Trazodone

371.86

371.86

243-317-1

YBK48BXK30

DTXSID5045043

C29510

Crystals

N06AX05|N - Nervous system

2933990090

42.4

2.8

Solid

1.3141 (rough estimate)

87 °C

528.5±60.0 °C(Predicted)

273.4ºC

1.5790 (estimate)

2.90e-01 g/L

Keep container tightly closed in a dry and well-ventilated place. Keep in a dry place. /Trazadone hydrochloride/

8.03X10-9 mm Hg at 25 deg C (est)

6.74None

Henry's Law constant = 1.74X10-15 atm-cu m/mol at 25 °C (est)

6.74|pKa = 6.14 (50 percent ethanol)

Highly lipophilic|Hydroxyl radical reaction rate constant = 3.16X10-10 cu cm/molec-sec at 25 °C (est)|Ozone reaction rate constant = 8.1X10-18 cu cm/molec-sec at 25 °C (est)

III

6.1(b)

3249

Stable under recommended storage conditions. /Trazadone hydrochloride/

P264, P270, P301+P312, P330, P501

H302

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material; Contaminated packaging:Dispose of as unused product. /Trazadone hydrochloride/|SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Incompatible materials: Strong oxidizing agents /Trazadone hydrochloride/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including trazodone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Trazodone hydrochloride/

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 3 companies from 1 notifications to the ECHA C&L Inventory.|H302: Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P264, P270, P281, P301+P312, P308+P313, P330, P405, and P501

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Trazadone hydrochloride/|Skin protection: Handle with gloves. /Trazadone hydrochloride/|Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Trazadone hydrochloride/|Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Trazadone hydrochloride/

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Trazadone hydrochloride/|Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /Trazadone hydrochloride/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust; Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains; Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Trazadone hydrochloride/

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection. /Trazadone hydrochloride/|Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Trazadone hydrochloride/|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Trazadone hydrochloride/|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

The oral LD50 of trazodone is 690 mg/kg in rats. An overdose of trazodone may result in central nervous system, cardiac, respiratory effects. Signs and symptoms may include dyspnea, bradycardia, hypotension, mental status changes, lack of coordination, and coma, among others. In addition, an overdose may result in priapism, a persistent unrelievable penile tissue erection that may cause permanent damage if not treated promptly. No specific antidote exists for a trazodone overdose. If an overdose occurs, consider the possibility that trazodone may have been combined with other drugs. Contact a poison control center in case of overdose for the most current management guidelines. Dialysis does not accelerate trazodone clearance.|IDENTIFICATION AND USE: Trazodone is in the form of crystals. Trazodone hydrochloride tablets USP are indicated for the treatment of major depressive disorder (MDD) in adults. Trazodone has been used in dogs for events that trigger anxiety. HUMAN EXPOSURE AND TOXICITY: The most severe reactions reported to have occurred with overdose of trazodone alone have been priapism, respiratory arrest, seizures, and ECG changes. The reactions reported most frequently have been drowsiness and vomiting. Trazodone is known to prolong the QT/QTc interval. Some drugs that prolong the QT/QTc interval can cause Torsades de Pointes with sudden, unexplained death. A study of pregnant women who had been exposed to trazodone suggested that the drug does not increase the rate of major malformations above the baseline rate. ANIMAL STUDIES: Tremors, vomiting and clonic convulsions were produced in dogs given 50 and 100 mg/kg/day orally for one month. Administration of approximately 250 mg/kg/day in the diet of rats for 6 months resulted in significantly greater liver weights and slightly lower weight gain in males. Rats were used to conduct a two year carcinogenicity study. In both treatment groups, larger numbers of female rats died sooner than controls; most deaths were related to the presence of pituitary tumors. In both treatment groups at 12, 13 and 14 months, the incidence of palpable masses (mammary tumors, cysts, etc.) was increased also. Two developmental rat studies were conducted: one in which rats were given 100 and 210 mg/kg/day orally during days 10-15 and 6-15 of gestation, respectively; and another in which doses of 150-450 mg/kg/day were given orally during days 9-14 of gestation. Only a sedative effect on dams was noted at 100 mg/kg. Increased sedation, decreased maternal and fetal weights and retarded ossification were produced at doses of 150 mg/kg and higher. A significant increase in resorptions and stillborn fetuses, in addition to retarded fetal growth, occurred with 300 and 450 mg/kg.

