prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated. amitriptyline and umeclidinium bromide/vilanterol inhaled both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Avoid or Use Alternate Drug. Exercise extreme caution if vilanterol coadministered with MAOIs or TCAs, or within 2 weeks of discontinuation of these drugs; adrenergic agonist effects on the cardiovascular system may be potentiatedvalbenazineMonitor Closely (1)valbenazine and amitriptyline both increase QTc interval. Use Caution/Monitor.valerianMonitor Closely (1)valerian and amitriptyline both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)valerian and chlordiazepoxide both increase sedation. Avoid or Use Alternate Drug.vandetanibSerious - Use Alternative (1)amitriptyline, vandetanib. Either increases toxicity of the other by QTc interval. Avoid or Use Alternate Drug. Avoid coadministration with drugs known to prolong QT interval; if a drug known to prolong QT interval must be used, more frequent ECG monitoring is recommended.vasopressinMinor (1)amitriptyline increases effects of vasopressin by pharmacodynamic synergism. Minor/Significance Unknown.vecuroniumMonitor Closely (1)vecuronium and amitriptyline both decrease cholinergic effects/transmission. Use Caution/Monitor.vemurafenibSerious - Use Alternative (1)vemurafenib and amitriptyline both increase QTc interval. Avoid or Use Alternate Drug. Concomitant use of vemurafenib with drugs that prolong QT interval is not recommended.venlafaxineMonitor Closely (1)amitriptyline and venlafaxine both increase QTc interval. Modify Therapy/Monitor Closely.Serious - Use Alternative (1)venlafaxine and amitriptyline both increase serotonin levels. Avoid or Use Alternate Drug.verapamilMonitor Closely (1)verapamil will increase the level or effect of amitriptyline by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. The frequency and severity of amitriptyline adverse effects (sedation, anticholinergic effects and orthostatic hypotension) may be increased. Cardiac dysrhythmic effects may be additive. Minor (2)verapamil will increase the level or effect of amitriptyline by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown. verapamil increases levels of amitriptyline by decreasing metabolism. Minor/Significance Unknown.vilanterol/fluticasone furoate inhaledSerious - Use Alternative (2)amitriptyline and vilanterol/fluticasone furoate inhaled both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Avoid or Use Alternate Drug. Exercise extreme caution if vilanterol coadministered with MAOIs or TCAs, or within 2 weeks of discontinuation of these drugs; adrenergic agonist effects on the cardiovascular system may be potentiated amitriptyline increases toxicity of vilanterol/fluticasone furoate inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.vilazodoneSerious - Use Alternative (1)amitriptyline, vilazodone. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug. Concomitant therapy should be discontinued immediately if signs or symptoms of serotonin syndrome emerge and supportive symptomatic treatment should be initiated. .vildagliptinMinor (1)amitriptyline increases effects of vildagliptin by pharmacodynamic synergism. Minor/Significance Unknown.vinpocetineMinor (1)chlordiazepoxide increases effects of vinpocetine by unspecified interaction mechanism. Minor/Significance Unknown. Desirable interaction enhanced memory improvement (based on preliminary trial).voclosporinMonitor Closely (1)voclosporin, amitriptyline. Either increases effects of the other by QTc interval. Use Caution/Monitor.voriconazoleMonitor Closely (3)voriconazole will increase the level or effect of chlordiazepoxide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. voriconazole will increase the level or effect of amitriptyline by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. amitriptyline and voriconazole both increase QTc interval. Modify Therapy/Monitor Closely.Minor (2)voriconazole increases levels of chlordiazepoxide by decreasing metabolism. Minor/Significance Unknown. voriconazole will increase the level or effect of amitriptyline by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.vortioxetineSerious - Use Alternative (1)amitriptyline, vortioxetine. Either increases effects of the other by serotonin levels. Avoid or Use Alternate Drug.voxelotorSerious - Use Alternative (1)voxelotor will increase the level or effect of chlordiazepoxide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.warfarinMonitor Closely (1)amitriptyline increases effects of warfarin by