Adult Dosing

Moderate-to-severe depression associated with moderate-to-severe anxiety

amitriptyline/chlordiazepoxide (generic), Limbitrol DS

• Initial dose: 1 tab [25 mg/10 mg] PO tid-qid; may be increased to 6 tabs [150 mg/60 mg]/day PRN

Note:

• Patients may respond to smaller doses and can be maintained on 2 tabs [50 mg/20 mg]/day
• The larger portion of the total daily dose may be taken at bedtime

amitriptyline/chlordiazepoxide (generic), Limbitrol

• 1 tab [12.5 mg/5 mg] PO tid-qid in patients who do not tolerate higher doses

Note:

• The larger portion of the total daily dose may be taken at bedtime

Pediatric Dosing

• Safety and effectiveness in pediatric patients have not been established

[Outline]

• Adult Dosing
• Pediatric Dosing

• For treating patients with moderate-to-severe depression associated with moderate-to-severe anxiety

• Hypersensitivity to any of the ingredients of the product
• Co-administration with MAO inhibitors or within 14 days of stopping MAO inhibitors
• Acute recovery phase following MI
• Abrupt withdrawal

• Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults compared to placebo in short-term studies of major depressive disorder (MDD) and other psychiatric diseases
• Assess potential benefits/risks before considering the use of amitriptyline/chlordiazepoxide or any other antidepressants in children, adolescents, or young adults
• Depression and other psychiatric disorders are themselves associated with increases in the risk of suicide
• In short-term studies of antidepressants vs. placebo, suicidality risk was not increased in patients >24 yrs and the risk decreased in patients >65 yrs. Carefully weigh the risks and benefits before starting treatment
• Monitor all patients started on antidepressant therapy and observe closely for clinical worsening, suicidal tendencies, or unusual changes in behavior, particularly early during therapy or during dose adjustment. Advise families and caregivers of the need for close observation and communication with the prescriber
• Therapy is not approved for use in pediatric patients

Renal Dose Adjustment

• Renal impairment: Use with caution; dose adjustments not defined

Hepatic Dose Adjustment

• Hepatic impairment: Use with caution; dose adjustments not defined

See Supplemental Patient Information

• Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in patients with MDD; this risk may persist until significant remission occurs
• Younger patients are more prone to suicidality; suicidality risk did not increase in patients >24 yrs of age and the risk decreased in patients >65 yrs of age [US Black Box Warning]
• Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have occurred in adults and pediatric patients receiving antidepressants; such symptoms may represent precursors to emerging suicidality
• Monitor and closely observe patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial few months of a course of drug therapy or at times of dose modifications
• Consider changing the therapeutic regimen or discontinuation of therapy on persistent worsening of depression, or on experiencing emergent suicidality, or on abrupt onset of symptoms suggesting worsening of depression or suicidality, especially if these symptoms are severe, abrupt in onset, and were not part of the patient’s presenting symptoms
• Considering discontinuation of treatment, taper medication as rapidly as feasible, but with due recognition that abrupt discontinuation can be associated with certain symptoms
• Alert families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and also for the emergence of suicidality, and to report such symptoms immediately to health care providers
• Prescribe smallest quantity of tablets consistent with good patient management to reduce the risk of overdose
• A major depressive episode may be the initial presentation of bipolar disorder. Prior to initiating treatment with an antidepressant, adequately screen patients with depressive symptoms to determine if they are at risk for bipolar disorder, as treating with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Consider a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression
• This combination drug is not approved for treating bipolar depression
• Use with caution in patients with cardiovascular diseases because of the tendency of the drug to produce tachycardia, hypotension, arrhythmias, and prolonged conduction time. Therapy may cause myocardial infarction and stroke
• Safe use of this drug during pregnancy and lactation has not been established. Use of minor tranquilizers during the first trimester of pregnancy is associated with an increased risk of congenital malformations; avoid use of this drug during this period. During therapy initiation, consider the possibility that a woman of childbearing potential may be pregnant
• Discontinuation of benzodiazepines are associated with withdrawal symptoms of the barbiturate type
• Closely monitor hyperthyroid patients or those on thyroid medication
• Severe constipation may occur in patients taking tricyclic antidepressants in combination with anticholinergic-type drugs
• Caution patients about the combined effects with alcohol or other CNS depressants because of the sedative effects of amitriptyline/chlordiazepoxide therapy
• Patients receiving this combination drug should be warned of the risks involved in performing hazardous tasks such as operating machinery or driving a car because the drug may impair the mental and/or physical abilities necessary for performing such tasks
• Therapy may block the antihypertensive action of guanethidine or similarly acting compounds
• Periodically perform LFTs and blood counts in patients undergoing prolonged treatment
• Discontinue the drug several days before elective surgery
• Both elevation as well as lowering of blood sugar levels have been reported during therapy
• Patients, their families and caregivers should be informed about the benefits and risks associated with this combination therapy and should be guided in its appropriate use
• Avoid administration of large doses in depressed patients