Liver test abnormalities occur in a proportion of patients on trazodone, but elevations are usually modest and usually do not require dose modification or discontinuation. At least a dozen instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on trazodone. The onset of injury varies from a few days to 6 months and the pattern of serum enzyme elevations is usually hepatocellular, but mixed and cholestatic forms have also been described. Several cases have had immunoallergic features (rash, fever, eosinophilia), but these were not prominent. Autoimmune (autoantibodies) features are uncommon. Rare instances of acute liver failure and death from trazodone have been reported. Nefazodone, an antidepressant similar in structure and mechanism of action to trazodone, was approved for use in 1998, but is currently not commonly used because of multiple reports of acute hepatocellular injury, with a high mortality rate arising 2 weeks to 6 months after starting therapy.

Concomitant use of trazodone with inhibitors of CYP3A4 can result in substantially increased plasma concentrations of trazodone and increase the potential for adverse effects. In one study, concomitant use of ritonavir (200 mg twice daily for 2 days) and trazodone (a single 50-mg dose) in healthy individuals increased maximum plasma concentrations and decreased clearance of trazodone by 34 and 52%, respectively, and increased area under the plasma concentration-time curve (AUC) and half-life of trazodone by greater than twofold. Adverse effects (e.g., nausea, hypotension, syncope) also were observed with concomitant use of trazodone and ritonavir. The manufacturers of trazodone state that a reduction in trazodone dosage should be considered in patients receiving a potent inhibitor of the CYP3A4 isoenzyme (e.g., indinavir, itraconazole, ketoconazole, nefazodone, ritonavir) concomitantly with trazodone.|... Three clinically significant cases of suspected trazodone & warfarin interactions were identified in a retrospective chart review based on changes in the prothrombin time (PT) & international normalized ratio (INR) that were not explained by other factors. In each of the cases, the INR changed by > or = 1.0 after the initiation or discontinuation of trazodone. In the patients who started trazodone, a subsequent decr in the PT & INR resulted; conversely, the PT & INR increased in the patient who stopped trazodone therapy. Although none of the patients experienced adverse effects due to the marked changes in PT & INR, the warfarin dosages had to be adjusted accordingly on initiation & discontinuation of trazodone. ... These cases show that there is a potentially clinically significant interaction between trazodone & warfarin. The time to onset of the interaction is variable; the mechanism behind it is not known, but it may involve substrate or protein-binding competition. ... The use of trazodone on an as-needed basis for sleep is strongly discouraged in patients who are receiving warfarin, due to the difficulty of achieving a therapeutic PT & INR. Until more is known, patients & clinicians should be educated about this potential interaction & monitor for changes in the anticoagulant effects when trazodone is initiated or stopped.|... Pharmacologic treatment of emotional disorders in HIV-infected patients can be more easily optimized by understanding of potential interactions of psychotropic drugs with medications used to treat HIV infection & its sequelae. ... Biotransformation of the antidepressant trazodone to its principal metabolite, meta-chlorophenylpiperazine (mCPP), was studied in vitro using human liver microsomes & heterologously expressed individual human cytochromes. Interactions of trazodone with the azole antifungal agent, ketoconazole, & with human immunodeficiency virus protease inhibitors (HIVPIs) were studied in the same system. ... Formation of mCPP from trazodone in liver microsomes had a mean (+/- SE) K(m) value of 163 (+/- 21) micromol/l. Ketoconazole, a relatively specific CYP3A inhibitor, impaired mCPP formation consistent with a competitive mechanism, having an inhibition constant (K(i)) of 0.12 (+/- 0.01) micromol/l. Among heterologously expressed human cytochromes, only CYP3A4 mediated formation of mCPP from trazodone; the K(m) was 180 micromol/l, consistent with the value in microsomes. The HIVPI ritonavir was a potent inhibitor of mCPP formation in liver microsomes (K(i) = 0.14 +/- 0.04 micromol/l). The HIVPI indinavir was also a strong inhibitor, whereas saquinavir & nelfinavir were weaker inhibitors. ... CYP3A-mediated clearance of trazodone is inhibited by ketoconazole, ritonavir & indinavir, & indicates the likelihood of pharmacokinetic interactions in vivo.|The effects of trazodone on subjective & objective sleep parameters were compared to those of placebo in a double-blind design in seven patients who developed insomnia during treatment with the selective & reversible MAO-A inhibitor, brofaromine. Trazodone significantly increased deep sleep & altered the architecture of sleep in these patients. Subjectively, patients reported a better & deeper sleep. No negative interactions between brofaromine & trazodone were observed & side-effects were minimal. A low dose of trazodone may be a safe & effective agent in the treatment of MAO-I induced insomnia.|For more Interactions (Complete) data for TRAZODONE (18 total), please visit the HSDB record page.

