chlordiazepoxide/amitriptyline (Limbitrol, Limbitrol DS)

Dosing and uses of Limbitrol, Limbitrol DS (chlordiazepoxide-amitriptyline)

• Adult
• Pediatric
• Geriatric

 

Adult dosage forms and strengths

chlordiazepoxide/amitriptyline

tablet: Schedule IV

• 5mg/12.5mg
• 10mg/25mg

 

Depression with Anxiety

1 tablet (5-10 mg chlordiazepoxide/12.5-25 mg amitriptyline) PO three/four times daily; may increase to 6 tablets if necessary; 2 tablets reported to be effective in some patients

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Geriatric dosage forms and strengths

Avoid; strong anticholinergic and sedative effects; may cause orthostatic hypotension (Beers criteria)

Consider alternatives; if must use, initiate with lower initial dose; long-acting active metabolites

1 tablet (5 mg/12.5 mg) PO three times daily

 

Limbitrol, Limbitrol DS (chlordiazepoxide-amitriptyline) adverse (side) effects

Frequency not defined

Drowsiness

Dry mouth

Constipation

Blurred vision

Dizziness

Bloating

Vivid dreams

Impotence

Tremor

Confusion

Nasal congestion

Edema

Syncope

Ataxia

EEG abnormalities

Menstrual irregularities

Blood dyscrasias (agranulocytosis)

Hepatic dysfunction (jaundice)

 

Warnings

Black box warnings

Children and Antidepressants

• In short-term studies, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults (age <24 yr) taking antidepressants for major depressive disorders and other psychiatric illnesses
• This increase was not seen in patients aged >24 yr; slight decrease in suicidal thinking was seen in adults >65 yr; risks must be weighed in children and young adults against the benefits of taking antidepressants
• Patients should be monitored closely for changes in behavior, clinical worsening, and suicidal tendencies; monitor during the initial 1-2 months of therapy and dosage adjustments
• Patient’s family should communicate to the healthcare provider any abrupt changes in behavior
• Worsening behavior and suicidal tendencies that are not part of the presenting symptoms may require discontinuation of therapy
• Not approved for pediatric patients

Antipsychotics & Dementia

• Patients with dementia-related psychosis that are treated with antipsychotic drugs are at an increased risk of death as shown in short-term controlled trials; deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature
• Not approved for treatment of dementia-related psychosis

 

Contraindications

Hypersensitivity

Severe cardiovascular disorders

Angle clossure glaucoma

Within 14 days of MAOIs

Any drugs or conditions that prolong QT intervaL

Acute recovery post-MI

 

Cautions

Caution in BPH, urinary/GI retention, increased IOP, thyroid dysfunction, open-angle glaucoma, seizure disorders, brain tumor, respiratory impairment, respiratory disease,

Clinical worsening & suicide ideation may occur despite medication in adolescents & young adults (aged 18-24 yr)

Write prescription for smallest effective dose

Risk of anticholinergic side-effects

May cause orthostatic hypotension

Paradoxical reactions including hyperactive or aggressive behavior reported

Both agents may cause sedation and impair ability to perform tasks requiring mental alertness

SIADH and hyponatremia reported with therapy

Some patients may experience a large increase in amitriptyline concentration in presence of topiramate; any adjustments in amitriptyline dose should be made according to patient's clinical response and not on basis of plasma leveL

 

Pregnancy and lactation

Pregnancy category: d

Lactation: Excretion in milk unknown; not recommended

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Limbitrol, Limbitrol DS (chlordiazepoxide-amitriptyline)

Mechanism of action

Chlordiazepoxide: Antianxiety agent; depresses all levels of CNS, including limbic and reticular formation, possibly by increasing gamma-aminobutyric acid (GABA) activity, a major inhibitory neurotransmitter

Amitriptyline: Antidepressant; neurotransmitter (especially norepinephrine and serotonin) reuptake inhibitor; elicits anticholinergic effects

 

Absorption

Bioavailability: Slow and erratic following IM admin (chlordiazepoxide)

Peak serum time: 4 hr (amitriptyline)

Peak serum time: 0.5-2 hr

Onset of action: 1-5 min (IV, chlordiazepoxide)

Onset of action: 6 weeks

Duration: 15-60 min (IV, chlordiazepoxide)

Vd: 3.3 L/kg (chlordiazepoxide)

 

Metabolism

Chlordiazepoxide: demoxepam, desmethylchlordiazepoxide, desmethyldiazepam, oxazepam

Amiptriptyline: hepatic metabolism via CYP2C19, CYP3A4; nortriptyline is an active metabolite

 

Elimination

Half-Life

• Chlordiazepoxide: 6.6-28 hr
• Amitriptyline: 9-27 hr

Excretion

• Chlordiazepoxide: Predominately urine
• Amitriptyline: Urine (25-50%), small amounts in bile