TRAZOTOR 100

Indications

• Major depressive disorder
• Anxiety disorders
• Insomnia

Dosage

Children: Refer to the BNF for Children for specific pediatric dosing recommendations.

Adults: For adults, the initial dose is typically 150 mg daily, which can be increased based on clinical response and tolerability. The maximum recommended dose is 400 mg per day, divided into multiple doses.

Mechanism of action

The precise mechanism of action of trazodone is not fully understood, however, it primarily works by inhibiting the reuptake of serotonin and blocking histamine and alpha-1-adrenergic receptors. Trazodone antagonizes several serotonin receptor subtypes, particularly 5-HT2a and 5-HT2c, which may enhance serotonergic neurotransmission. At varying doses, trazodone can act as a serotonin agonist or antagonist, illustrating its complex pharmacodynamic profile.

Pharmacodynamics

Trazodone is effective in alleviating symptoms of depression and anxiety, promoting sleep due to its sedative effects. It can prolong the cardiac QT-interval and may impair cognitive function, particularly in elderly patients. The drug has been associated with rare but serious side effects, such as priapism, necessitating immediate medical attention if symptoms arise. Trazodone's sedative properties make it useful in treating insomnia, but caution should be exercised regarding its central nervous system depressant effects.

Pharmacokinetics

Trazodone is well absorbed after oral administration, with peak plasma concentrations typically reached within 1 to 2 hours. It undergoes extensive hepatic metabolism, primarily via cytochrome P450 enzymes, and has a half-life of approximately 5 to 9 hours. The drug and its metabolites are primarily excreted in urine. The pharmacokinetics can be influenced by various drug interactions, particularly those affecting hepatic enzyme activity.

Adverse effects

• drowsiness
• dry mouth
• dizziness
• headache
• nausea
• priapism
• orthostatic hypotension

Interactions

• carbamazepine (decreases concentration)
• cobicistat (increases exposure)
• idelalisib (increases exposure)
• dronedarone (increases exposure - unknown significance)
• antifungals, azoles (increases exposure - unknown significance)
• crizotinib (increases exposure - unknown significance)
• imatinib (increases exposure - unknown significance)
• letermovir (increases exposure - unknown significance)
• erythromycin (increases exposure - unknown significance)
• nilotinib (increases exposure - unknown significance)

Precautions

• Use caution in patients with a history of cardiovascular disease due to potential QT interval prolongation.
• Elderly patients may be more susceptible to the sedative effects and cognitive impairment.
• Monitor for signs of priapism and advise immediate medical attention if suspected.

Pregnancy

Trazodone should only be used in pregnancy if the potential benefit justifies the potential risk to the fetus. Consult relevant guidelines.

Breast-feeding

Trazodone is excreted in breast milk; caution is advised when administered to breastfeeding mothers.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• tablets
• extended-release tablets

Indications

• Depressive illness (particularly where sedation is required)
• Anxiety disorders
• Insomnia associated with depression

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations, as pediatric dosing is not provided in the BNF.

Adults: Initially, 150 mg daily in divided doses, to be taken after food, or alternatively initially 150 mg once daily at bedtime. It may be increased if necessary to 300 mg daily, and higher doses up to 600 mg daily can be used in divided doses.

Mechanism of action

Trazodone works by inhibiting the reuptake of serotonin, thus increasing its availability in the synaptic cleft. Additionally, it acts as an antagonist at serotonin 5-HT2A receptors, which contributes to its antidepressant effects and sedation. This dual action enhances mood and alleviates anxiety, while promoting sleep.

Pharmacodynamics

The effects of trazodone can be attributed to its ability to modulate serotonin levels in the brain, which plays a key role in mood regulation. The sedative effects are thought to arise from its antagonistic action on 5-HT2A receptors and its impact on adrenergic receptors. These pharmacodynamic properties make trazodone effective for patients with depressive symptoms accompanied by sleep disturbances.

Pharmacokinetics

Trazodone is well absorbed after oral administration, with peak plasma concentrations occurring approximately 1-2 hours post-dose. It undergoes extensive hepatic metabolism, primarily via cytochrome P450 enzymes, to form active metabolites. The elimination half-life ranges from 5 to 13 hours. Trazodone is excreted mainly in urine, with approximately 70% of the dose appearing as metabolites and less than 1% as unchanged drug.

Contra-indications

• Hypersensitivity to trazodone or any of its components
• Concurrent use with monoamine oxidase inhibitors (MAOIs)
• Severe hepatic impairment

Adverse effects

• Drowsiness
• Dizziness
• Dry mouth
• Nausea
• Vomiting
• Constipation
• Blurred vision
• Orthostatic hypotension
• Arrhythmias
• Priapism

Interactions

• Increased risk of serotonin syndrome when used with other serotonergic drugs
• Caution with alcohol, as it may enhance sedative effects
• Potential interaction with anticoagulants and antiplatelet agents due to effects on platelet aggregation

Precautions

• Use with caution in patients with a history of seizures
• Monitor for signs of serotonin syndrome
• Assess risk of suicidal thoughts and behaviors in patients with depression
• Caution in elderly patients, as they may be more sensitive to side effects

Pregnancy

Avoid during first trimester; limited information available. Monitor infant for signs of withdrawal if used until delivery.

Breast-feeding

The amount secreted into breast milk is too small to be harmful.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Tablets: 50 mg, 100 mg, 150 mg, 300 mg
• Oral solution: 25 mg/5 ml

Mechanism of action

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.

Pharmacodynamics

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.