Chlordiazepoxide And Amitriptyline Hydrochloride

• Concomitant 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

  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 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 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 patient’s risk for abuse, misuse, and addiction (e.g., using a 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 a 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 a 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 a 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 1,000 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 Patients

  Age Range	Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients Treated
  	Increases Compared to Placebo
  < 18 years old	14 additional patients
  18 to 24 years old	5 additional patients
  	Decreases Compared to Placebo
  25 to 64 years old	1 fewer patient
  ≥ 65 years old	6 fewer patients

  
  
  

  It 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 a 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.

  
  
  

  Serotonin Syndrome

  : The development of a potentially life-threatening serotonin syndrome has been reported with tricyclic antidepressants, including chlordiazepoxide and amitriptyline hydrochloride tablets, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, SSRI/SNRI, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

  
  
  

  The concomitant use of chlordiazepoxide and amitriptyline hydrochloride tablets with MAOIs intended to treat psychiatric disorders is contraindicated. Chlordiazepoxide and amitriptyline hydrochloride tablets should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking chlordiazepoxide and amitriptyline hydrochloride tablets. Chlordiazepoxide and amitriptyline hydrochloride tablets should be discontinued before initiating treatment with the MAOI (see

  CONTRAINDICATIONS

  and

  DOSAGE AND ADMINISTRATION

  ). If concomitant use of chlordiazepoxide and amitriptyline hydrochloride tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with chlordiazepoxide and amitriptyline hydrochloride tablets and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

  
  
  

  Activation of Mania or Hypomania

  In patients with bipolar disorder, treating a depressive episode with chlordiazepoxide and amitriptyline hydrochloride tablets or another antidepressant may precipitate a 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.

  
  
  

  Hyponatremia

  
  
  

  Hyponatremia has occurred as a result of treatment with chlordiazepoxide and amitriptyline hydrochloride tablets

  .

  In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included syncope, seizure, coma, respiratory arrest, and death.

  
  
  

  In patients with symptomatic hyponatremia, discontinue chlordiazepoxide and amitriptyline hydrochloride tablets and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with chlordiazepoxide and amitriptyline hydrochloride tablets.

  
  
  

  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.

  
  
  

  Neonatal Sedation and Withdrawal Syndrome

  Use of chlordiazepoxide and amitriptyline hydrochloride tablets late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see

  PRECAUTIONS

  :

  Pregnancy)

  . Monitor neonates exposed to chlordiazepoxide and amitriptyline hydrochloride tablets during pregnancy or labor for signs of sedation and monitor neonates exposed to chlordiazepoxide and amitriptyline hydrochloride tablets during pregnancy for signs of withdrawal; manage these neonates accordingly.
  
  

  and
  
  

  PRECAUTIONS

  General

  Use with caution in patients with a 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.

  
  
  

  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 is used with opioids and not to use such drugs concomitantly unless supervised by a 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 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 a 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 a 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

  ).

  
  
  

  Pregnancy

  Advise pregnant females that use of chlordiazepoxide and amitriptyline hydrochloride tablets late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see

  WARNINGS

  :

  Neonatal Sedation and Withdrawal Syndrome

  and

  PRECAUTIONS

  :

  Pregnancy

  ). Instruct patients to inform their healthcare provider if they are pregnant.

  
  
  

  Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to chlordiazepoxide and amitriptyline hydrochloride tablets during pregnancy (see

  PRECAUTIONS

  :

  Pregnancy

  ).

  
  
  

  Nursing

  Advise patients that breastfeeding is not recommended during treatment with chlordiazepoxide and amitriptyline hydrochloride tablets (see

  PRECAUTIONS

  :

  Nursing Mothers

  ).

  
  
  

  Essential Laboratory Tests

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

  
  
  

  Drug-Drug 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 GABA_Asites 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.

  
  
  

  Topiramate

  Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels.

  
  
  

  Drug and Treatment Interactions

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

  
  
  

  Drugs Metabolized by P450 2D6

  The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small or quite large (8-fold increase in plasma AUC of the TCA).

  
  
  

  In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines,  and  the  type 1c  antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).

  
  
  

  Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from cotherapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered 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).

  
  
  

  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

  Pregnancy Exposure Registry

  There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including chlordiazepoxide and amitriptyline hydrochloride tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at

  https://womensmentalhealth.org/pregnancyregistry/

  .

  
  
  

  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

  PRECAUTIONS

  :

  Clinical Considerations

  ). Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a 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 a 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.

