ABUSE SECTION.

Abuse Chlordiazepoxide and amitriptyline hydrochloride tablets are benzodiazepine and CNS depressant with potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of drug by an individual in way other than prescribed by health care provider or for whom it was not prescribed. Drug addiction is cluster of behavioral, cognitive, and physiological phenomena that may include strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders (see WARNINGS: Abuse, Misuse, and Addiction).The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

ADVERSE REACTIONS SECTION.

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 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. 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.

BOXED WARNING SECTION.

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; DEPENDENCE AND WITHDRAWAL REACTIONS; and SUICIDAL THOUGHTS AND BEHAVIORS. oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation (see WARNINGS and PRECAUTIONS). oThe use of benzodiazepines, including chlordiazepoxide and amitriptyline hydrochloride tablets, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing chlordiazepoxide and amitriptyline hydrochloride tablets and throughout treatment, assess each patients risk for abuse, misuse, and addiction (see WARNINGS). oThe continued use of benzodiazepines, including chlordiazepoxide and amitriptyline hydrochloride tablets, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of chlordiazepoxide and amitriptyline hydrochloride tablets after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue chlordiazepoxide and amitriptyline hydrochloride tablets or reduce the dosage (see DOSAGE AND ADMINISTRATION and WARNINGS). oAntidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors (see WARNINGS). Chlordiazepoxide and amitriptyline hydrochloride tablets are not approved for use in pediatric patients (see PRECAUTIONS).. oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation (see WARNINGS and PRECAUTIONS). oThe use of benzodiazepines, including chlordiazepoxide and amitriptyline hydrochloride tablets, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing chlordiazepoxide and amitriptyline hydrochloride tablets and throughout treatment, assess each patients risk for abuse, misuse, and addiction (see WARNINGS). oThe continued use of benzodiazepines, including chlordiazepoxide and amitriptyline hydrochloride tablets, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of chlordiazepoxide and amitriptyline hydrochloride tablets after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue chlordiazepoxide and amitriptyline hydrochloride tablets or reduce the dosage (see DOSAGE AND ADMINISTRATION and WARNINGS). oAntidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors (see WARNINGS). Chlordiazepoxide and amitriptyline hydrochloride tablets are not approved for use in pediatric patients (see PRECAUTIONS).

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Both components of chlordiazepoxide and amitriptyline hydrochloride tablets exert their action in the central nervous system. Extensive studies with chlordiazepoxide in many animal species suggest action in the limbic system. Recent evidence indicates that the limbic system is involved in emotional response. Taming action was observed in some species. The mechanism of action of amitriptyline in man is not known, but the drug appears to interfere with the reuptake of norepinephrine into adrenergic nerve endings. This action may prolong the sympathetic activity of biogenic amines.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Chlordiazepoxide and amitriptyline hydrochloride tablets are contraindicated in patients with hypersensitivity to either benzodiazepines or tricyclic antidepressants. It should not be given concomitantly with monoamine oxidase inhibitor. Hyperpyretic crises, severe convulsions and deaths have occurred in patients receiving tricyclic antidepressant and monoamine oxidase inhibitor simultaneously. When it is desired to replace monoamine oxidase inhibitor with chlordiazepoxide and amitriptyline hydrochloride tablets, 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.

CONTROLLED SUBSTANCE SECTION.

Controlled Substance Chlordiazepoxide and amitriptyline hydrochloride tablets contain chlordiazepoxide, Schedule IV controlled substance.

DEPENDENCE SECTION.

Dependence Physical Dependence. Chlordiazepoxide and amitriptyline hydrochloride tablets may produce physical dependence from continued therapy. Physical dependence is state that develops as result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dose reduction of drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use (see WARNINGS: Dependence and Withdrawal Reactions).To reduce the risk of withdrawal reactions, use gradual taper to discontinue chlordiazepoxide and amitriptyline hydrochloride tablets or reduce the dosage (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Chlordiazepoxide and Amitriptyline Hydrochloride Tablets and WARNINGS: Dependence and Withdrawal Reactions).. Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. Protracted Withdrawal Syndrome Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond to weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.

DESCRIPTION SECTION.

