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Product Name
:
TRANQUIL
Chemical Name
:
Clorazepate Dipotassium
Therapeutic Category
:
Central nervous system drugs
Pharmacologic Category
:
Benzodiazepine
Pharmaceutical Form
:
Capsules
Composition
:
Clorazepate Dipotassium 5mg / 10mg
Monitoring Parameters
Dosing
 
Dosing: Adult
Anxiety: Oral: 7.5-15 mg 2-4 times/day
Ethanol withdrawal: Oral: Initial: 30 mg, then 15 mg 2-4 times/day on first day; maximum daily dose: 90 mg; gradually decrease dose over subsequent days.
Seizures (anticonvulsant): Oral: Initial: Up to 7.5 mg/dose 2-3 times/day; increase dose by 7.5 mg at weekly intervals; not to exceed 90 mg/day

Dosing: Pediatric

Seizures (anticonvulsant): Oral:
Children 9-12 years: Initial: 3.75-7.5 mg/dose twice daily; increase dose by 3.75 mg at weekly intervals, not to exceed 60 mg/day in 2-3 divided doses.
Children >12 years: Refer to adult dosing.

Dosing: Geriatric

Oral: Anxiety: 7.5 mg 1-2 times/day; use is not recommended in the elderly.
Use
 
Treatment of generalized anxiety disorder; management of ethanol withdrawal; adjunct anticonvulsant in management of partial seizures
Adverse Reactions
 
Frequency not defined.
Cardiovascular: Hypotension
Central nervous system: Drowsiness, fatigue, ataxia, lightheadedness, memory impairment, insomnia, anxiety, headache, depression, slurred speech, confusion, nervousness, dizziness, irritability
Dermatologic: Rash
Endocrine & metabolic: Libido decreased
Gastrointestinal: Xerostomia, constipation, diarrhea, salivation decreased, nausea, vomiting, appetite increased or decreased
Hepatic: Jaundice, transaminase increased
Neuromuscular & skeletal: Dysarthria, tremor
Ocular: Blurred vision, diplopia
Contraindications
 
Hypersensitivity to clorazepate or any component of the formulation (cross-sensitivity with other benzodiazepines may exist); narrow-angle glaucoma
Warnings / Precautions Drug
 
Concerns related to adverse effects:
• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia.
• 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.
• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.
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. Tolerance, psychological and physical dependence may occur with prolonged use.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Impaired gag reflex: Use with caution in patients with an impaired gag reflex.
• Renal impairment: Use with caution in patients with renal impairment.
• Respiratory disease: Use with caution in patients with respiratory disease.
Concurrent drug therapy issues:
• CNS depressants/psychoactive medications: Use with caution in patients receiving other CNS depressants or psychoactive medication; effects with other sedative drugs or ethanol may be potentiated.
Special populations:
• Debilitated patients: Use with caution in debilitated patients; active metabolites with extended half-lives may lead to delayed accumulation and adverse effects.
• Elderly: Benzodiazepines with long half-lives may produce prolonged sedation and increase the risk of falls and fracture. Short- or intermediate-acting benzodiazepines are preferred in elderly patients (Beers Criteria).
• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury.
• Pediatrics: Safety and efficacy have not been established in children <9 years of age.
Other warnings/precautions:
• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties.
• 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.
Controlled Substance
C-IV
Metabolism/Transport Effects
Substrate of CYP3A4 (major).
Interactions
 
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Management: The following combinations are specifically contraindicated: itraconazole with alprazolam, estazolam, oral midazolam, or triazolam; ketoconazole with alprazolam, estazolam, or triazolam. Consider initial dose reductions of other benzodiazepines. Risk D: Consider therapy modification
Aprepitant: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Bepridil [Off Market]. Risk D: Consider therapy modification
CarBAMazepine: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Cimetidine: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). 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. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination
Contraceptives (Estrogens): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Contraceptives (Progestins): May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. 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 (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Fluconazole: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification
Fosamprenavir: May increase the serum concentration of Clorazepate. Risk C: Monitor therapy
Fosaprepitant: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Specifically, the active metabolite aprepitant is likely responsible for this effect. Risk C: Monitor therapy
Fosphenytoin: Benzodiazepines may increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Risk C: Monitor therapy
Grapefruit Juice: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Isoniazid: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Macrolide Antibiotics: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Azithromycin; Azithromycin (Systemic); Fidaxomicin (Systemic); Spiramycin. Risk D: Consider therapy modification
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
Nefazodone: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification
OLANZapine: May enhance the adverse/toxic effect of Benzodiazepines. Management: Avoid concomitant use of parenteral benzodiazepines and IM olanzapine due to risks of additive adverse events (e.g., cardiorespiratory depression). Olanzapine prescribing information provides no specific recommendations regarding oral administration. Risk X: Avoid combination
Phenytoin: Benzodiazepines may increase the serum concentration of Phenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Risk C: Monitor therapy
Proton Pump Inhibitors: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Exceptions: Lansoprazole; Pantoprazole; RABEprazole. Risk C: Monitor therapy
Rifamycin Derivatives: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification
Ritonavir: May increase the serum concentration of Clorazepate. Risk C: Monitor therapy
Saquinavir: May increase the serum concentration of Clorazepate. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Citalopram; Escitalopram; PARoxetine; Sertraline. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy
St Johns Wort: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk D: Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: Monitor therapy
Pregnancy
 
Nordiazepam, the active metabolite of clorazepate, crosses the placenta and is measurable in cord blood and amniotic fluid. Teratogenic effects have been observed with some benzodiazepines (including clorazepate); 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.
Lactation
 
Enters breast milk/not recommended
Breast-Feeding Considerations
Nordiazepam, the active metabolite of clorazepate, is found in breast milk and is measurable in the serum of breast-feeding infants. Drowsiness, lethargy, or weight loss in nursing infants have been observed in case reports following maternal use of some benzodiazepines.
Mechanism of Action
 
Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, 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.
Pharmacodynamics / Kinetics
 
Onset of action: 1-2 hours
Duration: Variable, 8-24 hours
Distribution: Appears in urine
Protein binding: Nordiazepam 97% to 98%
Metabolism: Rapidly decarboxylated to nordiazepam (active) in acidic stomach prior to absorption; hepatically to oxazepam (active)
Half-life elimination: Adults: Nordiazepam: 40-50 hours; Oxazepam: 6-8 hours
Time to peak, serum: ~1 hour
Excretion: Primarily urine
 
   
 
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