chlordiazepoxide and amitriptyline hydrochloride

INDICATIONS 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.

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.