DESCRIPTION. Chlordiazepoxide and amitriptyline hydrochloride tablets, USP combine for oral administration, chlordiazepoxide, an agent for the relief of anxiety and tension, and amitriptyline, an antidepressant. Chlordiazepoxide, USP is benzodiazepine with the formula 7-chloro-2-(methylamino)-5-phenyl-3H-1,4-benzodiazepine-4-oxide. It is yellow crystalline powder and is insoluble in water. The chemical structure is:C16H14CIN3O MW: 299.76Amitriptyline hydrochloride, USP is dibenzocycloheptadiene derivative. The formula is 10,11-dihydro-N,N-dimethyl-5H-dibenzo[a,d]cycloheptene-5,-propylamine hydrochloride. It is white or practically white crystalline powder that is freely soluble in water. The chemical structure is:C20H23NoHCl MW: 313.87Each film-coated tablet for oral administration contains mg of chlordiazepoxide and 14 mg of amitriptyline hydrochloride equivalent to 12.5 mg of amitriptyline or 10 mg of chlordiazepoxide and 27.98 mg of amitriptyline hydrochloride equivalent to 25 mg of amitriptyline. Each tablet contains the following inactive ingredients: 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 mg/12.5 mg tablets also contain D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. Aluminum Lake and FD&C Yellow No. Aluminum Lake and the 10 mg/25 mg tablets also contain calcium sulfate and talc.. Chlordiazepoxide Structural Formula. Amitriptyline Structural Formula.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 5 mg/12.5 mg NDC 0378-0211-01Chlordiazepoxide and Amitriptyline HCl Tablets, USPCIV5 mg/12.5 mgRx only 100 Tablets Each film-coated tablet contains5 mg of chlordiazepoxide, USP and14 mg of amitriptyline hydrochloride,USP equivalent to 12.5 mg ofamitriptyline.Dispense in tight, light-resistantcontainer as defined in the USPusing child-resistant closure.Keep container tightly closed.Keep this and all medicationout of the reach of children.Store at 20 to 25C (68 to 77F).[See USP Controlled RoomTemperature.]Store in dry place.Usual Adult Dosage: See accompanying prescribing information.PHARMACIST: Dispense theaccompanying MedicationGuide to each patient.Manufactured for:Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Made in AustraliaRALP0211A. Chlordiazepoxide and Amitriptyline HCl Tablets, USP mg/12.5 mg Bottle Label.

PEDIATRIC USE SECTION.

Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS: Suicidal Thoughts and Behaviors in Adolescents and Young Adults).Anyone considering the use of chlordiazepoxide and amitriptyline hydrochloride tablets in child or adolescent must balance the potential risks with the clinical need.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Optimum dosage varies with the severity of the symptoms and the response of the individual patient. When 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, 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 or tablets daily in divided doses; this may be increased to tablets daily as required. Some patients respond to smaller doses and can be maintained on tablets daily.Chlordiazepoxide and amitriptyline hydrochloride tablets mg/12.5 mg in an initial dosage of or tablets daily in divided doses may be satisfactory in patients who do not tolerate higher doses.. Screen for Bipolar Disorder Prior to Starting Chlordiazepoxide and Amitriptyline Hydrochloride Tablets Prior to initiating treatment with chlordiazepoxide and amitriptyline hydrochloride tablets or another antidepressant, screen patients for personal or family history of bipolar disorder, mania, or hypomania (see WARNINGS: Activation of Mania or Hypomania).. Discontinuation or Dosage Reduction of Chlordiazepoxide and Amitriptyline Hydrochloride Tablets To reduce the risk of withdrawal reactions, use gradual taper to discontinue chlordiazepoxide and amitriptyline hydrochloride tablets or reduce the dosage. If patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE: Dependence).

DRUG ABUSE AND DEPENDENCE SECTION.

DRUG ABUSE AND DEPENDENCE. Controlled Substance Chlordiazepoxide and amitriptyline hydrochloride tablets contain chlordiazepoxide, Schedule IV controlled substance.. Abuse Chlordiazepoxide and amitriptyline hydrochloride tablets are benzodiazepine and CNS depressant with potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of drug by an individual in way other than prescribed by health care provider or for whom it was not prescribed. Drug addiction is cluster of behavioral, cognitive, and physiological phenomena that may include strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders (see WARNINGS: Abuse, Misuse, and Addiction).The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).. Dependence Physical Dependence. Chlordiazepoxide and amitriptyline hydrochloride tablets may produce physical dependence from continued therapy. Physical dependence is state that develops as result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dose reduction of drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use (see WARNINGS: Dependence and Withdrawal Reactions).To reduce the risk of withdrawal reactions, use gradual taper to discontinue chlordiazepoxide and amitriptyline hydrochloride tablets or reduce the dosage (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Chlordiazepoxide and Amitriptyline Hydrochloride Tablets and WARNINGS: Dependence and Withdrawal Reactions).. Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. Protracted Withdrawal Syndrome Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond to weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used. Tolerance Tolerance to chlordiazepoxide and amitriptyline hydrochloride tablets may develop from continued therapy. Tolerance is physiological state characterized by reduced response to drug after repeated administration (i.e., higher dose of drug is required to produce the same effect that was once obtained at lower dose). Tolerance to the therapeutic effect of chlordiazepoxide and amitriptyline hydrochloride tablets may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

GENERAL PRECAUTIONS SECTION.

