Trazodone

Trazodone is an Antidepressant agent belonging to the Serotonin Reuptake Inhibitor/Antagonist class.

Trazodone is a serotonin uptake inhibitor used to treat major depressive disorder.

Trazodone hydrochloride is absorbed after oral administration without selective localization in any tissue. When trazodone hydrochloride is taken shortly after ingestion of food, there may be an increase in the amount of drug absorbed, a decrease in maximum concentration, and a lengthening in the time to maximum concentration. Trazodone is 89 to 95% protein bound with therapeutic doses in humans. It is primarily excreted in urine (74%, <1% excreted unchanged); secondarily in feces (~21%).

Trazodone shows side effects like Blurred vision, Dizziness, Dry mouth, Headache, Sweating, Shortness of breath, Decreased concentration, etc.

Trazodone is available in the form of Oral tablets.

Trazodone is available in India, Canada, the US, Malaysia, Singapore, Japan, France, Italy, China, and Germany.

Trazodone belongs to the Serotonin Reuptake Inhibitor/Antagonist class and acts as Antidepressant Agent.

Trazodone is known to inhibit serotonin reuptake and block histamine and alpha-1-adrenergic receptors. Even though 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 Onset of action of Trazodone is not clinically established.

The Time to peak plasma concentration of Trazodone is approximately 30 to 100 minutes (immediate release) and 9 hours (Extended release).

Trazodone is available in the form of an Oral Tablet.

Trazodone Tablet is taken orally, usually once or twice daily.

Trazodone is an antidepressant agent used in the treatment of depression.

Trazodone is an Antidepressant agent belonging to the Serotonin Reuptake Inhibitor/Antagonist class.

Trazodone works by increasing the levels of a chemical called serotonin in the brain, which helps to improve mood and reduce the feeling of anxiety.

Trazodone is approved for use in the following clinical indications

Adult indication:

• Aggressive or agitated behavior associated with dementia
• Insomnia, sleep onset, and sleep maintenance
• Major depressive disorder

Pediatric Indication:

• Insomnia; sleep disturbances
• Migraine, prophylaxis

Adult Dose:

• Aggressive or agitated behavior associated with dementia (off-label)

Oral: Immediate release: Initial: 25 to 50 mg once daily at bedtime; may increase the dose gradually based on response and tolerability up to 300 mg/day in 1 to 3 divided doses.

• Insomnia, sleep onset, and sleep maintenance (off-label)

Oral: Usual dose: 50 mg to 100 mg at bedtime.

• Major depressive disorder

Immediate release: Initial: 50 mg twice daily; may increase in increments of 50 mg/day every 3 to 7 days to a target dose of 75 to 150 mg twice daily. Thereafter may further increase by 50 to 100 mg/day every 2 to 4 weeks based on response and tolerability; usual dosage range is 200 to 400 mg/day; with maximum 600 mg/day.

Extended release: Initial: 150 mg once daily at bedtime; may increase by 75 mg/day at intervals no less than every 3 days based on the response, tolerability, and severity of symptoms; maximum dose: 375 mg/day.

Pediatric Dose:

• Insomnia; sleep disturbances

Oral: Immediate-release formulation:

Children 18 months to <3 years: Initial: 1 to 2 mg/kg/dose at bedtime; maximum dose: 25 mg/dose; may increase the dose at 2-week intervals in 12.5 to 25 mg increments up to 3 mg/kg/dose once daily at bedtime, not to exceed a maximum dose: 100 mg/dose.

Children 3 to 5 years: Initial: 1 to 2 mg/kg/dose at bedtime; maximum dose: 50 mg/dose; may increase the dose at 2-week intervals in 12.5 to 25 mg increments up to 3 mg/kg/dose once daily at bedtime, not to exceed a maximum dose: 150 mg/dose.

Children >5 years and Adolescents: Initial: 0.75 to 1 mg/kg/dose or 25 to 50 mg at bedtime; may increase at 2-week intervals in 12.5 to 25 mg increments up to a maximum dose of 200 mg/dose; reported range: 0.5 to 2 mg/kg/day. When used for palliative care, multiple daily doses may be necessary; in patients >18 years of age, 25 to 50 mg/dose increased gradually to twice or 3 times daily as needed.