unspecified interaction mechanism. Use Caution/Monitor.xylometazolineMonitor Closely (2)chlordiazepoxide increases and xylometazoline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor. amitriptyline increases and xylometazoline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.Serious - Use Alternative (1)amitriptyline, xylometazoline. Other (see comment). Avoid or Use Alternate Drug. Comment: Tricyclic antidepressants increase or decrease effects of sympathomimetics, by blocking reuptake of NE, or blocking uptake of indirect sympathomimetics into the adrenergic neuron.yohimbeSerious - Use Alternative (1)yohimbe, amitriptyline. Mechanism: unspecified interaction mechanism. Contraindicated. May cause increase or decrease in blood pressure.yohimbineMonitor Closely (2)amitriptyline increases and yohimbine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor. chlordiazepoxide increases and yohimbine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.Serious - Use Alternative (1)amitriptyline, yohimbine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tricyclic antidepressants increase or decrease effects of sympathomimetics, by blocking reuptake of NE, or blocking uptake of indirect sympathomimetics into the adrenergic neuron.zafirlukastMinor (1)zafirlukast will increase the level or effect of amitriptyline by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.ziconotideMonitor Closely (2)amitriptyline and ziconotide both increase sedation. Use Caution/Monitor. chlordiazepoxide and ziconotide both increase sedation. Use Caution/Monitor.ziprasidoneMonitor Closely (2)chlordiazepoxide and ziprasidone both increase sedation. Use Caution/Monitor. ziprasidone and amitriptyline both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)amitriptyline and ziprasidone both increase QTc interval. Avoid or Use Alternate Drug.zolmitriptanMonitor Closely (1)zolmitriptan and amitriptyline both increase serotonin levels. Modify Therapy/Monitor Closely.zolpidemMinor (2)zolpidem, chlordiazepoxide. Either increases effects of the other by pharmacodynamic synergism. Minor/Significance Unknown. Additive CNS depression. zolpidem, amitriptyline. Either increases effects of the other by pharmacodynamic synergism. Minor/Significance Unknown. Additive CNS depression.zotepineMonitor Closely (1)chlordiazepoxide and zotepine both increase sedation. Use Caution/Monitor. Frequency Not Defined Drowsiness Dry mouth Constipation Blurred vision Dizziness Bloating Vivid dreams Impotence Tremor Confusion Nasal congestion Edema Syncope Ataxia EEG abnormalities Menstrual irregularities Blood dyscrasias (agranulocytosis) Hepatic dysfunction (jaundice) Black Box Warnings Children and Antidepressants In short-term studies, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults (age <24 yr) taking antidepressants for major depressive disorders and other psychiatric illnesses This increase was not seen in patients aged >24 yr; slight decrease in suicidal thinking was seen in adults >65 yr; risks must be weighed in children and young adults against the benefits of taking antidepressants Patients should be monitored closely for changes in behavior, clinical worsening, and suicidal tendencies; monitor during the initial 1-2 months of therapy and dosage adjustments Patient’s family should communicate to the healthcare provider any abrupt changes in behavior Worsening behavior and suicidal tendencies that are not part of the presenting symptoms may require discontinuation of therapy Not approved for pediatric patients Antipsychotics & Dementia Patients with dementia-related psychosis that are treated with antipsychotic drugs are at an increased risk of death as shown in short-term controlled trials; deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature Not approved for treatment of dementia-related psychosis Central nervous system (CNS) depressants Concomitant use of benzodiazepines and opioids may result in profound respiratory depression, coma, and death; administer concomitantly when there are no alternative options; limit dosages and durations to minimum required; monitor for signs and symptoms of respiratory depression and sedation Addiction, abuse, and misuse On September 2020, FDA addressed serious risks of benzodiazepine addiction, abuse, and misuse, which can lead to overdose and death Physical dependence can occur when taken steadily for several days to weeks, even as prescribed Stopping abruptly or reducing dosage too quickly can result in withdrawal reactions, including seizures, which can be