  
  
  

  Clinical Considerations

  Fetal/Neonatal Adverse Reactions

  Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates. Monitor neonates exposed to chlordiazepoxide and amitriptyline hydrochloride tablets during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to chlordiazepoxide and amitriptyline hydrochloride tablets during pregnancy for signs of withdrawal. Manage these neonates accordingly (see

  WARNINGS

  :

  Neonatal Sedation and Withdrawal Syndrome

  ).

  
  
  

  Data

  Human Data

  Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

  
  
  

  Nursing Mothers

  Risk Summary

  It is not known whether this drug is excreted in human milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. Because of the potential for serious adverse reaction, including sedation and withdrawal symptoms in breastfed neonates and infants, advise patients that breastfeeding is not recommended during treatment with chlordiazepoxide and amitriptyline hydrochloride tablets.

  
  
  

  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 a child or adolescent must balance the potential risks with the clinical need.

  
  
  

  Geriatric Use

  In elderly and debilitated patients it is recommended that dosage be limited to the smallest effective amount to preclude the development of ataxia, 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.

  
  
  

  ).
  
  

• The use of benzodiazepines, including c
  hlordiazepoxide 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 c
  hlordiazepoxide and amitriptyline hydrochloride
  tablets
  and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (see
  
  

  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 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 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 patient’s risk for abuse, misuse, and addiction (e.g., using a 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 a 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 a 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 a 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 1,000 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 Patients

  Age Range	Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients Treated
  	Increases Compared to Placebo
  < 18 years old	14 additional patients
  18 to 24 years old	5 additional patients
  	Decreases Compared to Placebo
  25 to 64 years old	1 fewer patient
  ≥ 65 years old	6 fewer patients

  
  
  

  It 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 a 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.

  
  
  

  Serotonin Syndrome

  : The development of a potentially life-threatening serotonin syndrome has been reported with tricyclic antidepressants, including chlordiazepoxide and amitriptyline hydrochloride tablets, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, SSRI/SNRI, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

  
  
  

  The concomitant use of chlordiazepoxide and amitriptyline hydrochloride tablets with MAOIs intended to treat psychiatric disorders is contraindicated. Chlordiazepoxide and amitriptyline hydrochloride tablets should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking chlordiazepoxide and amitriptyline hydrochloride tablets. Chlordiazepoxide and amitriptyline hydrochloride tablets should be discontinued before initiating treatment with the MAOI (see

  CONTRAINDICATIONS

  and

  DOSAGE AND ADMINISTRATION

  ). If concomitant use of chlordiazepoxide and amitriptyline hydrochloride tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with chlordiazepoxide and amitriptyline hydrochloride tablets and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

  
  
  

  Activation of Mania or Hypomania

  In patients with bipolar disorder, treating a depressive episode with chlordiazepoxide and amitriptyline hydrochloride tablets or another antidepressant may precipitate a 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.

  
  
  

  Hyponatremia

  
  
  

  Hyponatremia has occurred as a result of treatment with chlordiazepoxide and amitriptyline hydrochloride tablets

  .

  In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included syncope, seizure, coma, respiratory arrest, and death.

  
  
  

  In patients with symptomatic hyponatremia, discontinue chlordiazepoxide and amitriptyline hydrochloride tablets and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with chlordiazepoxide and amitriptyline hydrochloride tablets.

  
  
  

  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.

  
  
  

  Neonatal Sedation and Withdrawal Syndrome

  Use of chlordiazepoxide and amitriptyline hydrochloride tablets late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see

  PRECAUTIONS

  :

  Pregnancy)

  . Monitor neonates exposed to chlordiazepoxide and amitriptyline hydrochloride tablets during pregnancy or labor for signs of sedation and monitor neonates exposed to chlordiazepoxide and amitriptyline hydrochloride tablets during pregnancy for signs of withdrawal; manage these neonates accordingly.
  
  

  ).
  
  

• The continued use of benzodiazepines, including c
  hlordiazepoxide 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 c
  hlordiazepoxide 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 a gradual taper to discontinue c
  hlordiazepoxide and amitriptyline hydrochloride
  tablets
  or reduce the dosage (see 
  
  

  DOSAGE AND ADMINISTRATION

  Optimum dosage varies with the severity of the symptoms and the response of the individual patient. When a satisfactory response is obtained, dosage should be reduced to the smallest amount needed to maintain the remission. The larger portion of the total daily dose may be taken at bedtime. In some patients, a single dose at bedtime may be sufficient. In general, lower dosages are recommended for elderly patients.

  
  
  

  Chlordiazepoxide and amitriptyline hydrochloride 10 mg/25 mg strength tablets are recommended in an initial dosage of 3 or 4 tablets daily in divided doses; this may be increased to 6 tablets daily as required. Some patients respond to smaller doses and can be maintained on 2 tablets daily.

