester (ASAM 2020). Although recommendations vary by guideline, the use of chlordiazepoxide may be considered when treating pregnant patients (BAP [McAllister-Williams 2017]; SOGC [Graves 2020]; WFSBP/IAWMH [Thibaut 2019]). Monitor newborns for fetal alcohol spectrum disorders in addition to benzodiazepine intoxication (ASAM 2020).
Therapy for anxiety during pregnancy should be individualized. Untreated or inadequately treated psychiatric illness may lead to poor adherence to prenatal care and adverse pregnancy outcomes (ACOG 2008). Benzodiazepines are not preferred when pharmacologic treatment for anxiety disorders is needed during pregnancy (BAP [McAllister-Williams 2017]; Larsen 2015) and when a benzodiazepine is needed, the use of chlordiazepoxide is not preferred. If possible, avoid scheduled doses of benzodiazepines in the month prior to delivery to reduce the risk of withdrawal symptoms in the newborn (Larsen 2015).
Data collection to monitor pregnancy and infant outcomes following exposure to chlordiazepoxide is ongoing. Health care providers are encouraged to enroll patients exposed to chlordiazepoxide during pregnancy in the National Pregnancy Registry for Psychiatric Medications (1-866-961-2388).
Benzodiazepines are present in breast milk.
Drowsiness, lethargy, or weight loss in breastfeeding infants have been observed in case reports following maternal use of some benzodiazepines (Iqbal 2002).
Breastfeeding during benzodiazepine therapy is not recommended due to the potential for drowsiness in the breastfeeding infant (Larsen 2015). Due to the long half-life of chlordiazepoxide, the potential to accumulate in breast milk, and the potential for serious adverse events in a breastfed infant (eg, sedation, withdrawal), breastfeeding is not recommended by the manufacturer. If a benzodiazepine is needed in breastfeeding patients, the use of a short-acting agent is preferred, and infants should be monitored (WHO 2002); however, some guidelines suggest chlordiazepoxide may be used cautiously if treatment with a benzodiazepine is needed (BAP [McAllister-Williams 2017]).
Breastfeeding is not recommended when pharmacologic treatment is needed for the management of acute alcohol withdrawal symptoms (WFSBP/IAWMH [Thibaut 2019]).
Respiratory and cardiovascular status (including orthostasis); mental status; paradoxical reactions (eg, excitement, stimulation, acute rage); if used for ethanol withdrawal, signs/symptoms of ethanol withdrawal
Long-acting benzodiazepine (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 (Vinkers 2012).
Duration of action: Classified as a long-acting benzodiazepine; classification based on benzodiazepines with half-life >40 hours (Griffin 2013).
Distribution: Vd: 3.3 L/kg (Schwartz 1971)
Protein binding: 96% (Baskin 1982)
Metabolism: Extensively hepatic to desmethyldiazepam (active and long-acting), desmethylchlordiazepoxide, and demoxepam (Baskin 1982; Schwartz 1971).
Half-life elimination: Parent: 24 to 48 hours; demoxepam 14 to 95 hours (Schwartz 1971)
Time to peak, serum: 0.5 to 2 hours (Baskin 1982)
Excretion: Urine (1% to 2% unchanged; 3% to 6% as metabolite)
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