General. Use with caution in patients with history of seizures.Close supervision is required when chlordiazepoxide and amitriptyline hydrochloride tablets are 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.

GERIATRIC USE SECTION.

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, oversedation, confusion or anticholinergic effects.Of the total number of subjects in clinical studies of chlordiazepoxide and amitriptyline hydrochloride tablets, 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 cannot be ruled out.The active ingredients in chlordiazepoxide and amitriptyline hydrochloride tablets 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 tablets and observed closely.Clinical studies of chlordiazepoxide and amitriptyline hydrochloride tablets 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.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Chlordiazepoxide and Amitriptyline Hydrochloride Tablets, USP are available containing mg of chlordiazepoxide, USP and 14 mg of amitriptyline hydrochloride, USP equivalent to 12.5 mg of amitriptyline or 10 mg of chlordiazepoxide, USP and 27.98 mg of amitriptyline hydrochloride, USP equivalent to 25 mg of amitriptyline.The mg/12.5 mg tablets are green, film-coated, round, unscored tablets debossed with MYLAN on one side of the tablet and 211 on the other side. They are available as follows:NDC 0378-0211-01bottles of 100 tabletsNDC 0378-0211-05bottles of 500 tabletsThe 10 mg/25 mg tablets are white, film-coated, round, unscored tablets debossed with MYLAN on one side of the tablet and 277 on the other side. They are available as follows:NDC 0378-0277-01bottles of 100 tabletsNDC 0378-0277-05bottles of 500 tabletsStore at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Store in dry place.Dispense in tight, light-resistant container as defined in the USP using child-resistant closure.PHARMACIST: Dispense Medication Guide with each prescription.

INDICATIONS & USAGE SECTION.

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.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. Advise the patient to read the FDA-approved patient labeling (Medication Guide).

NURSING MOTHERS SECTION.

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

OVERDOSAGE SECTION.

OVERDOSAGE. Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible.. Manifestations. Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity.Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia or any of the symptoms listed under ADVERSE REACTIONS.. Management. General. Obtain an ECG and immediately initiate cardiac monitoring. Protect the patients airway, establish an intravenous line and initiate gastric decontamination. minimum of hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient.. Gastrointestinal Decontamination. All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated.. Cardiovascular. maximal limb-lead QRS duration of >= 0.10 seconds may be the best indication of the severity of the overdose. Serum alkalinization, to pH of 7.45 to 7.56, using intravenous sodium bicarbonate and hyperventilation (as needed) should be instituted for patients with dysrhythmias and/or QRS widening. pH 7.60 or pCO2 20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide and procainamide).In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning.. CNS. In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with poison control center.. Psychiatric Follow-up. Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.. Pediatric Management. The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.Poisindex(R) Toxicologic Management. Topic: Antidepressants, Tricyclic. Micromedex Inc. Vol. 85.. Chlordiazepoxide Overdosage. Manifestations of benzodiazepine overdosage include somnolence, confusion, coma and diminished reflexes. Dialysis is of limited value. There have been occasional reports of excitation in patients following benzodiazepine overdosage; if this occurs, barbiturates should not be used. Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE). Since chlordiazepoxide and amitriptyline hydrochloride tablets contain amitriptyline, it is important to note that use of the benzodiazepine antagonist flumazenil is contraindicated in patients who are showing signs of serious cyclic antidepressant overdose.

PRECAUTIONS SECTION.

