Trazodon

There is no specific antidote for Trazodone. Treatment should be symptomatic and supportive in the case of hypotension or excessive sedation. Any patient suspected of having taken an overdose should have the stomach emptied by gastric lavage. Forced diuresis may be useful in facilitating elimination of the drug. (L1712)

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.

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.

The primary adverse effects of trazodone include headaches, fatigue, dizziness, drowsiness, and somnolence. Other risks include anticholinergic effects (dry mouth), orthostatic hypotension, syncope, QT prolongation, Torsade de pointes, priapism, and increased suicidal thoughts. QT prolongation and arrhythmia risks are due to the interaction of trazodone with hERG potassium channels.

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.

Due to trazodone's hepatic and renal metabolism, special care is necessary for patients with severe hepatic and renal impairment. Serotonin syndrome, while rare, is potentially life-threatening, presenting as a triad of mental status alteration, neuromuscular abnormality, and autonomic instability. Initial clinical suspicion varies from presenting tremor, clonus, or akathisia. The first steps to address this condition should be discontinuing serotonergic agents, hydration, and controlling agitation with anxiolytics. The risk is higher with certain antidepressants, antibiotics, migraine medications, antiemetics, and analgesics. Idiopathic drug-induced liver injury may result from trazodone administration. The timeframe typically is 3 months, but reported cases require liver transplantation.

Trazodone binds at 5-HT2 receptor, it acts as a serotonin agonist at high doses and a serotonin antagonist at low doses. Like fluoxetine, trazodone's antidepressant activity likely results from blockage of serotonin reuptake by inhibiting serotonin reuptake pump at the presynaptic neuronal membrane. If used for long time periods, postsynaptic neuronal receptor binding sites may also be affected. The sedative effect of trazodone is likely the result of alpha-adrenergic blocking action and modest histamine blockade at H1 receptor. It weakly blocks presynaptic alpha2-adrenergic receptors and strongly inhibits postsynaptic alpha1 receptors. Trazodone does not affect the reuptake of norepinephrine or dopamine within the CNS.

/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.

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

trazodone

Desyrel

Antidepressants

5

less-DILI-concern drugs

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Administration of approximately 250 mg/kg/day in the diet of rats for 6 months resulted in significantly greater liver weights than in control rats and slightly lower weight gain in males.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Tremors, vomiting and clonic convulsions were produced in dogs given 50 and 100 mg/kg/day p.o. for one month.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Several subacute studies were conducted in rats using doses ranging from 100 to 450 mg/kg/day p.o. for one to four months. The main toxic effects observed were decreased body weight gain and slight liver enlargement in males. There were some deaths at the highest dose.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Rats were used to conduct a two year carcinogenicity study at doses of 0, 40 and 80 mg/kg/day. 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. These observations may be related to trazodone's effects on prolactin secretion. (Acute administration caused an increase in prolactin blood levels whereas chronic administration did not. Turnover, however, was not studied. When a neuroleptic was used as a positive control, similar results were produced.) The relative incidences of male rats with pituitary tumors were reversed. These results may have been influenced by the early deaths due to nephritis and other causes, however.

For more Non-Human Toxicity Excerpts (Complete) data for TRAZODONE (8 total), please visit the HSDB record page.

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/

Anti-Anxiety Agents; Antidepressive Agents, Second-Generation; Serotonin Uptake Inhibitors

MEDICATION

MEDICATION (VET)

Use (kg; approx.) in Germany (2009): >500

For the treatment of depression.

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#6674]