Data from FDA - Curated by EPG Health - Last updated 19 December 2016

Indication(s)

INDICATIONS AND USAGE Chlordiazepoxide and amitriptyline hydrochloride tablets are indicated for the treatment of patients with moderate to severe depression associated with moderate to severe anxiety.

The therapeutic response to chlordiazepoxide and amitriptyline hydrochloride tablets occurs earlier and with fewer treatment failures than when either amitriptyline or chlordiazepoxide is used alone.

Symptoms likely to respond in the first week of treatment include: insomnia, feelings of guilt or worthlessness, agitation, psychic and somatic anxiety, suicidal ideation and anorexia.

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Advisory information

contraindications

CONTRAINDICATIONS Chlordiazepoxide and amitriptyline hydrochloride is contraindicated in patients with hypersensitivity to either benzodiazepines or tricyclic antidepressants.

It should not be given concomitantly with a monoamine oxidase inhibitor.

Hyperpyretic crises, severe convulsions and deaths have occurred in patients receiving a tricyclic antidepressant and a monoamine oxidase inhibitor simultaneously.

When it is desired to replace a monoamine oxidase inhibitor with chlordiazepoxide and amitriptyline hydrochloride, a minimum of 14 days should be allowed to elapse after the former is discontinued.

Chlordiazepoxide and amitriptyline hydrochloride should then be initiated cautiously with gradual increase in dosage until optimum response is achieved.

This drug is contraindicated during the acute recovery phase following myocardial infarction.

Special warnings and precautions

GENERIAL PRECAUTIONS Use with caution in patients with a history of seizures.

Close supervision is required when chlordiazepoxide and amitriptyline hydrochloride is given to hyperthyroid patients or those on thyroid medication.

The usual precautions should be observed when treating patients with impaired renal or hepatic function.

Patients with suicidal ideation should not have easy access to large quantities of the drug.

The possibility of suicide in depressed patients remains until significant remission occurs.

Essential Laboratory Tests Patients on prolonged treatment should have periodic liver function tests and blood counts.

Drug and Treatment Interactions Because of its amitriptyline component, chlordiazepoxide and amitriptyline hydrochloride may block the antihypertensive action of guanethidine or compounds with a similar mechanism of action.

Drugs Metabolized by P450 2D6: The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7 % to 10 % of Caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available.

Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses.

Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small or quite large (8-fold increase in plasma AUC of the TCA).

In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers.

An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy.

The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the type 1c antiarrhythmics propafenone and flecainide).

While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition.

The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved.

Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other.

Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).

Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug.

Furthermore, whenever one of these other drugs is withdrawn from cotherapy, an increased dose of tricyclic antidepressant may be required.

It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6.

The effects of concomitant administration of chlordiazepoxide and amitriptyline hydrochloride and other psychotropic drugs have not been evaluated.

Sedative effects may be additive.

Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants and benzodiazepines, thereby delaying elimination and increasing steady-state concentrations of these drugs.

Clinically significant effects have been reported with the tricyclic antidepressants when used concomitantly with cimetidine (Tagamet®).

The drug should be discontinued several days before elective surgery.

Concurrent administration of ECT and chlordiazepoxide and amitriptyline hydrochloride should be limited to those patients for whom it is essential.

Pregnancy See WARNINGS section.

Nursing Mothers It is not known whether this drug is excreted in human milk.

As a general rule, nursing should not be undertaken while a patient is on a drug, since many drugs are excreted in human milk.

Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS- Clinical Worsening and Suicide Risk).

Anyone considering the use of Chlordiazepoxide and Amitriptyline Hydrochloride Tablets in a child or adolescent must balance the potential risks with the clinical need.

Geriatric Use In elderly and debilitated patients it is recommended that dosage be limited to the smallest effective amount to preclude the development of ataxia, over sedation, confusion or anticholinergic effects.

Of the total number of subjects in clinical studies of chlordiazepoxide and amitriptyline hydrochloride, 74 individuals were 65 years and older.

An additional 34 subjects were between 60 and 69 years of age.

No overall differences in safety and effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals can not be ruled out.

The active ingredients in chlordiazepoxide and amitriptyline hydrochloride are known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.

Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of chlordiazepoxide and amitriptyline hydrochloride and observed closely.

Clinical studies of chlordiazepoxide and amitriptyline hydrochloride did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.

Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with chlordiazepoxide and amitriptyline hydrochloride and should counsel them in its appropriate use.

A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for chlordiazepoxide and amitriptyline hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents.

Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.

The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking chlordiazepoxide and amitriptyline hydrochloride.

Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression , and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down.

Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt.

Such symptoms should be reported to the patient 's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient 's presenting symptoms.

Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

To assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug.

Adverse reactions

ADVERSE REACTIONS Adverse reactions to chlordiazepoxide and amitriptyline hydrochloride are those associated with the use of either component alone.