PRECAUTIONS. General. Use with caution in patients with history of seizures.Close supervision is required when chlordiazepoxide and amitriptyline hydrochloride tablets are 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-Drug Interactions Topiramate. Some patients may experience large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patients clinical response and not on the basis of plasma levels.. Drug and Treatment Interactions The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation. Because of its amitriptyline component, chlordiazepoxide and amitriptyline hydrochloride tablets may block the antihypertensive action of guanethidine or compounds with 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 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 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 patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 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 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 tablets 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(R)).The drug should be discontinued several days before elective surgery.Concurrent administration of ECT and chlordiazepoxide and amitriptyline hydrochloride tablets 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 general rule, nursing should not be undertaken while patient is on 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: Suicidal Thoughts and Behaviors in Adolescents and Young Adults).Anyone considering the use of chlordiazepoxide and amitriptyline hydrochloride tablets in 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, oversedation, confusion or anticholinergic effects.Of the total number of subjects in clinical studies of chlordiazepoxide and amitriptyline hydrochloride tablets, 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 cannot be ruled out.The active ingredients in chlordiazepoxide and amitriptyline hydrochloride tablets 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 tablets and observed closely.Clinical studies of chlordiazepoxide and amitriptyline hydrochloride tablets 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. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. Risks from Concomitant Use with Opioids Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when chlordiazepoxide and amitriptyline hydrochloride tablets are used with opioids and not to use such drugs concomitantly unless supervised by health care provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see WARNINGS: Risks from Concomitant Use with Opioids and PRECAUTIONS: Drug-Drug Interactions).. Abuse, Misuse, and Addiction Inform patients that the use of chlordiazepoxide and amitriptyline hydrochloride tablets, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug (see WARNINGS: Abuse, Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE).. Withdrawal Reactions Inform patients that the continued use of chlordiazepoxide and amitriptyline hydrochloride tablets may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of chlordiazepoxide and amitriptyline hydrochloride tablets may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Instruct patients that discontinuation or dosage reduction of chlordiazepoxide and amitriptyline hydrochloride tablets may require slow taper (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE). Suicidal Thoughts and Behaviors Advise patients and caregivers to look for the emergence of suicidal thoughts and behaviors, especially early during treatment and when the dosage is adjusted up or down (see WARNINGS: Suicidal Thoughts and Behaviors in Adolescents and Young Adults).Patients should be advised that taking chlordiazepoxide and amitriptyline hydrochloride tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have prophylactic procedure (e.g., iridectomy), if they are susceptible.

PREGNANCY SECTION.

Pregnancy See WARNINGS section.

SPL MEDGUIDE SECTION.