  
  
  

  Chlordiazepoxide and amitriptyline hydrochloride 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.

  
  
  

  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 a 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 a gradual taper to discontinue chlordiazepoxide and amitriptyline hydrochloride tablets or reduce the dosage. If a 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

  ).

  and
  
  

  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 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 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 patient’s risk for abuse, misuse, and addiction (e.g., using a 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 a 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 a 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 a 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 1,000 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 Patients

  Age Range	Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients Treated
  	Increases Compared to Placebo
  < 18 years old	14 additional patients
  18 to 24 years old	5 additional patients
  	Decreases Compared to Placebo
  25 to 64 years old	1 fewer patient
  ≥ 65 years old	6 fewer patients

  
  
  

  It 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 a 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.

  
  
  

  Serotonin Syndrome

  : The development of a potentially life-threatening serotonin syndrome has been reported with tricyclic antidepressants, including chlordiazepoxide and amitriptyline hydrochloride tablets, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, SSRI/SNRI, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

  
  
  

  The concomitant use of chlordiazepoxide and amitriptyline hydrochloride tablets with MAOIs intended to treat psychiatric disorders is contraindicated. Chlordiazepoxide and amitriptyline hydrochloride tablets should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking chlordiazepoxide and amitriptyline hydrochloride tablets. Chlordiazepoxide and amitriptyline hydrochloride tablets should be discontinued before initiating treatment with the MAOI (see

  CONTRAINDICATIONS

  and

  DOSAGE AND ADMINISTRATION

  ). If concomitant use of chlordiazepoxide and amitriptyline hydrochloride tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with chlordiazepoxide and amitriptyline hydrochloride tablets and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

  
  
  

  Activation of Mania or Hypomania

  In patients with bipolar disorder, treating a depressive episode with chlordiazepoxide and amitriptyline hydrochloride tablets or another antidepressant may precipitate a 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.

  
  
  

  Hyponatremia

  
  
  

  Hyponatremia has occurred as a result of treatment with chlordiazepoxide and amitriptyline hydrochloride tablets

  .

  In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included syncope, seizure, coma, respiratory arrest, and death.

  
  
  

  In patients with symptomatic hyponatremia, discontinue chlordiazepoxide and amitriptyline hydrochloride tablets and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with chlordiazepoxide and amitriptyline hydrochloride tablets.

  
  
  

  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.

  
  
  

  Neonatal Sedation and Withdrawal Syndrome

  Use of chlordiazepoxide and amitriptyline hydrochloride tablets late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see

  PRECAUTIONS

  :

  Pregnancy)

  . Monitor neonates exposed to chlordiazepoxide and amitriptyline hydrochloride tablets during pregnancy or labor for signs of sedation and monitor neonates exposed to chlordiazepoxide and amitriptyline hydrochloride tablets during pregnancy for signs of withdrawal; manage these neonates accordingly.
  
  

  ).
  
  

•  
  Antidepressants 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

  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 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 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 patient’s risk for abuse, misuse, and addiction (e.g., using a 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 a 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 a 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 a 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 1,000 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 Patients

  Age Range	Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients Treated
  	Increases Compared to Placebo
  < 18 years old	14 additional patients
  18 to 24 years old	5 additional patients
  	Decreases Compared to Placebo
  25 to 64 years old	1 fewer patient
  ≥ 65 years old	6 fewer patients

  
  
  

  It 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 a 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.

  
  
  

  Serotonin Syndrome

  : The development of a potentially life-threatening serotonin syndrome has been reported with tricyclic antidepressants, including chlordiazepoxide and amitriptyline hydrochloride tablets, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, SSRI/SNRI, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

  
  
  

  The concomitant use of chlordiazepoxide and amitriptyline hydrochloride tablets with MAOIs intended to treat psychiatric disorders is contraindicated. Chlordiazepoxide and amitriptyline hydrochloride tablets should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking chlordiazepoxide and amitriptyline hydrochloride tablets. Chlordiazepoxide and amitriptyline hydrochloride tablets should be discontinued before initiating treatment with the MAOI (see

  CONTRAINDICATIONS

  and

  DOSAGE AND ADMINISTRATION

  ). If concomitant use of chlordiazepoxide and amitriptyline hydrochloride tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with chlordiazepoxide and amitriptyline hydrochloride tablets and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

  
  
  

  Activation of Mania or Hypomania

  In patients with bipolar disorder, treating a depressive episode with chlordiazepoxide and amitriptyline hydrochloride tablets or another antidepressant may precipitate a 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.