• Migraine, prophylaxis

Children ≥7 years and Adolescents: Oral: Immediate-release formulation: 1 mg/kg/day in 3 divided doses; maximum dose: 150 mg/dose.

Trazodone is available in various strengths as 50 mg, 75 mg, 100 mg, 150 mg and 300mg.

Trazodone is available in the form of an Oral Tablet.

• Dosage Adjustment in Kidney Patient

Mild to severe impairment: No dosage adjustment necessary.

• Dosage Adjustment in Hepatic Impairment Patient

There are no dosage adjustments provided.

Avoid St. John's Wort. The risk of serotonin syndrome may be increased.

Trazodone is contraindicated in patients with

• Hypersensitivity to trazodone or any component of the formulation
• Use of MAOIs intended to treat psychiatric disorders (concurrently or within 14 days of discontinuing either trazodone or the MAOI)
• Initiation of trazodone in a patient receiving linezolid or intravenous methylene blue.

• Suicidal tendencies

Trazodone may cause changes in mood and behavior and may lead to suicidal tendencies.

• Hypotension

Hypotension is a decrease in blood pressure. Trazodone should be used with caution if you have hypotension as this medicine may cause a further decrease in blood pressure and worsen your condition. Monitor your blood pressure regularly, especially when the dose of Trazodone has been altered. It is advised to get up slowly from a sitting or a lying position to avoid a sudden drop in blood pressure.

• Hyponatraemia

Hyponatraemia is a condition in which sodium levels in your blood are lower than normal. Trazodone should be used with caution as it may increase the risk of hyponatremia. This risk is especially higher in the elderly or if you are taking diuretics (water pills that increase sodium and water excretion from the body).

• Use in children

Trazodone is not recommended for use in children less than 18 years of age as the safety and efficacy data are not clinically established.

• Bleeding

Trazodone may alter platelet (blood cell that helps form blood clots) function and prolong the bleeding time. Some serious adverse reactions may experience such as any unusual bleeding or bruising, black and tarry stools, etc. Also using Aspirin, Ibuprofen, or Naproxen together with Trazodone as it may cause you to bruise or bleed easily.

• Withdrawal symptoms

Avoid sudden discontinuation of Trazodone as it may cause withdrawal symptoms such as agitation, irritability, nausea, dizziness, trouble sleeping, etc. Reduce the dose gradually over a period to avoid such undesired effects.

Consumption of alcohol is not recommended during treatment with Trazodone as it can increase the side effects such as dizziness, drowsiness, and difficulty in concentration.

Trazodone and/or its metabolites have been found in the milk of lactating rats, suggesting that the drug may be secreted in human milk. Caution should be exercised when trazodone is administered to a nursing woman.

Trazodone hydrochloride has been shown to cause increased fetal resorption and other adverse effects on the fetus in the rat when given at dose levels approximately 6 to 9 times the maximum recommended human dose (MRHD) of 400 mg/day of mg/m2 in adolescents. There was also an increase in congenital anomalies in the rabbit at approximately 6 to 17 times the MRHD on a mg/m2 basis in adolescents. There are no adequate and well-controlled studies in pregnant women. Trazodone hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Avoid St. John's Wort. The risk of serotonin syndrome may be increased.

• Common

Nausea and vomiting, xerostomia, Dizziness, drowsiness, fatigue, headache, nervousness, Blurred vision.

• Rare

Anemia, Angioedema, hypersensitivity reaction, Akathisia, ataxia, confusion, delusion, disorientation, hallucination, heavy-headedness, hypomania, lack of concentration, malaise, memory impairment, numbness, paresthesia, speech disturbance, Muscle twitching, myalgia, tremor, Asthenopia, eye pruritus, eye redness, Dyspnea, nasal congestion, paranasal sinus congestion.