Medication Guide Chlordiazepoxide and Amitriptyline Hydrochloride Tablets, USP CIV(klor dye az pox ide am trip ti leen hye droe klor ide) What is the most important information should know about chlordiazepoxide and amitriptyline hydrochloride tabletsoChlordiazepoxide is benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. Get emergency help right away if any of the following happens:oshallow or slowed breathingobreathing stops (which may lead to the heart stopping)oexcessive sleepiness (sedation) Do not drive or operate heavy machinery until you know how taking chlordiazepoxide and amitriptyline hydrochloride tablets with opioids affect you.oRisk of abuse, misuse, and addiction. There is risk of abuse, misuse, and addiction with benzodiazepines, including chlordiazepoxide and amitriptyline hydrochloride tablets, which can lead to overdose and serious side effects including coma and death. oSerious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including chlordiazepoxide and amitriptyline hydrochloride tablets. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. oYou can develop an addiction even if you take chlordiazepoxide and amitriptyline hydrochloride tablets exactly as prescribed by your healthcare provider. oTake chlordiazepoxide and amitriptyline hydrochloride tablets exactly as your healthcare provider prescribed.oDo not share your chlordiazepoxide and amitriptyline hydrochloride tablets with other people. oKeep chlordiazepoxide and amitriptyline hydrochloride tablets in safe place and away from children. oPhysical dependence and withdrawal reactions. Chlordiazepoxide and amitriptyline hydrochloride tablets can cause physical dependence and withdrawal reactions.oDo not suddenly stop taking chlordiazepoxide and amitriptyline hydrochloride tablets. Stopping chlordiazepoxide and amitriptyline hydrochloride tablets suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. oSome people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. oPhysical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.oDo not take more chlordiazepoxide and amitriptyline hydrochloride tablets than prescribed or take chlordiazepoxide and amitriptyline hydrochloride tablets for longer than prescribed. oIncreased risk of suicidal thoughts or actions in children, adolescents and young adults. Chlordiazepoxide and amitriptyline hydrochloride tablets and other antidepressant medicines may increase suicidal thoughts or actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed.oDepression or other serious mental illnesses are the most important cause of suicidal thoughts or actions. Some people may have higher risk of having suicidal thoughts or actions. These include people who have (or have family history of) depression, bipolar illness (also called manic-depressive illness), or history of suicidal thoughts or actions. How can watch for and try to prevent suicidal thoughts and actions in myself or family memberoPay close attention to any changes, especially sudden changes in mood, behavior, thoughts, or feelings or if you or your family member develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed. oCall your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings or if you or your family member develop suicidal thoughts or actions.oKeep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms. Call your healthcare provider right away if you or your family member have any of the following symptoms, especially if they are new, worse, or worry you:othoughts about suicide or dyingonew or worse depressionofeeling agitated or restlessotrouble sleepingoacting aggressive, being angry or violentoother unusual changes in behavior or moodoattempts to commit suicideonew or worse anxiety or irritabilityoan extreme increase in activity and talkingonew or worse panic attacksoacting on dangerous impulsesWhat are chlordiazepoxide and amitriptyline hydrochloride tabletsoChlordiazepoxide and amitriptyline hydrochloride tablets are prescription medicine used to treat moderate to severe depression that can happen with moderate to severe anxiety.oChlordiazepoxide and amitriptyline hydrochloride tablets are federal controlled substance (C-IV) because they contain chlordiazepoxide that can be abused or lead to dependence. Keep chlordiazepoxide and amitriptyline hydrochloride tablets in safe place to prevent misuse and abuse. Selling or giving away chlordiazepoxide and amitriptyline hydrochloride tablets may harm others, and is against the law. Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription medicines or street drugs.oIt is not known if chlordiazepoxide and amitriptyline hydrochloride tablets are safe and effective in children.Do not take chlordiazepoxide and amitriptyline hydrochloride tablets if you:oare allergic to chlordiazepoxide and amitriptyline hydrochloride or any of the ingredients in chlordiazepoxide and amitriptyline hydrochloride tablets. See the end of this Medication Guide for complete list of ingredients in chlordiazepoxide and amitriptyline hydrochloride tablets.ohave had an allergic reaction to other benzodiazepines or tricyclic antidepressant medicinesotake medicine called Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI.oare recovering from heart attackBefore you take chlordiazepoxide and amitriptyline hydrochloride tablets, tell your healthcare provider about all of your medical conditions, including if you:ohave or have family history of suicide, bipolar disorder, or depressionohave history of drug or alcohol abuse or addictionohave eye problemsohave problems urinating or emptying your bladderohave kidney or liver problemsohave or had heart problems, including heart attack or strokeohave or have had seizuresohave thyroid problemoplan to have surgeryoreceive electroconvulsive therapy (ECT)oare pregnant or plan to become pregnant. Chlordiazepoxide and amitriptyline hydrochloride tablets may harm your unborn baby. Avoid taking chlordiazepoxide and amitriptyline hydrochloride tablets during the first trimester of pregnancy. Tell your healthcare provider right away if you become pregnant during treatment with chlordiazepoxide and amitriptyline hydrochloride tablets. oare breastfeeding or plan to breastfeed. It is not known if chlordiazepoxide and amitriptyline hydrochloride pass into your breastmilk. You should not breastfeed while taking chlordiazepoxide and amitriptyline hydrochloride tablets. Talk to your healthcare provider about the best way to feed your baby if you take chlordiazepoxide and amitriptyline hydrochloride tablets.