Chlordiazepoxide and Amitriptyline Hydrochloride

INDICATIONS AND USAGE Chlordiazepoxide and amitriptyline hydrochloride tablets are indicated for the treatment of patients with moderate to severe depression associated with moderate to severe anxiety. The therapeutic response to chlordiazepoxide and amitriptyline hydrochloride tablets occurs earlier and with fewer treatment failures than when either amitriptyline or chlordiazepoxide is used alone. Symptoms likely to respond in the first week of treatment include: insomnia, feelings of guilt or worthlessness, agitation, psychic and somatic anxiety, suicidal ideation and anorexia.

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 tablets 10 mg/25 mg are recommended in an initial dosage of 3 or 4 tablets daily in divided doses; this may be increased to 6 tablets daily as required. Some patients respond to smaller doses and can be maintained on 2 tablets daily. Chlordiazepoxide and amitriptyline hydrochloride tablets 5 mg/12.5 mg in an initial dosage of 3 or 4 tablets daily in divided doses may be satisfactory in patients who do not tolerate higher doses. 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 ).

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-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 amitripty…

CONTRAINDICATIONS Chlordiazepoxide and amitriptyline hydrochloride tablets are contraindicated in patients with hypersensitivity to either benzodiazepines or tricyclic antidepressants. It should not be given concomitantly with a monoamine oxidase inhibitor. Hyperpyretic crises, severe convulsions and deaths have occurred in patients receiving a tricyclic antidepressant and a monoamine oxidase inhibitor simultaneously. When it is desired to replace a monoamine oxidase inhibitor with chlordiazepoxide and amitriptyline hydrochloride tablets, a minimum of 14 days should be allowed to elapse after the former is discontinued. Chlordiazepoxide and amitriptyline hydrochloride tablets should then be initiated cautiously with gradual increase in dosage until optimum response is achieved. This drug is contraindicated during the acute recovery phase following myocardial infarction.

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 ). 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 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.

ADVERSE REACTIONS Adverse reactions to chlordiazepoxide and amitriptyline hydrochloride are those associated with the use of either component alone. Most frequently reported were drowsiness, dry mouth, constipation, blurred vision, dizziness and bloating. Other side effects occurring less commonly included vivid dreams, impotence, tremor, confusion and nasal congestion. Many symptoms common to the depressive state, such as anorexia, fatigue, weakness, restlessness and lethargy, have been reported as side effects of treatment with both chlordiazepoxide and amitriptyline hydrochloride tablets and amitriptyline. Granulocytopenia, jaundice and hepatic dysfunction of uncertain etiology have also been observed rarely with chlordiazepoxide and amitriptyline hydrochloride tablets. When treatment with chlordiazepoxide and amitriptyline hydrochloride tablets is prolonged, periodic blood counts and liver function tests are advisable. Note Included in the listing which follows are adverse reactions which have not been reported with chlordiazepoxide and amitriptyline hydrochloride. However, they are included because they have been reported during therapy with one or both of the components or closely related drugs. Cardiovascular: Hypotension, hypertension, tachycardia, palpitations, myocardial infarction, arrhythmias, heart block, stroke. Psychiatric: Euphoria, apprehension, poor concentration, delusions, hallucinations, hypomania and increased or decreased libido. Neurologic: Incoordination, ataxia, numbness, tingling and paresthesias of the extremities, extrapyramidal symptoms, syncope, changes in EEG patterns. Anticholinergic: Disturbance of accommodation, paralytic ileus, urinary retention, dilatation of urinary tract. Allergic: Skin rash, urticaria, photosensitization, edema of face and tongue, pruritus, drug reaction with eosinophilia and systemic symptoms (DRESS). Hematologic: Bone marrow depression including agranulocytosis, eosinophilia, purpura, thrombocytopenia. Gastrointestinal: Nausea, epigastric distress, vomiting, anorexia, stomatitis, peculiar taste, diarrhea, black tongue. Endocrine: Testicular swelling and gynecomastia in the male, breast enlargement, galactorrhea and minor menstrual irregularities in the female, elevation and lowering of blood sugar levels, and syndrome of inappropriate ADH (antidiuretic hormone) secretion. Other: Headache, weight gain or loss, increased perspiration, urinary frequency, mydriasis, jaundice, alopecia, parotid swelling, hyponatremia.