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Chlordiazepoxide

N05B - Anxiolytics ATC N05BA02 Small molecule approved 1960 Oral Parenteral First-in-class Natural product Black-box warning

JFDA label: Limbitrol

⚠ Black-Box Warning
  • Risks from concomitant use of benzodiazepines and opioids:

Mechanism of Action

Positive Allosteric Modulator of GABA-A receptor; anion channel — GABA-A receptor; anion channel positive allosteric modulator

TargetActionGene / class
GABA-A receptor; anion channel efficacy POSITIVE ALLOSTERIC MODULATOR

Indications

Approved

  • Acute alcohol withdrawal
  • Anxiety
  • Preoperative anxiety

Contraindications

Source: Lexicomp

  • Hypersensitivity to chlordiazepoxide or any component of the formulation. Documentation of allergenic cross-reactivity for benzodiazepines is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (2)

Not Known Edema · syncope

Nervous system disorders (5)

Not Known Abnormal electroencephalogram · ataxia · confusion · drowsiness · drug-induced extrapyramidal reaction

Hepatobiliary disorders (2)

Not Known Hepatic insufficiency · jaundice

Blood and lymphatic system disorders (2)

Not Known Agranulocytosis · bone marrow depression

Metabolism and nutrition disorders (2)

Not Known Change in libido · menstrual disease

Gastrointestinal disorders (2)

Not Known Constipation · nausea

Skin and subcutaneous tissue disorders (1)

Not Known Skin rash

General disorders and administration site conditions (1)

Not Known Paradoxical reaction

Dosing

Source: Lexicomp

Acute alcohol withdrawal: Oral: Initial: 50 to 100 mg; dose may be repeated as necessary to a maximum of 300 mg/day. Note: Frequency of repeat doses is often based on institution-specific protocols. Once agitation is under control, maintain therapy at lowest effective dose. Anxiety: Oral: Mild-moderate anxiety: Usual dose: 5 to 10 mg 3 to 4 times daily. Severe anxiety: Usual dose: 20 to 25 mg 3 to 4 times daily. Debilitated patients: Usual dose: 5 mg 2 to 4 times daily. Preoperative anxiety: Oral: 5 to 10 mg 3 to 4 times daily on the days preceding surgery
Anxiety: Oral: Children ≥6 years and Adolescents: Usual dose: 5 mg 2 to 4 times daily. Dose may be increased to 10 mg 2 to 3 times daily in some patients, if necessary.
Note: Avoid use; however, use may be appropriate in older adults when used for seizure disorders, rapid eye movement disorders, benzodiazepine or ethanol withdrawal, severe generalized anxiety disorder, or periprocedural anesthesia (Beers Criteria [AGS 2015]). Anxiety: Oral: 5 mg 2 to 4 times daily; use with caution.
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 (Aronoff 2007). CrCl Peritoneal dialysis: Administer 50% of dose (Aronoff 2007).
There are no dosage adjustments provided in the manufacturer’s labeling; however, chlordiazepoxide undergoes hepatic metabolism and should be used with caution.

Warnings & Precautions

Source: Lexicomp

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, particularly in adolescent/pediatric or psychiatric patients. Disease-related concerns:

Depression

Use caution in patients with depression, particularly if suicidal risk may be present.

Drug abuse

Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Psychological and physical dependence, as well as tolerance to sedative and anticonvulsive effects, may occur with prolonged use (Vinkers 2012).

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

Use with caution in patients with respiratory disease (Smoller 1996). Concurrent drug therapy issues:

Benzodiazepines and opioids

The concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions for more detailed information. 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.

Elderly

Avoid use; if used, use with caution in the elderly; active metabolites with extended half-lives may lead to delayed accumulation and adverse effects, including ataxia and over-sedation.

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:

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.

Withdrawal

Rebound or withdrawal symptoms may occur following abrupt discontinuation or large decreases in dose. Use caution when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.

Pregnancy & Lactation

Pregnancy

Teratogenic

Adverse events have been observed in some animal reproduction studies. Chlordiazepoxide crosses the human placenta and fetal serum concentrations are similar to those in the mother. Teratogenic effects have been observed with some benzodiazepines (including chlordiazepoxide); 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) has been reported with some benzodiazepines (Bergman 1992; Iqbal 2002; Wikner 2007).

Lactation

Chlordiazepoxide is excreted 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).

LactMed: monitor the infant.

Monitoring

Clinical pearlRespiratory and cardiovascular status (including orthostasis); mental status; paradoxical reactions (eg, excitement, stimulation, acute rage); if used for ethanol withdrawal, signs/symptoms of ethanol withdrawal

Chemistry & Properties

2D structure
FormulaC16H14ClN3O
Molecular weight299.76 g/mol
IUPAC name7-chloro-4-hydroxy-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-imine
CAS58-25-3
PubChem CID2712
InChIKeyANTSCNMPPGJYLG-UHFFFAOYSA-N
logP2.95 (XLogP 2.4)
Polar surface area50.46 Ų
H-bond acceptors / donors3 / 1
Drug-likeness (QED)0.65
Lipinski violations0
SMILESCNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=[N+]([O-])C1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrantYes

Enzyme interactions

EnzymeRoleDetail
CYP1A2Inhibitor
CYP1A2Substrate
CYP2B6Inhibitor
CYP2C19Substrate
CYP2C8Inhibitor
CYP2C9Inhibitor
CYP2C9Substrate
CYP3A4Substrate

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (85, DDInter)

Interacting drugSeverityManagement
Codeine major
Hydrocodone major
Morphine major
Morphine (liposomal) major
Aldesleukin moderate
Alimemazine moderate
Amyl Nitrite moderate
Anagrelide moderate
Azatadine moderate
Azelastine (nasal) moderate
Brimonidine (ophthalmic) moderate
Brimonidine (topical) moderate
Brompheniramine moderate
Bupropion moderate
Carbinoxamine moderate
Cetirizine moderate
Chlorphenesin moderate
Chlorpheniramine moderate
Cimetidine moderate
Clarithromycin moderate
Clemastine moderate
Clofedanol moderate
Cyclizine moderate
Cyproheptadine moderate
Dexbrompheniramine moderate
Dextromethorphan moderate
Diazoxide moderate
Diphenhydramine moderate
Disulfiram moderate
Doxepin moderate
Doxepin (topical) moderate
Doxylamine moderate
Dronabinol moderate
Erythromycin moderate
Ethanol moderate
Flumazenil moderate
Fostamatinib moderate
Ifosfamide moderate
Imatinib moderate
Iodide I-123 moderate

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Registered Products (4)

BrandForm / strengthPackAgentCitizen (JOD)
Poxidium F.C Tablets Film-Coated Tablet 5 mg, 2.5 mg 30 tab pack varies Hikma Pharmaceuticals Co.Ltd/Jordan 1.400
Limbitrol Tablet 5 mg, 12.5 mg 30 tab ORIENT DRUG STORE CO 2.700
Librax 5mg/2.5mg Tablet 5 mg, 2.5 mg 30 tab Khoury Drug Store 3.570
Poxidium Tablets Tablet 5 mg, 2.5 mg 1000 tab pack varies Hikma Pharmaceuticals Co.Ltd/Jordan 22.800