Chlordiazepoxide,Amitriptyline

Chlordiazepoxide and amitriptyline hydrochloride tablets, USP combine for oral administration, chlordiazepoxide, an agent for the relief of anxiety and tension, and amitriptyline, an antidepressant. It is available as white, film-coated, round, unscored tablets, each containing 10 mg chlordiazepoxide and 27.98 mg of amitriptyline hydrochloride equivalent to 25 mg amitriptyline; and in green, film-coated, round, unscored tablets, each containing 5 mg chlordiazepoxide and 14 mg of amitriptyline hydrochloride equivalent to 12.5 mg amitriptyline. Each tablet contains colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch (corn), sodium lauryl sulfate and titanium dioxide. In addition, the 5 mg/12.5 mg tablets also contain D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake and the 10 mg/25 mg tablets also contain calcium sulfate and talc.

Chlordiazepoxide, USP is a benzodiazepine with the formula 7-chloro-2-(methylamino)-5-phenyl-3H-1,4-benzodiazepine-4-oxide. It is a yellow crystalline powder and is insoluble in water. The molecular weight is 299.76.

Amitriptyline hydrochloride, USP is a dibenzocycloheptadiene derivative. The formula is 10,11-dihydro-N,N-dimethyl-5H-dibenzo[a,d]cycloheptene-Δ5,γ-propylamine hydrochloride. It is a white or practically white crystalline powder that is freely soluble in water. The molecular weight is 313.87.

Chlordiazepoxide and amitriptyline hydrochloride tablets are 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 tablets, a minimum of 14 days should be allowed to elapse after the former is discontinued. Chlordiazepoxide and amitriptyline hydrochloride tablets 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.

Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including chlordiazepoxide and amitriptyline hydrochloride tablets, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids

alone. If a decision is made to prescribe chlordiazepoxide and amitriptyline hydrochloride tablets concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of chlordiazepoxide and amitriptyline hydrochloride tablets than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking chlordiazepoxide and amitriptyline hydrochloride tablets, prescribe a lower initial dose of the opioid and titrate based upon clinical response.

Advise both patients and caregivers about the risks of respiratory depression and sedation when chlordiazepoxide and amitriptyline hydrochloride tablets are used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see PRECAUTIONS: Drug-Drug Interactions).

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 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 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.

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 health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for chlordiazepoxide and amitriptyline hydrochloride tablets 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 tablets are not approved for use in treating bipolar depression.

Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including chlordiazepoxide and amitriptyline hydrochloride tablets may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

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 tablets, 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 tablets 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.)

Adverse reactions to chlordiazepoxide and amitriptyline hydrochloride tablets 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 hydrochloride tablets and amitriptyline.

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

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 10 mg/25 mg 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 5 mg/12.5 mg in an initial dosage of 3 or 4 tablets daily in divided doses may be satisfactory in patients who do not tolerate higher doses.

NDC 0378-0211-01

Chlordiazepoxide
and
Amitriptyline HCl
Tablets, USP
CIV
5 mg/
12.5 mg*

Rx only     100 Tablets

*Each film-coated tablet contains
5 mg of chlordiazepoxide, USP and
14 mg of amitriptyline hydrochloride,
USP equivalent to 12.5 mg of
amitriptyline.

Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication
out of the reach of children.

Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]

Store in a dry place.

Usual Adult Dosage: See
accompanying prescribing
information.

PHARMACIST: Dispense the
accompanying Medication
Guide to each patient.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

RM0211A13