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking chlordiazepoxide and amitriptyline hydrochloride tablets with certain other medicines can cause side effects or affect how well chlordiazepoxide and amitriptyline hydrochloride tablets or the other medicines work. Ask your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare provider can tell you if it is safe to take chlordiazepoxide and amitriptyline hydrochloride tablets with your other medicines. Do not start or stop any other medicines during treatment with chlordiazepoxide and amitriptyline hydrochloride tablets without talking to your healthcare provider first. Stopping chlordiazepoxide and amitriptyline hydrochloride tablets suddenly may cause you to have serious side effects. See, What are the possible side effects of chlordiazepoxide and amitriptyline hydrochloride tablets Know the medicines you take. Keep list of them to show to your healthcare provider and pharmacist when you get new medicine.How should take chlordiazepoxide and amitriptyline hydrochloride tabletsoTake chlordiazepoxide and amitriptyline hydrochloride tablets exactly as your healthcare provider tells you to take them.oIf you take too many chlordiazepoxide and amitriptyline hydrochloride tablets, call your healthcare provider or go to the nearest emergency room right away.What are the possible side effects of chlordiazepoxide and amitriptyline hydrochloride tabletsChlordiazepoxide and amitriptyline hydrochloride tablets may cause serious side effects, including:oSee What is the most important information should know about chlordiazepoxide and amitriptyline hydrochloride tabletsoChlordiazepoxide and amitriptyline hydrochloride tablets can make you sleepy or dizzy, and can slow your thinking and motor skills.oDo not drive, operate heavy machinery, or do other dangerous activities until you know how chlordiazepoxide and amitriptyline hydrochloride tablets affect you.oDo not drink alcohol or take other drugs that may make you sleepy or dizzy while taking chlordiazepoxide and amitriptyline hydrochloride tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, chlordiazepoxide and amitriptyline hydrochloride tablets may make your sleepiness or dizziness much worse. The most common side effects of chlordiazepoxide and amitriptyline hydrochloride tablets include: odrowsinessodizzinessoblurred visionoconstipationodry mouthobloatingThese are not all the possible side effects of chlordiazepoxide and amitriptyline hydrochloride tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store chlordiazepoxide and amitriptyline hydrochloride tabletsoStore chlordiazepoxide and amitriptyline hydrochloride tablets at room temperature between 20 to 25C (68 to 77F). oStore in dry place.oKeep chlordiazepoxide and amitriptyline hydrochloride tablets in tightly closed, child-resistant container and out of the light.Keep chlordiazepoxide and amitriptyline hydrochloride tablets and all medicines out of the reach of children.General information about the safe and effective use of chlordiazepoxide and amitriptyline hydrochloride tablets. Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use chlordiazepoxide and amitriptyline hydrochloride tablets for condition for which they were not prescribed. Do not give chlordiazepoxide and amitriptyline hydrochloride tablets to other people, even if they have the same symptoms that you have. They may harm them. You can ask your pharmacist or healthcare provider for information about chlordiazepoxide and amitriptyline hydrochloride tablets that is written for health professionals.What are the ingredients in chlordiazepoxide and amitriptyline hydrochloride tabletsActive ingredients: chlordiazepoxide, amitriptyline hydrochlorideInactive ingredients: 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 mg/12.5 mg tablets also contain D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. Aluminum Lake and FD&C Yellow No. Aluminum Lake and the 10 mg/25 mg tablets also contain calcium sulfate and talc.Manufactured by: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).The brands listed are trademarks of their respective owners.This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured for:Mylan Pharmaceuticals Inc.Morgantown, WV 26505 U.S.A.Manufactured by: ALPHAPHARM PTY LTD15 Garnet StreetCarole Park QLD 4300Australia.Revised: 3/2021ALP:CDAM:R3mmh/ALP:MG:CDAM:R3m/ALP:MG:CDAM:R3mh. oChlordiazepoxide is benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. Get emergency help right away if any of the following happens:oshallow or slowed breathingobreathing stops (which may lead to the heart stopping)oexcessive sleepiness (sedation). oshallow or slowed breathing. obreathing stops (which may lead to the heart stopping). oexcessive sleepiness (sedation). Do not drive or operate heavy machinery until you know how taking chlordiazepoxide and amitriptyline hydrochloride tablets with opioids affect you.. oRisk of abuse, misuse, and addiction. There is risk of abuse, misuse, and addiction with benzodiazepines, including chlordiazepoxide and amitriptyline hydrochloride tablets, which can lead to overdose and serious side effects including coma and death. oSerious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including chlordiazepoxide and amitriptyline hydrochloride tablets. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. oYou can develop an addiction even if you take chlordiazepoxide and amitriptyline hydrochloride tablets exactly as prescribed by your healthcare provider. oTake chlordiazepoxide and amitriptyline hydrochloride tablets exactly as your healthcare provider prescribed.oDo not share your chlordiazepoxide and amitriptyline hydrochloride tablets with other people. oKeep chlordiazepoxide and amitriptyline hydrochloride tablets in safe place and away from children. oSerious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including chlordiazepoxide and amitriptyline hydrochloride tablets. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. oYou can develop an addiction even if you take chlordiazepoxide and amitriptyline hydrochloride tablets exactly as prescribed by your healthcare provider. oTake chlordiazepoxide and amitriptyline hydrochloride tablets exactly as your healthcare provider prescribed.. oDo not share your chlordiazepoxide and amitriptyline hydrochloride tablets with other people. oKeep chlordiazepoxide and amitriptyline hydrochloride tablets in safe place and away from children.. oPhysical dependence and withdrawal reactions. Chlordiazepoxide and amitriptyline hydrochloride tablets can cause physical dependence and withdrawal reactions.oDo not suddenly stop taking chlordiazepoxide and amitriptyline hydrochloride tablets. Stopping chlordiazepoxide and amitriptyline hydrochloride tablets suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. oSome people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. oPhysical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.oDo not take more chlordiazepoxide and amitriptyline hydrochloride tablets than prescribed or take chlordiazepoxide and amitriptyline hydrochloride tablets for longer than prescribed. oDo not suddenly stop taking chlordiazepoxide and amitriptyline hydrochloride tablets. Stopping chlordiazepoxide and amitriptyline hydrochloride tablets suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. oSome