life-threatening Assess each patient’s risk prior to prescribing and monitor regularly for the development of these behaviors or conditions 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 and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction Risks of dependence and withdrawal increase with longer treatment duration and higher daily dose; although injection is indicated only for intermittent use, if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction may precipitate acute withdrawal reactions, including seizures, which can be life-threatening; use gradual taper when discontinuing therapy to reduce withdrawal reactions risk Contraindications Hypersensitivity Severe cardiovascular disorders Angle clossure glaucoma Within 14 days of MAOIs Any drugs or conditions that prolong QT interval Acute recovery post-MI Cautions Caution in BPH, urinary/GI retention, increased IOP, thyroid dysfunction, open-angle glaucoma, seizure disorders, brain tumor, respiratory impairment, respiratory disease, Clinical worsening & suicide ideation may occur despite medication in adolescents & young adults (aged 18-24 yr) Write prescription for smallest effective dose Risk of anticholinergic side-effects May cause orthostatic hypotension Paradoxical reactions including hyperactive or aggressive behavior reported Both agents may cause sedation and impair ability to perform tasks requiring mental alertness SIADH and hyponatremia reported with therapy Some patients may experience a large increase in amitriptyline concentration in presence of topiramate; any adjustments in amitriptyline dose should be made according to patient's clinical response and not on basis of plasma level Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases risk of drug-related mortality compared to use of opioids alone; if a decision is made to prescribe the drug concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use; follow patients closely for signs and symptoms of respiratory depression and sedation; advise both patients and caregivers about risks of respiratory depression and sedation when the drug is used with opioids Use of drug, particularly in patients at elevated risk of abuse, necessitates counseling about risks and proper use of drug along with monitoring for signs and symptoms of abuse, misuse, and addiction; do not exceed recommended dosing frequency Avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (eg, opioid analgesics, stimulants); advise patients on proper disposal of unused drug; if a substance use disorder is suspected, evaluate patient and institute (or refer them for) early treatment, as appropriate For patients using treated more frequently than recommended, to reduce risk of withdrawal reactions, use a gradual taper to discontinue therapy (a patient-specific plan should be used to taper the dose) 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 In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months Pregnancy Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to this drug combination during pregnancy Use of this medication 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 Advise pregnant females that receiving therapy 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 Instruct patients to inform their healthcare provider if they are pregnant Monitor neonates exposed during pregnancy or labor for signs of sedation and monitor neonates exposed during pregnancy for signs of withdrawal; manage these neonates accordingly Lactation Advise patients that breastfeeding is not recommended during treatment Pregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action Chlordiazepoxide: Antianxiety agent; depresses all levels of CNS, including limbic and reticular formation, possibly by increasing gamma-aminobutyric acid (GABA) activity, a major inhibitory neurotransmitter Amitriptyline: Antidepressant; neurotransmitter (especially norepinephrine and serotonin) reuptake inhibitor; elicits anticholinergic effects Absorption Bioavailability: Slow and erratic following IM admin (chlordiazepoxide) Peak serum time: 4 hr (amitriptyline) Peak serum time: 0.5-2 hr Onset of action: 1-5 min (IV, chlordiazepoxide) Onset of action: 6 weeks Duration: 15-60 min (IV, chlordiazepoxide) Vd: 3.3 L/kg (chlordiazepoxide) Metabolism Chlordiazepoxide: demoxepam, desmethylchlordiazepoxide, desmethyldiazepam, oxazepam Amiptriptyline: hepatic metabolism via CYP2C19, CYP3A4; nortriptyline is an active metabolite Elimination Half-Life Chlordiazepoxide: 6.6-28 hr Amitriptyline: 9-27 hr Excretion