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Basic Drug Info
Drug Name:Chlordiazepoxide and Amitriptyline Hydrochloride
Manufacturer:Mylan Pharmaceuticals Inc.
Other Info:Mylan Pharmaceuticals Inc.Morgantown, WV 26505REVISED AUGUST 2007CDAM:R12mc



Clinical Trials:


Indications and Usage
Chlordiazepoxide and amitriptyline hydrochloride is 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 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.
Symptoms -- An indication that a person has a condition or disease. Some examples of symptoms are headache, fever, fatigue, nausea, vomiting, and pain.

Sleeplessness -- Difficulty in going to sleep or getting enough sleep.

Agitation -- A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions.

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.
Hypersensitivity -- Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen.

Convulsions -- the most dramatic type of seizure, characterized by tonic and clonic contraction of most skeletal muscles.

Myocardial Infarction -- NECROSIS of the MYOCARDIUM caused by an obstruction of the blood supply to the heart (CORONARY CIRCULATION).

Warnings

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.

Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients.

The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.

There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.

There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.

The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications.

These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.Table 1 Age RangeDrug-Placebo Difference in Number of Cases of Suicidality Per 1,000 Patients Treated Increases Compared to Placebo < 1814 additional cases 18 to 245 additional cases Decreases Compared to Placebo 25 to 641 fewer case ? 656 fewer cases No suicides occurred in any of the pediatric trials.

There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.

However, there is substantial evidence from placbo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.

Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers.

Such monitoring should include daily observation by families and caregivers.

Prescriptions for chlordiazepoxide and amitriptyline should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

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