people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. oPhysical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.. oDo not take more chlordiazepoxide and amitriptyline hydrochloride tablets than prescribed or take chlordiazepoxide and amitriptyline hydrochloride tablets for longer than prescribed.. oIncreased risk of suicidal thoughts or actions in children, adolescents and young adults. Chlordiazepoxide and amitriptyline hydrochloride tablets and other antidepressant medicines may increase suicidal thoughts or actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed.oDepression or other serious mental illnesses are the most important cause of suicidal thoughts or actions. Some people may have higher risk of having suicidal thoughts or actions. These include people who have (or have family history of) depression, bipolar illness (also called manic-depressive illness), or history of suicidal thoughts or actions.. oDepression or other serious mental illnesses are the most important cause of suicidal thoughts or actions. Some people may have higher risk of having suicidal thoughts or actions. These include people who have (or have family history of) depression, bipolar illness (also called manic-depressive illness), or history of suicidal thoughts or actions.. How can watch for and try to prevent suicidal thoughts and actions in myself or family memberoPay close attention to any changes, especially sudden changes in mood, behavior, thoughts, or feelings or if you or your family member develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed. oCall your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings or if you or your family member develop suicidal thoughts or actions.oKeep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.. oPay close attention to any changes, especially sudden changes in mood, behavior, thoughts, or feelings or if you or your family member develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed. oCall your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings or if you or your family member develop suicidal thoughts or actions.. oKeep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.. Call your healthcare provider right away if you or your family member have any of the following symptoms, especially if they are new, worse, or worry you:. othoughts about suicide or dying. onew or worse depression. ofeeling agitated or restless. otrouble sleeping. oacting aggressive, being angry or violent. oother unusual changes in behavior or mood. oattempts to commit suicide. onew or worse anxiety or irritability. oan extreme increase in activity and talking. onew or worse panic attacks. oacting on dangerous impulses. oChlordiazepoxide and amitriptyline hydrochloride tablets are prescription medicine used to treat moderate to severe depression that can happen with moderate to severe anxiety.. oChlordiazepoxide and amitriptyline hydrochloride tablets are federal controlled substance (C-IV) because they contain chlordiazepoxide that can be abused or lead to dependence. Keep chlordiazepoxide and amitriptyline hydrochloride tablets in safe place to prevent misuse and abuse. Selling or giving away chlordiazepoxide and amitriptyline hydrochloride tablets may harm others, and is against the law. Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription medicines or street drugs.. oIt is not known if chlordiazepoxide and amitriptyline hydrochloride tablets are safe and effective in children.. oare allergic to chlordiazepoxide and amitriptyline hydrochloride or any of the ingredients in chlordiazepoxide and amitriptyline hydrochloride tablets. See the end of this Medication Guide for complete list of ingredients in chlordiazepoxide and amitriptyline hydrochloride tablets.. ohave had an allergic reaction to other benzodiazepines or tricyclic antidepressant medicines. otake medicine called Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI.. oare recovering from heart attack. ohave or have family history of suicide, bipolar disorder, or depression. ohave history of drug or alcohol abuse or addiction. ohave eye problems. ohave problems urinating or emptying your bladder. ohave kidney or liver problems. ohave or had heart problems, including heart attack or stroke. ohave or have had seizures. ohave thyroid problem. oplan to have surgery. oreceive electroconvulsive therapy (ECT). oare pregnant or plan to become pregnant. Chlordiazepoxide and amitriptyline hydrochloride tablets may harm your unborn baby. Avoid taking chlordiazepoxide and amitriptyline hydrochloride tablets during the first trimester of pregnancy. Tell your healthcare provider right away if you become pregnant during treatment with chlordiazepoxide and amitriptyline hydrochloride tablets. oare breastfeeding or plan to breastfeed. It is not known if chlordiazepoxide and amitriptyline hydrochloride pass into your breastmilk. You should not breastfeed while taking chlordiazepoxide and amitriptyline hydrochloride tablets. Talk to your healthcare provider about the best way to feed your baby if you take chlordiazepoxide and amitriptyline hydrochloride tablets.. oTake chlordiazepoxide and amitriptyline hydrochloride tablets exactly as your healthcare provider tells you to take them.. oIf you take too many chlordiazepoxide and amitriptyline hydrochloride tablets, call your healthcare provider or go to the nearest emergency room right away.. oSee What is the most important information should know about chlordiazepoxide and amitriptyline hydrochloride tablets. oChlordiazepoxide and amitriptyline hydrochloride tablets can make you sleepy or dizzy, and can slow your thinking and motor skills.oDo not drive, operate heavy machinery, or do other dangerous activities until you know how chlordiazepoxide and amitriptyline hydrochloride tablets affect you.oDo not drink alcohol or take other drugs that may make you sleepy or dizzy while taking chlordiazepoxide and amitriptyline hydrochloride tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, chlordiazepoxide and amitriptyline hydrochloride tablets may make your sleepiness or dizziness much worse. oDo not drive, operate heavy machinery, or do other dangerous activities until you know how chlordiazepoxide and amitriptyline hydrochloride tablets affect you.. oDo not drink alcohol or take other drugs that may make you sleepy or dizzy while taking chlordiazepoxide and amitriptyline hydrochloride tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, chlordiazepoxide and amitriptyline hydrochloride tablets may make your sleepiness or dizziness much worse. odrowsiness. odizziness. oblurred vision. oconstipation. odry mouth. obloating. oStore chlordiazepoxide and amitriptyline hydrochloride tablets at room temperature between 20 to 25C (68 to 77F). oStore in dry place.. oKeep chlordiazepoxide and amitriptyline hydrochloride tablets in tightly closed, child-resistant container and out of the light.