Most frequently reported were drowsiness, dry mouth, constipation, blurred vision, dizziness and bloating.

Other side effects occurring less commonly included vivid dreams, impotence, tremor, confusion and nasal congestion.

Many symptoms common to the depressive state, such as anorexia, fatigue, weakness, restlessness and lethargy, have been reported as side effects of treatment with both chlordiazepoxide and amitriptyline HCl tablets and amitriptyline.

Granulocytopenia, jaundice and hepatic dysfunction of uncertain etiology have also been observed rarely with chlordiazepoxide and amitriptyline hydrochloride.

When treatment with chlordiazepoxide and amitriptyline hydrochloride is prolonged, periodic blood counts and liver function tests are advisable.

Note:

Included in the listing which follows are adverse reactions which have not been reported with chlordiazepoxide and amitriptyline hydrochloride.

However, they are included because they have been reported during therapy with one or both of the components or closely related drugs.

Cardiovascular: Hypotension, hypertension, tachycardia, palpitations, myocardial infarction, arrhythmias, heart block, stroke.

Psychiatric: Euphoria, apprehension, poor concentration, delusions, hallucinations, hypomania and increased or decreased libido.

Neurologic: Incoordination, ataxia, numbness, tingling and paresthesias of the extremities, extrapyramidal symptoms, syncope, changes in EEG patterns.

Anticholinergic: Disturbance of accommodation, paralytic ileus, urinary retention, dilatation of urinary tract.

Allergic: Skin rash, urticaria, photosensitization, edema of face and tongue, pruritus.

Hematologic: Bone marrow depression including agranulocytosis, eosinophilia, purpura, thrombocytopenia.

Gastrointestinal: Nausea, epigastric distress, vomiting, anorexia, stomatitis, peculiar taste, diarrhea, black tongue.

Endocrine: Testicular swelling and gynecomastia in the male, breast enlargement, galactorrhea and minor menstrual irregularities in the female, elevation and lowering of blood sugar levels, and syndrome of inappropriate ADH (antidiuretic hormone) secretion.

Other: Headache, weight gain or loss, increased perspiration, urinary frequency, mydriasis, jaundice, alopecia, parotid swelling.

Usage information

Dosing and administration

DOSAGE AND ADMINISTRATION Optimum dosage varies with the severity of the symptoms and the response of the individual patient.

When a satisfactory response is obtained, dosage should be reduced to the smallest amount needed to maintain the remission.

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

In some patients, a single dose at bedtime may be sufficient.

In general, lower dosages are recommended for elderly patients.

Chlordiazepoxide and amitriptyline hydrochloride tablets are recommended in an initial dosage of 3 or 4 tablets daily in divided doses; this may be increased to 6 tablets daily as required.

Some patients respond to smaller doses and can be maintained on 2 tablets daily.

Chlordiazepoxide and amitriptyline hydrochloride tablets in an initial dosage of three or four tablets daily in divided doses may be satisfactory in patients who do not tolerate higher doses.

Pregnancy and lactation
Nursing Mothers It is not known whether this drug is excreted in human milk. As a general rule, nursing should not be undertaken while a patient is on a drug, since many drugs are excreted in human milk.

Interactions

Drug and Treatment Interactions Because of its amitriptyline component, chlordiazepoxide and amitriptyline hydrochloride may block the antihypertensive action of guanethidine or compounds with a similar mechanism of action.

Drugs Metabolized by P450 2D6: The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7 % to 10 % of Caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available.

Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses.

Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small or quite large (8-fold increase in plasma AUC of the TCA).

In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers.

An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy.

The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the type 1c antiarrhythmics propafenone and flecainide).

While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition.

The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved.

Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other.

Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).

Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug.

Furthermore, whenever one of these other drugs is withdrawn from cotherapy, an increased dose of tricyclic antidepressant may be required.

It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6.

The effects of concomitant administration of chlordiazepoxide and amitriptyline hydrochloride and other psychotropic drugs have not been evaluated.

Sedative effects may be additive.

Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants and benzodiazepines, thereby delaying elimination and increasing steady-state concentrations of these drugs.

Clinically significant effects have been reported with the tricyclic antidepressants when used concomitantly with cimetidine (Tagamet®).

The drug should be discontinued several days before elective surgery.

Concurrent administration of ECT and chlordiazepoxide and amitriptyline hydrochloride should be limited to those patients for whom it is essential.

More information

Category Value
Authorisation number ANDA072277
Agency product number 6RZ6XEZ3CR
Orphan designation No
Product NDC 49884-265,49884-266
Date Last Revised 13-06-2012
Type HUMAN PRESCRIPTION DRUG
RXCUI 856769
Marketing authorisation holder Par Pharmaceutical Inc
Warnings Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term stu