Amitriptyline and chlordiazepoxide

U.S. BRAND NAMES — Limbitrol® DS; Limbitrol®

PHARMACOLOGIC CATEGORY
Antidepressant, Tricyclic (Tertiary Amine)
Benzodiazepine

DOSING: ADULTS — Depression and anxiety: Oral: Initial: 3-4 tablets in divided doses; this may be increased to 6 tablets/day as required. Some patients respond to smaller doses and can be maintained on 2 tablets.

DOSING: ELDERLY — Refer to adult dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet: 12.5/5: Amitriptyline hydrochloride 12.5 mg and chlordiazepoxide 5 mg; 25/10: Amitriptyline hydrochloride 25 mg and chlordiazepoxide 10 mg
Limbitrol®: 12.5/5: Amitriptyline hydrochloride 12.5 mg and chlordiazepoxide 5 mg
Limbitrol® DS: 25/10: Amitriptyline hydrochloride 25 mg and chlordiazepoxide 10 mg

DOSAGE FORMS: CONCISE
Tablet: 12.5/5: Amitriptyline 12.5 mg and chlordiazepoxide 5 mg; 25/10: Amitriptyline 25 mg and chlordiazepoxide 10 mg
Limbitrol®: 12.5/5: Amitriptyline 12.5 mg and chlordiazepoxide 5 mg
Limbitrol® DS: 25/10: Amitriptyline 25 mg and chlordiazepoxide 10 mg

GENERIC EQUIVALENT AVAILABLE — Yes

USE — Treatment of moderate to severe anxiety and/or agitation and depression

ADVERSE REACTIONS SIGNIFICANT — See individual agents.

CONTRAINDICATIONS — Hypersensitivity to benzodiazepines, tricyclic antidepressants, or any component of the formulation; depression of CNS; MAO inhibitors; acute recovery phase following MI; angle-closure glaucoma; pregnancy

WARNINGS / PRECAUTIONS
Based on amitriptyline component:

Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with major depressive disorder (MDD) and other depressive disorders; consider risk prior to prescribing. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the child's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. A medication guide should be dispensed with each prescription.

The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Monitor for worsening of depression or suicidality, especially during initiation of therapy or with dose increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression occur.

May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder.

Often causes drowsiness/sedation, resulting in impaired performance of tasks requiring alertness (eg, operating machinery or driving). Sedative effects may be additive with other CNS depressants and/or ethanol. The degree of sedation is very high relative to other antidepressants. May cause hyponatremia/SIADH. May increase the risks associated with electroconvulsive therapy. Consider discontinuing, when possible, prior to elective surgery. Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.

May cause orthostatic hypotension; the risk of this problem is very high relative to other antidepressants. Use with caution in patients at risk of hypotension or in patients where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). The degree of anticholinergic blockade produced by this agent is very high relative to other cyclic antidepressants; use with caution in patients with urinary retention, benign prostatic hyperplasia, narrow-angle glaucoma, xerostomia, visual problems, constipation, or a history of bowel obstruction. May alter glucose control - use with caution in patients with diabetes.

Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities). The risk of conduction abnormalities with this agent is high relative to other antidepressants. May lower seizure threshold - use caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage, alcoholism, or concurrent therapy with other drugs which lower the seizure threshold. Use with caution in hyperthyroid patients or those receiving thyroid supplementation. Use with caution in patients with hepatic or renal dysfunction and in elderly patients.

Based on chlordiazepoxide component:

Active metabolites with extended half-lives may lead to delayed accumulation and adverse effects. Use with caution in elderly or debilitated patients, pediatric patients, patients with hepatic disease (including alcoholics) or renal impairment. Use with caution in patients with respiratory disease or impaired gag reflex. Use with caution in patients with porphyria.

Parenteral administration should be avoided in comatose patients or shock. Adequate resuscitative equipment/personnel should be available, and appropriate monitoring should be conducted at the time of injection and for several hours following administration. The parenteral formulation should be diluted for I.M. administration with the supplied diluent only. This diluent should not be used when preparing the drug for intravenous administration.

Causes CNS depression (dose related) resulting in sedation, dizziness, confusion, or ataxia which may impair physical and mental capabilities. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Use with caution in patients receiving other CNS depressants or psychoactive agents (lithium, phenothiazines). Effects with other sedative drugs or ethanol may be potentiated. Benzodiazepines have been associated with falls and traumatic injury and should be used with extreme caution in patients who are at risk of these events (especially the elderly).

Use caution in patients with depression, particularly if suicidal risk may be present. Use with caution in patients with a history of drug dependence. Benzodiazepines have been associated with dependence and acute withdrawal symptoms on discontinuation or reduction in dose. Acute withdrawal, including seizures, may be precipitated after administration of flumazenil to patients receiving long-term benzodiazepine therapy.

Benzodiazepines have been associated with anterograde amnesia. Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients. Does not have analgesic, antidepressant, or antipsychotic properties.

Amitriptyline and chlordiazepoxide combination is FDA approved for depression associated with anxiety in children 12 years of age. This combination is not FDA approved for the treatment of bipolar depression.

RESTRICTIONS — C-IV

An FDA-approved medication guide concerning the use of antidepressants in children and teenagers must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm. Dispense to parents or guardians of children and teenagers receiving this medication.

DRUG INTERACTIONS
Amitriptyline: Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6 (weak), 2E1 (weak)

Chlordiazepoxide: Substrate of CYP3A4 (major)

Also see individual agents.

PREGNANCY RISK FACTOR — D (show table)

LACTATION — Excretion in breast milk unknown/contraindicated

PRICING — (data from drugstore.com)
Tablets (Chlordiazepoxide-Amitriptyline)
5-12.5 mg (60): $38.12

Tablets (Limbitrol DS)
10-25 mg (60): $109.99

CANADIAN BRAND NAMES — Limbitrol®

INTERNATIONAL BRAND NAMES — Limbatril (DE); Limbatrilin (CL); Limbitrol (AE, AT, BH, BR, CA, CY, EG, FI, FR, GB, GH, GR, ID, IE, IQ, IR, JO, KE, KW, LB, LY, NL, OM, QA, SA, SY, TW, TZ, UG, YE, ZA, ZM); Limbitrol F (ZA); Limbitryl (IT)

MECHANISM OF ACTION — See individual agents.

PHARMACODYNAMICS / KINETICS — See individual agents.