Chlordiazepoxide And Amitriptyline Hcl
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Questions & Answers
Side Effects & Adverse Reactions
Clinical Worsening and Suicide Risk: 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 18-24) 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 4400 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 the 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 1000 patients treated) are provided in Table 1.
| Increases Compared to Placebo |
| < 18 |
| 14 additional cases |
| 18-24 |
| 5 additional cases |
| Decreases Compared to Placebo |
| 25-64 |
| 1 fewer case |
| ≥ 65 |
| 6 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 the 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 placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All pediatric 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 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 healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for chlordiazepoxide and amitriptyline hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that chlordiazepoxide and amitriptyline hydrochloride is not approved for use in treating bipolar depression.
General: Because of the atropine-like action of the amitriptyline component, great care should be used in treating patients with a history of urinary retention or angle-closure glaucoma. In patients with glaucoma, even average doses may precipitate an attack. Severe constipation may occur in patients taking tricyclic antidepressants in combination with anticholinergic-type drugs.
Patients with cardiovascular disorders should be watched closely. Tricyclic antidepressant drugs, particularly when given in high doses, have been reported to produce arrhythmias, sinus tachycardia and prolongation of conduction time. Myocardial infarction and stroke have been reported in patients receiving drugs of this class.
Because of the sedative effects of chlordiazepoxide and amitriptyline hydrochloride, patients should be cautioned about combined effects with alcohol or other CNS depressants. The additive effects may produce a harmful level of sedation and CNS depression.
Patients receiving chlordiazepoxide and amitriptyline hydrochloride should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle.
Usage in Pregnancy: Safe use of chlordiazepoxide and amitriptyline hydrochloride tablets during pregnancy and lactation has not been established. Because of the chlordiazepoxide component, please note the following:
An increased risk of congenital malformations associated with the use of minor tranquilizers (chlordiazepoxide, diazepam and meprobamate) during the first trimester of pregnancy has been suggested in several studies. Because use of these drugs is rarely a matter of urgency, their use during this period should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug.
Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE section).
Legal Issues
There is currently no legal information available for this drug.
FDA Safety Alerts
There are currently no FDA safety alerts available for this drug.
Manufacturer Warnings
There is currently no manufacturer warning information available for this drug.
FDA Labeling Changes
There are currently no FDA labeling changes available for this drug.
Uses
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.
History
There is currently no drug history available for this drug.
Other Information
Chlordiazepoxide and amitriptyline hydrochloride tablets combine for oral administration, chlordiazepoxide, an agent for the relief of anxiety and tension, and amitriptyline, an antidepressant. Each film coated tablet for oral administration contains 5 mg chlordiazepoxide and 12.5 mg amitriptyline (as the hydrochloride salt) or 10 mg chlordiazepoxide and 25 mg amitriptyline as the hydrochloride salt).
Each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, hypromellose, hydroxypropyl cellulose, isopropyl alcohol, lactose anhydrous, macrogol/PEG-400, magnesium stearate, povidone, pregelatinized starch, sodium lauryl sulfate, and titanium dioxide. In addition, the 5mg/12.5 mg tablet includes FD&C Yellow #6 and FD&C Red #40
Chlordiazepoxide is a benzodiazepine with the formula 7-chloro-2-(methyl-amino)-5-phenyl-3H-1,4 benzodiazepine 4-oxide. It is a slightly yellow crystalline material and is insoluble in water. The chemical structure is:
Amitriptyline is a dibenzocycloheptadiene derivative. The formula is 10, 11-dihydro-N,N-dimethyl-5H dibenzo[a,d]cycloheptene-Δ5γ-propylamine hydrochloride. It is a white or practically white crystalline compound that is freely soluble in water. The chemical structure is:
Sources
Chlordiazepoxide And Amitriptyline Hcl Manufacturers
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Par Pharmaceutical Inc
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Chlordiazepoxide And Amitriptyline Hcl | Par Pharmaceutical Inc
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.
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