SPL UNCLASSIFIED SECTION.

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 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 opioidsalone. If 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 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 patient already taking chlordiazepoxide and amitriptyline hydrochloride tablets, prescribe 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).

WARNINGS SECTION.

WARNINGS. 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 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 opioidsalone. If 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 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 patient already taking chlordiazepoxide and amitriptyline hydrochloride tablets, prescribe 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).. Abuse, Misuse, and Addiction. The use of benzodiazepines, including chlordiazepoxide and amitriptyline hydrochloride tablets, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see DRUG ABUSE AND DEPENDENCE: Abuse).Before prescribing chlordiazepoxide and amitriptyline hydrochloride tablets and throughout treatment, assess each patients risk for abuse, misuse, and addiction (e.g., using standardized screening tool). Use of chlordiazepoxide and amitriptyline hydrochloride tablets, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of chlordiazepoxide and amitriptyline hydrochloride tablets along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. Dependence and Withdrawal Reactions To reduce the risk of withdrawal reactions, use gradual taper to discontinue chlordiazepoxide and amitriptyline hydrochloride tablets or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Chlordiazepoxide and Amitriptyline Hydrochloride Tablets).Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. Acute Withdrawal Reactions. The continued use of benzodiazepines, including chlordiazepoxide and amitriptyline hydrochloride tablets, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of chlordiazepoxide and amitriptyline hydrochloride tablets after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see DRUG ABUSE AND DEPENDENCE: Dependence).. Protracted Withdrawal Syndrome. In some cases, benzodiazepine users have developed protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see DRUG ABUSE AND DEPENDENCE: Dependence). Suicidal Thoughts and Behaviors in Adolescent and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1.Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult PatientsAge RangeDrug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients TreatedIncreases Compared to Placebo< 18 years old14 additional patients18-24 years old5 additional patientsDecreases Compared to Placebo25-64 years old1 fewer patient>= 65 years old6 fewer patientsIt is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing chlordiazepoxide and amitriptyline hydrochloride tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. Activation of Mania or Hypomania In patients with bipolar disorder, treating depressive episode with chlordiazepoxide and amitriptyline hydrochloride tablets or another antidepressant may precipitate mixed/manic episode. Prior to initiating treatment with chlordiazepoxide and amitriptyline hydrochloride tablets, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. 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 patient with anatomically narrow angles who does not have patent iridectomy.. General. Because of the atropine-like action of the amitriptyline component, great care should be used in treating patients with 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 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 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 matter of urgency, their use during this period should almost always be avoided. The possibility that 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.

RISKS.

Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome, and Clinical Considerations). Available data from published observational studies of pregnant women exposed to benzodiazepines do not report clear association with benzodiazepines and major birth defects (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.