LD50 Rat oral 690 mg/kg|LD50 Rat iv 91 mg/kg|LD50 Rat ip 178 mg/kg|LD50 Mouse oral 610 mg/kg|LD50 Mouse iv 91 mg/kg

Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including trazodone hydrochloride tablets may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

The plasma protein binding of trazodone is 89-95% according to in vitro studies.

Trazodone's production and administration as an antidepressant(1) may result in its release to the environment through various waste streams(SRC).

A fatal case of suicide with trazodone alone in a 40-yr-old patient is reported. ... Blood collected at admission contained a trazodone toxic concn of 25.4 ug/ml. ... /Salt not specified/

Trazodone is indicated for the treatment of major depressive disorder (MDD). It has been used off-label for adjunct therapy in alcohol dependence, and off-label to treat anxiety and insomnia. It may also be used off-label to treat symptoms of dementia, Alzheimer’s disease, schizophrenia, eating disorders, and fibromyalgia due to its effects on various neurotransmitter receptors.

Trazodone is a serotoninergic modulating antidepressant that is used in therapy of depression, aggressive behavior and panic disorder. Trazodone therapy can be associated with transient, usually asymptomatic elevations in serum aminotransferase levels and has been linked to rare instances of clinically apparent acute liver injury.

Antidepressant Agents

Anti-Anxiety Agents; Antidepressive Agents, Second-Generation; Serotonin Uptake Inhibitors|/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Trazodone is included in the database.|Trazodone hydrochloride tablets USP are indicated for the treatment of major depressive disorder (MDD) in adults. The efficacy of trazodone hydrochloride tablets has been established in trials with the immediate release formulation of trazodone. /Included in US product label/|Although trazodone has been used in the treatment of schizophrenic disorder, the drug is less effective than chlorpromazine. Depressive symptomatology may improve during trazodone therapy, but the drug does not appear to relieve psychotic symptoms in most schizophrenic patients. Based on limited data, trazodone has little value when used alone in patients with chronic schizophrenic disorder without depression; however, it may be a useful adjunct to antipsychotic agents (e.g., phenothiazines) in patients with chronic schizophrenic disorder and associated depression. Unlike tricyclic antidepressants, trazodone does not appear to worsen psychotic symptoms in these patients. /NOT included in US product label/|For more Therapeutic Uses (Complete) data for TRAZODONE (11 total), please visit the HSDB record page.

/BOXED WARNING/ WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of trazodone hydrochloride tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Trazodone hydrochloride tablets are not approved for use in pediatric patients.|All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.|The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with antidepressants alone and may occur with trazodone treatment, but particularly with concomitant use of other serotoninergic drugs (including SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors (MAOIs)), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.|A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described for clinical worsening and suicide risk represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that trazodone hydrochloride tablets is not approved for use in treating bipolar depression.|For more Drug Warnings (Complete) data for TRAZODONE (32 total), please visit the HSDB record page.

