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CLORAZEPATE

ClassCLORAZEPATE commonly prescribed forHow CLORAZEPATE worksHow long until CLORAZEPATE worksNotable Side EffectsLife Threatening Side Effectsweight gainsedationWhat to do about CLORAZEPATE side effectsusual dosage rangeDosage Formslong term usehabit formingRenal ImpairmentHepatic ImpairmentCardiac ImpairmentElderlyChildren and AdolescentsPregnancyBreast Feeding

THERAPEUTICS

Class

  • Neuroscience-based Nomenclature: GABA positive allosteric modulator (GABA-PAM)
  • Benzodiazepine (anxiolytic)

CLORAZEPATE commonly prescribed for

(Bold for FDA approved)

• Anxiety disorder
• Symptoms of anxiety
• Acute alcohol withdrawal

• Partial seizures (adjunct)
• Catatonia

How CLORAZEPATE works

• Binds to benzodiazepine receptors at the GABA-A ligand-gated chloride channel complex

• Enhances the inhibitory effects of GABA

• Boosts chloride conductance through GABA-regulated channels

• Inhibits neuronal activity presumably in amygdala-centered fear circuits to provide therapeutic benefits in anxiety disorders

How long until CLORAZEPATE works

• Some immediate relief with first dosing is common; can take several weeks with daily dosing for maximal therapeutic benefit

SIDE EFFECTS

Notable Side Effects

• Sedation, fatigue, depression

• Dizziness, ataxia, slurred speech, weakness

• Forgetfulness, confusion

• Nervousness

• Rare hallucinations, mania

• Rare hypotension

• Hypersalivation, dry mouth

Life Threatening Side Effects

• Respiratory depression, especially when taken with CNS depressants in overdose

• Rare hepatic dysfunction, renal dysfunction, blood dyscrasias

weight gain

unusual

unusual

sedation

common

common

What to do about CLORAZEPATE side effects

• Wait

• Wait

• Wait

• Lower the dose

• Take largest dose at bedtime to avoid sedative effects during the day

• Switch to another agent

• Administer flumazenil if side effects are severe or life-threatening

DOSING AND USE

usual dosage range

• Anxiety: 15–60 mg/day in divided doses

• Alcohol withdrawal: 30–60 mg/day in divided doses

Dosage Forms

• Tablet 3.75 mg scored, 7.5 mg scored, 15 mg scored

long term use

• Evidence of efficacy for up to 16 weeks

• Risk of dependence, particularly for periods longer than 12 weeks and especially in patients with past or current polysubstance abuse

habit forming

• Clorazepate is a Schedule IV drug

• Patients may develop dependence and/or tolerance with long-term use

SPECIAL POPULATIONS

Renal Impairment

• Initial 7.5–15 mg/day in divided doses or in 1 dose at bedtime

Hepatic Impairment

• Initial 7.5–15 mg/day in divided doses or in 1 dose at bedtime

Cardiac Impairment

• Benzodiazepines have been used to treat anxiety associated with acute myocardial infarction

Elderly

• Initial 7.5–15 mg/day in divided doses or in 1 dose at bedtime

Children and Adolescents

• Not recommended for use in children under age 9

• Recommended initial dose: 7.5 mg twice a day

Pregnancy

• Effective June 30, 2015, the FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

• Possible increased risk of birth defects when benzodiazepines are taken during pregnancy

• Because of the potential risks, clorazepate is not generally recommended as treatment for anxiety during pregnancy, especially during first trimester

• Drug should be tapered if discontinued

• Infants whose mothers received a benzodiazepine late in pregnancy may experience withdrawal effects

• Neonatal flaccidity has been reported in infants whose mothers took a benzodiazepine during pregnancy

• Seizures, even mild seizures, may cause harm to the embryo/fetus

Breast Feeding

• Some drug is found in mother’s breast milk

• Recommended either to discontinue drug or bottle feed

• Effects of benzodiazepines on nursing infants have been reported and include feeding difficulties, sedation, and weight loss

Based on data Published online by Cambridge University Press

Compiled by Dr. Jash Ajmera