  
  
  

  Hyponatremia

  
  
  

  Hyponatremia has occurred as a result of treatment with chlordiazepoxide and amitriptyline hydrochloride tablets

  .

  In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included syncope, seizure, coma, respiratory arrest, and death.

  
  
  

  In patients with symptomatic hyponatremia, discontinue chlordiazepoxide and amitriptyline hydrochloride tablets and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with chlordiazepoxide and amitriptyline hydrochloride tablets.

  
  
  

  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.

  
  
  

  Neonatal Sedation and Withdrawal Syndrome

  Use of chlordiazepoxide and amitriptyline hydrochloride tablets late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see

  PRECAUTIONS

  :

  Pregnancy)

  . Monitor neonates exposed to chlordiazepoxide and amitriptyline hydrochloride tablets during pregnancy or labor for signs of sedation and monitor neonates exposed to chlordiazepoxide and amitriptyline hydrochloride tablets during pregnancy for signs of withdrawal; manage these neonates accordingly.
  
  

  ). C
  
  
  hlordiazepoxide and amitriptyline hydrochloride tablet is not approved for use in pediatric patients (see
  
  

  PRECAUTIONS

  General

  Use with caution in patients with a 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.

  
  
  

  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 is used with opioids and not to use such drugs concomitantly unless supervised by a 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 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 a 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 a 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

  ).

  
  
  

  Pregnancy

  Advise pregnant females that use of chlordiazepoxide and amitriptyline hydrochloride tablets late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see

  WARNINGS

  :

  Neonatal Sedation and Withdrawal Syndrome

  and

  PRECAUTIONS

  :

  Pregnancy

  ). Instruct patients to inform their healthcare provider if they are pregnant.

  
  
  

  Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to chlordiazepoxide and amitriptyline hydrochloride tablets during pregnancy (see

  PRECAUTIONS

  :

  Pregnancy

  ).

  
  
  

  Nursing

  Advise patients that breastfeeding is not recommended during treatment with chlordiazepoxide and amitriptyline hydrochloride tablets (see

  PRECAUTIONS

  :

  Nursing Mothers

  ).

  
  
  

  Essential Laboratory Tests

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

  
  
  

  Drug-Drug 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 GABA_Asites 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.

  
  
  

  Topiramate

  Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels.

  
  
  

  Drug and Treatment Interactions

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

  
  
  

  Drugs Metabolized by P450 2D6

  The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small or quite large (8-fold increase in plasma AUC of the TCA).

  
  
  

  In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines,  and  the  type 1c  antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).

  
  
  

  Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from cotherapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered 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).

  
  
  

  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

  Pregnancy Exposure Registry

  There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including chlordiazepoxide and amitriptyline hydrochloride tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at

  https://womensmentalhealth.org/pregnancyregistry/

  .

  
  
  

  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

  PRECAUTIONS

  :

  Clinical Considerations

  ). Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a 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 a 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.

  
  
  

  Clinical Considerations

  Fetal/Neonatal Adverse Reactions

  Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates. Monitor neonates exposed to chlordiazepoxide and amitriptyline hydrochloride tablets during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to chlordiazepoxide and amitriptyline hydrochloride tablets during pregnancy for signs of withdrawal. Manage these neonates accordingly (see

  WARNINGS

  :

  Neonatal Sedation and Withdrawal Syndrome

  ).

  
  
  

  Data

  Human Data

  Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

  
  
  

  Nursing Mothers

  Risk Summary

  It is not known whether this drug is excreted in human milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. Because of the potential for serious adverse reaction, including sedation and withdrawal symptoms in breastfed neonates and infants, advise patients that breastfeeding is not recommended during treatment with chlordiazepoxide and amitriptyline hydrochloride tablets.

  
  
  

  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 a child or adolescent must balance the potential risks with the clinical need.

  
  
  

  Geriatric Use

  In elderly and debilitated patients it is recommended that dosage be limited to the smallest effective amount to preclude the development of ataxia, 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.

  
  
  

  ).
  
  

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 tablet 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.

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 10 mg/25 mg strength tablets are recommended in an initial dosage of 3 or 4 tablets daily in divided doses; this may be increased to 6 tablets daily as required. Some patients respond to smaller doses and can be maintained on 2 tablets daily.

Chlordiazepoxide and amitriptyline hydrochloride 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.

Prior to initiating treatment with chlordiazepoxide and amitriptyline hydrochloride tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania (see

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue chlordiazepoxide and amitriptyline hydrochloride tablets or reduce the dosage. If a 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

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 tablet is prolonged, periodic blood counts and liver function tests are advisable.

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 GABA
_Asites 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.