Cautions: Use cautiously in

• Renal impairment
• Hepatic impairment
• Diabetes mellitus
• History of conduction abnormalities
• Schizophrenia
• Bipolar disorder
• Electroconvulsive therapy
• Risk of suicide
• Alcohol abuse
• GI/GU obstruction
• Increased IOP
• Urinary retention
• Prostatic hypertrophy
• Angle-closure glaucoma
• History or risk of seizure disorder
• Thyroid disease
• Asthma
• Porphyria
• Parkinson disease
• Concurrent use with alcohol or other CNS depressants
• Elderly patients
• High environmental temperature

Supplemental Patient Information

• Inform the patients, families and caregivers to be alert for the unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and during dose adjustments and instruct them to immediately report such symptoms to the health professional
• Advise patients to refrain from hazardous activities requiring mental alertness such as operating a machinery or driving an automobile
• Patients should be advised to avoid excessive use of alcohol during the therapy
• Advise patients to communicate with their physicians if they become pregnant during course of therapy or intend to become pregnant

Pregnancy Category:NR

Breastfeeding: Amitriptyline and its metabolites are excreted in small amounts in breastmilk. Immediate adverse events have not been reported and limited data on follow-up found no adverse effects on infant growth and development. Usually not expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. However, other agents with fewer active metabolites may be preferred when large doses are required, especially while nursing a newborn/preterm infant. This information is based upon LactMed database (available at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT last accessed 21 June 2011). As many drugs are excreted in human milk, manufacturer advises to avoid nursing while a patient is treated with this combination drug.

• CV: Hypertension, orthostatic hypotension, ventricular arrhythmias, QT prolongation, torsades de pointes, AV block, MI, stroke, palpitations, tachycardia
• CNS: Drowsiness, dizziness, confusion, restlessness, seizures, syncope, abuse, disorientation, insomnia, anxiety, agitation, paradoxical CNS stimulation, incoordination
• NEURO: Tremor, extrapyramidal symptoms, ataxia, tardive dyskinesia, paresthesias
• PSYCHIATRY: Vivid dreams, hallucinations, exacerbation of psychosis, hypomania, mania, suicidality, worsening depression, anticholinergic psychosis
• GI: Dry mouth, constipation, bloating, nausea, vomiting, paralytic ileus, hepatitis, increased appetite
• GU: Urinary retention, urinary frequency
• EENT: Blurred vision, nasal congestion, increased IOP
• DERM: Sweating, rash, urticaria, pruritus
• ENDO: Impotence, SIADH, libido changes, gynecomastia in the male, breast enlargement, galactorrhea in the female, testicular swelling, elevation or depression of blood sugar levels
• METABOLIC: Anorexia, weight gain
• HEMA: Agranulocytosis, leukopenia, thrombocytopenia
• MISC: Fatigue, weakness, lethargy, withdrawal symptoms if abruptly discontinued, hyperthermia, heat stroke, photosensitivity

Amitriptyline

• Tricyclic antidepressant; inhibits presynaptic reuptake of norepinephrine and serotonin in the CNS
• Well absorbed after oral administration
• Extensively metabolized in the liver; CYP450: 1A2, 2D6, 3A4 substrate
• Primarily excreted in urine
• Half-life: 10-50 hrs

Chlordiazepoxide

• Benzodiazepine; potentiates action of GABA to produce CNS depression
• Well absorbed from GI tract
• Metabolized in the liver; CYP450: 3A4 (partial) substrate
• Excretion: Urine (3%-6% as conjugate), (1%-2% unchanged)
• Half-life: 5-30 hrs

US Trade Name(s)

• Limbitrol
• Limbitrol DS

US Availability

amitriptyline/chlordiazepoxide (generic)

• TABS:
• 12.5 mg/5 mg
• 25 mg/10 mg

Limbitrol (amitriptyline/chlordiazepoxide)

• TABS: 12.5 mg/5 mg

Limbitrol DS (amitriptyline/chlordiazepoxide)

• TABS: 25 mg/10 mg

Canadian Trade Name(s)

• N/A

Canadian Availability

• N/A

UK Trade Name(s)

• N/A

UK Availability

• N/A

Australian Trade Name(s)

• N/A

Australian Availability

• N/A

[Outline]

Psychiatric

Antidepressants

Tricyclic Antidepressants/Benzodiazepines; Combination

Pricing data from www.DrugStore.com in U.S.A.

• Limbitrol DS 10-25 MG TABS [Bottle] (VALEANT)
  60 mg = $115.99
  180 mg = $305.98

Warning: This pricing information is subject to change at the sole discretion of DS Pharmacy. For the most current and up-to-date pricing information, please visit drugstore.com.

• Amitriptyline Hydrochloride 12.5 MG / Chlordiazepoxide 5 MG Oral Tablet (Mylan Pharmaceuticals Inc.)
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• Amitriptyline Hydrochloride 25 MG / Chlordiazepoxide 10 MG Oral Tablet (Mylan Pharmaceuticals Inc.)
• Amitriptyline Hydrochloride 25 MG / Chlordiazepoxide 10 MG Oral Tablet (Par Pharmaceutical Inc)
• Limbitrol 12.5/5 Oral Tablet (Valeant Pharmaceuticals International)
• Limbitrol 25/10 mg Oral Tablet (Valeant Pharmaceuticals International)