Trazodone treats depressed mood and other depression-related symptoms and shows benefit in the treatment of insomnia due to its sedating effects. It is known to prolong the cardiac QT-interval. Memory, alertness, and cognition may be decreased by trazodone, especially in elderly patients due to its central nervous system depressant effects. A note on priapism Trazodone has been associated with the occurrence of priapism, a painful and persistent incidence of penile tissue erection that is unrelievable and can cause permanent neurological damage if left untreated. Patients must be advised to seek immediate medical attention if priapism is suspected.

A structurally and mechanistically diverse group of drugs that are not tricyclics or monoamine oxidase inhibitors. The most clinically important appear to act selectively on serotonergic systems, especially by inhibiting serotonin reuptake. (See all compounds classified as Antidepressive Agents, Second-Generation.)|Agents that alleviate ANXIETY, tension, and ANXIETY DISORDERS, promote sedation, and have a calming effect without affecting clarity of consciousness or neurologic conditions. ADRENERGIC BETA-ANTAGONISTS are commonly used in the symptomatic treatment of anxiety but are not included here. (See all compounds classified as Anti-Anxiety Agents.)|Compounds that specifically inhibit the reuptake of serotonin in the brain. (See all compounds classified as Serotonin Uptake Inhibitors.)

Trazodone is rapidly absorbed in the gastrointestinal tract after oral administration, with a bioavailability ranging from 63-91% and an AUC0−t of 18193.0 ng·h/mL. Food may impact absorption in a variable fashion, and may sometimes lead to decreases in the Cmax of trazodone. In the fed state in 8 healthy volunteers, the Cmax was measured to be 1.47 +/- 0.16 micrograms/mL, and in the fasted state, was measured at 1.88 +/- 0.42 micrograms/mL. The average Tmax after a single dose of 300 mg was 8 hours. Food may increase absorption by up to 20%.|Less than 1% of an oral dose is excreted unchanged in the urine. In a pharmacokinetic study, about 60-70% of radiolabeled was excreted urine within 48 hours. Approximately 9-29% was found to be excreted in feces over a range of 60 to 100 hours. According to the FDA medical review, the kidneys are responsible for 70 to 75% of trazodone excretion. About 21% of trazodone is reported to be excreted by the fecal route and 0.13% of the parent drug is eliminated in the urine as unchanged drug.|A single-dose pharmacokinetic study of 8 volunteers taking trazodone determined a volume of distribution of 0.84 +/- 0.16 L/kg. The FDA medical review of trazodone reports a volume of distribution of 0.47 to 0.84 L/kg.|A decrease in total apparent clearance (5.1 versus 10.8 L/h) was seen elderly volunteers in the fasted state when compared with younger volunteers. Another pharmacokinetic study determined the total body clearance of trazodone to be 5.3 +/- 0.9 L/hr in 8 healthy patients taking a single dose of trazodone.|Following oral administration of single doses of 25, 50, or 100 mg of trazodone to healthy, fasted adults in another study, mean peak plasma trazodone concentrations were 490, 860, and 1620 ng/mL, respectively. The areas under the plasma concentration-time curves (AUCs) were 3.44, 5.95, and 11.19 ug-hr/mL, for the 25-, 50-, and 100-mg doses, respectively. Limited crossover data are available comparing AUCs in fasted and nonfasted patients; however, it appears that the presence of food slightly increases the AUC for trazodone.|Following oral administration of a single 25-mg dose of radiolabeled trazodone to healthy adults in one study, mean peak plasma drug concentrations of 650 and 480 ng/mL occurred at 1.5 and 2.5 hours after ingestion, in the fasted and nonfasted state, respectively.|/MILK/ The excretion of breast milk was studied in six lactating women following the oral administration of a single trazodone tablet (50 mg). The milk/plasma ratio of trazodone based on area under the plasma and milk curves was small: 0.142 +/- 0.045 (mean +/- s.d.). Assuming that the babies would drink 500 mL 12 h-1, they would be exposed to less than 0.005 mg kg-1 as compared to 0.77 mg kg-1 for the mothers. It is concluded that exposure of babies to trazodone via breast milk is very small.|Peak plasma concentrations of trazodone occur approximately 1 hour after oral administration when the drug is taken on an empty stomach or 2 hours after oral administration when taken with food. Following oral administration of multiple doses of trazodone (25 mg 2 or 3 times daily), steady-state plasma concentrations of the drug are usually attained within 4 days and exhibit wide interpatient variation.|For more Absorption, Distribution and Excretion (Complete) data for TRAZODONE (8 total), please visit the HSDB record page.