• Monoamine Oxidase Inhibitors (MAOIs): The concomitant use of MAOIs and serotonergic drugs including Trazodone increases the risk of serotonin syndrome.
• Antiplatelet Agents and Anticoagulants: Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with DESYREL may potentiate the risk of bleeding.
• Strong CYP3A4 Inhibitors: The concomitant use of Trazodone and strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of Trazodone alone.
• Strong CYP3A4 Inducers: The concomitant use of Trazodone and strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of Trazodone alone.
• Digoxin and Phenytoin: Digoxin and phenytoin are narrow therapeutic index drugs. Concomitant use of Trazodone can increase digoxin or phenytoin concentrations.
• Central Nervous System (CNS) Depressants: Desyrel may enhance the response to CNS depressants.
• QT Interval Prolongation: Concomitant use of drugs that prolong the QT interval may add to the QT effects of Trazodone and increase the risk of cardiac arrhythmia.

The common side effects of Trazodone include the following

• Common side effects

Blurred vision, Dizziness, Dry mouth, Headache, Sweating, Shortness of breath, Decreased concentration, General feeling of discomfort, Fatigue, Nausea and Vomiting, Constipation, Drowsiness, Confusion, and Tremors.

• Pregnancy

Teratogenic Effects

Pregnancy Category C: Trazodone hydrochloride has been shown to cause increased fetal resorption and other adverse effects on the fetus in the rat when given at dose levels approximately 6 to 9 times the maximum recommended human dose (MRHD) of 400 mg/day on mg/m2 in adolescents. There was also an increase in congenital anomalies in the rabbit at approximately 6 to 17 times the MRHD on a mg/m2 basis in adolescents. There are no adequate and well-controlled studies in pregnant women. Trazodone hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Nursing Mothers

Trazodone and/or its metabolites have been found in the milk of lactating rats, suggesting that the drug may be secreted in human milk. Caution should be exercised when trazodone is administered to a nursing woman.

• Pediatric Use

Safety and effectiveness in the pediatric population have not been established. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients.

• Geriatric Use

Reported clinical literature and experience with trazodone have not identified differences in responses between elderly and younger patients. However, as experience in the elderly with trazodone hydrochloride is limited, it should be used with caution in geriatric patients.

Symptoms: Drowsiness, dizziness, nausea, vomiting, bradycardia, ECG changes, QT prolongation, torsade de pointes, tachycardia, hypotension, hyponatremia, convulsions, seizures, priapism, respiratory failure, coma.

Management: Administer activated charcoal or gastric lavage within 1 hour of ingestion. Give oxygen supply as needed. Correct acid-base and metabolic disturbances. May give IV diazepam or lorazepam, or an IV infusion of phenytoin for seizures. Monitor BP, pulse, and Glasgow Coma Scale. Symptomatic and supportive treatment for hypotension and excessive sedation. May give inotropes (e.g., dopamine, dobutamine) for severe hypotension.

• Pharmacodynamic

Trazodone treats depressed mood and other depression-related symptoms and shows benefits 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.

• Pharmacokinetics

Absorption

Trazodone hydrochloride is absorbed after oral administration without selective localization in any tissue. When trazodone hydrochloride is taken shortly after ingestion of food, there may be an increase in the amount of drug absorbed, a decrease in maximum concentration, and a lengthening in the time to maximum concentration. Peak plasma levels occur approximately one hour after dosing when trazodone hydrochloride is taken on an empty stomach or 2 hours after dosing when taken with food.

Distribution

Trazodone is 89 to 95% protein bound in vitro at concentrations attained with therapeutic doses in humans. The volume of distribution of Trazodone is about 0.84 +/- 0.16 L/kg.

Metabolism and Excretion

In vitro studies in human liver microsomes show that trazodone is metabolized, via oxidative cleavage, to an active metabolite, m-chlorophenyl piperazine (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. It is primarily excreted in urine (74%, <1% excreted unchanged); secondarily in feces (~21%).

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018207s032lbl.pdf
• https://go.drugbank.com/drugs/DB00656
• https://www.drugs.com/trazodone.html#dosage
• https://medlineplus.gov/druginfo/meds/a681038.html#side-effects
• https://www.uptodate.com/contents/trazodone-drug-information#F230266
• https://www.rxlist.com/trazodone/generic-drug.htm#what_other_drugs_interact_with_trazodone