Trazodone is heavily metabolized and activated in the liver by CYP3A4 enzyme to the active metabolite, m-chlorophenylpiperazine (mCPP). The full metabolism of trazodone has not been thoroughly. Some other metabolites that have been identified are a dihydrodiol metabolite and carboxylic acid.|Trazodone is extensively metabolized in the liver via hydroxylation, oxidation, N-oxidation, and splitting of the pyridine ring. A hydroxylated metabolite and oxotriazolopyridinpropionic acid (an inactive metabolite excreted in urine) are conjugated with glucuronic acid. Results of in vitro studies indicate that metabolism of trazodone to an active metabolite, m-chlorophenylpiperazine, is mediated by the cytochrome P-450 (CYP) 3A4 isoenzyme. The manufacturers state that other metabolic pathways involved in metabolism of trazodone have not been well characterized. Results from animal studies indicate that trazodone does not induce its own metabolism.|In vitro studies in human liver microsomes show that trazodone is metabolized, via oxidative cleavage, to an active metabolite, m-chlorophenylpiperazine (mCPP) by CYP3A4. Other metabolic pathways that may be involved in the metabolism of trazodone have not been well characterized. Trazodone is extensively metabolized; less than 1% of an oral dose is excreted unchanged in the urine.|Approximately 70-75% of an oral dose of trazodone is excreted in urine within 72 hours of administration, principally as metabolites. About 20% of an oral dose of trazodone is excreted in urine as oxotriazolopyridinpropionic acid and its conjugates, and about 10% as a dihydrodiol metabolite; less than 1% of a dose is excreted unchanged. The remainder of an oral dose of the drug is excreted in feces via biliary elimination, principally as metabolites.|Trazodone has known human metabolites that include 1-(3-Chlorophenyl)piperazine, Trazodone epoxide, and p-Hydroxytrazodone.

The plasma elimination half-life was markedly prolonged (13.6 versus 6 hours) elderly volunteers in the fasted state when compared with younger volunteers. Another study of 8 healthy individuals taking a single dose of trazodone indicated a terminal elimination half-life of 7.3 +/- 0.8 hr. A two-phase pattern of trazodone elimination has been reported. Initially, the half-life is reported to range from 3 to 6 hours and the second phase of elimination to range from 5 to 9 hours.|The half-life of trazodone in the initial phase is about 3-6 hours and the half-life in the terminal phase is about 5-9 hours.|... Following IV administration /of trazodone HCl to beagle dogs/, the mean +/- SD elimination half-life /was/ 169 +/- 53 minutes ... . Following oral administration, the mean +/- SD elimination half-life /was/ 166 +/- 47 minutes ... .|In dogs after 8 mg/kg IV, volume of distribution was (all value are means ) 2.53 L/kg, elimination half life 169 minutes, and plasma total body clearance was 11.15 mL/min/kg. After 8 mg/kg PO, bioavailability was 85%, and elimination half life was 166 minutes, peak plasma levels occurred at 445 minutes (mean), but there was wider inter-subject variation (+ or - 271 minutes).

The mechanism of action of trazodone is not fully understood, however, it is known to inhibit the reuptake of serotonin and block both histamine and alpha-1-adrenergic receptors. Despite the fact that trazodone is frequently considered a selective serotonin reuptake inhibitor, several reports have shown that other mechanisms including antagonism at serotonin 5-HT1a, 5-HT1c, and 5-HT2 receptor subtypes may occur. The strongest antagonism of trazodone is reported to occur at the serotonin 5-HT21c receptors, preventing serotonin uptake. In addition to acting on serotonin receptors, trazodone has been shown to inhibit serotonin transporters. The antidepressant effects of trazodone result from the inhibition of receptor uptake, which normally decreases circulating neurotransmitters, contributing to depressive symptoms.|The precise mechanism of antidepressant action of trazodone is unclear, but the drug has been shown to selectively block the reuptake of serotonin (5-HT) at the presynaptic neuronal membrane. The effects of serotonin may thus be potentiated. Unlike other antidepressant agents (e.g., tricyclic antidepressants), trazodone may have a dual effect on the central serotonergic system. Animal studies indicate that trazodone acts as a serotonin agonist at high doses (6-8 mg/kg), while at low doses (0.05-1 mg/kg), it antagonizes the actions of serotonin. Trazodone does not appear to influence the reuptake of dopamine or norepinephrine within the CNS; however, animal studies indicate that trazodone may enhance release of norepinephrine from neuronal tissue. Trazodone does not cause serotonin release in vitro.

...1-(3-chloropropyl)-4-(3-chlorophenyl)piperazine HCl (CCP HCl) a process related impurity in trazodone. /Genotoxic Impurity/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|There is no specific antidote for trazodone hydrochloride overdose. Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the treatment of major depressive disorder. Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Forced diuresis may be useful in facilitating elimination of the drug. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose.|For more Antidote and Emergency Treatment (Complete) data for TRAZODONE (8 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.|/SIGNS AND SYMPTOMS/ The most severe reactions reported to have occurred with overdose of trazodone alone have been priapism, respiratory arrest, seizures, and ECG changes, including QT prolongation. The reactions reported most frequently have been drowsiness and vomiting. Overdosage may cause an increase in incidence or severity of any of the reported adverse reactions.|/SIGNS AND SYMPTOMS/ The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with antidepressants alone and may occur with trazodone treatment, but particularly with concomitant use of other serotoninergic drugs (including SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors (MAOIs)), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.|/SIGNS AND SYMPTOMS/ Trazodone is known to prolong the QT/QTc interval. Some drugs that prolong the QT/QTc interval can cause Torsades de Pointes with sudden, unexplained death. The relationship of QT prolongation is clearest for larger increases (20 msec and greater), but it is possible that smaller QT/QTc prolongations may also increase risk, especially in susceptible individuals, such as those with hypokalemia, hypomagnesemia, or a genetic predisposition to prolonged QT/QTc. Although Torsades de Pointes has not been observed with the use of trazodone hydrochloride tablets at recommended doses in premarketing trials, experience is too limited to rule out an increased risk. However, there have been postmarketing reports of Torsades de Pointes with the immediate-release form of trazodone (in the presence of multiple confounding factors), even at doses of 100 mg per day or less.|For more Human Toxicity Excerpts (Complete) data for TRAZODONE (17 total), please visit the HSDB record page.

AF 1161

Beneficat; Depyrel; Taxagon; Trazodil|AF-1161; Molipaxin; Oleptro; Thombran; Trazolan; Trittico. /Trazodone hydrochloride/|The main ingredient in the drug Desyrel ... (tablets)|Table: Trazodone Hydrochloride Preparations [Table#6685]

Analyte: trazodone hydrochloride; matrix: pharmaceutical preparation (tablet); procedure: liquid chromatography with detection at 254 nm and comparison to standards (assay purity)|Analyte: trazodone hydrochloride; matrix: pharmaceutical preparation (tablet); procedure: retention time of liquid chromatogram with comparison to standards (chemical identification)|Analyte: trazodone hydrochloride; matrix: pharmaceutical preparation (tablet); procedure: thin-layer chromatography with comparison to standards (chemical identification)|Analyte: trazodone hydrochloride; matrix: chemical purity; procedure: liquid chromatography with detection at 254 nm and comparison to standards|For more Analytic Laboratory Methods (Complete) data for TRAZODONE (7 total), please visit the HSDB record page.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Pharmaceuticals