Trazodone Hydrochloride Prescribing Information
In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1.
No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide.
Age Range (years) | Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated |
Increases Compared to Placebo | |
| <18 | 14 additional patients |
| 18 to 24 | 5 additional patients |
Decreases Compared to Placebo | |
| 25 to 64 | 1 fewer patient |
| ≥65 | 6 fewer patients |
It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression.
Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing trazodone hydrochloride tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.
Safety and effectiveness in the pediatric population have not been established. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients
Trazodone hydrochloride tablets are indicated for the treatment of major depressive disorder (MDD) in adults.
- Starting dose: 150 mg in divided doses daily. May be increased by 50 mg per day every three to four days. Maximum dose: 400 mg per day in divided doses ().2 DOSAGE AND ADMINISTRATION
- Starting dose: 150 mg in divided doses daily. May be increased by 50 mg per day every three to four days. Maximum dose: 400 mg per day in divided doses .
- Trazodone hydrochloride tablets should be taken shortly after a meal or light snack .
- Tablets should be swallowed whole or broken in half along the score line, and should not be chewed or crushed .
- When discontinued, gradual dose reduction is recommended .
2.1 Dose SelectionAn initial dose of 150 mg/day in divided doses is suggested. The dosage should be initiated at a low-dose and increased gradually, noting the clinical response and any evidence of intolerance. Occurrence of drowsiness may require the administration of a major portion of the daily dose at bedtime or a reduction of dosage.
The dose may be increased by 50 mg/day every 3 to 4 days. The maximum dose for outpatients usually should not exceed 400 mg/day in divided doses. Inpatients (i.e., more severely depressed patients) may be given up to but not in excess of 600 mg/day in divided doses.
Once an adequate response has been achieved, dosage may be gradually reduced, with subsequent adjustment depending on therapeutic response.2.2 Important Administration InstructionsTrazodone hydrochloride tablets can be swallowed whole or administered as a half tablet by breaking the tablet along the score line. Trazodone hydrochloride tablets should be taken shortly after a meal or light snack.
2.3 Screen for Bipolar Disorder Prior to Starting Trazodone Hydrochloride TabletsPrior to initiating treatment with trazodone hydrochloride tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania
[see Warnings and Precautions (5.7)].2.4 Switching to or from Monoamine Oxidase Inhibitor AntidepressantAt least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of trazodone hydrochloride tablets. In addition, at least 14 days must elapse after stopping trazodone hydrochloride tablets before starting an MAOI antidepressant
[see Contraindications (4), Warnings and Precautions (5.2)].2.5 Dosage Recommendations for Concomitant Use with Strong CYP3A4 Inhibitors or InducersCoadministration with Strong CYP3A4 Inhibitors
Consider reducing trazodone hydrochloride tablets dose based on tolerability when trazodone hydrochloride tablets are coadministered with a strong CYP3A4 inhibitor[see Drug Interactions (7.1)].Coadministration with Strong CYP3A4 Inducers
Consider increasing trazodone hydrochloride tablets dose based on therapeutic response when trazodone hydrochloride tablets are coadministered with a strong CYP3A4 inducer[see Drug Interactions (7.1)].2.6 Discontinuation of Treatment with Trazodone Hydrochloride TabletsAdverse reactions may occur upon discontinuation of trazodone hydrochloride tablets
[See Warnings and Precautions (5.8)]. Gradually reduce the dosage rather than stopping trazodone hydrochloride tablets abruptly whenever possible. - Trazodone hydrochloride tablets should be taken shortly after a meal or light snack ().2 DOSAGE AND ADMINISTRATION
- Starting dose: 150 mg in divided doses daily. May be increased by 50 mg per day every three to four days. Maximum dose: 400 mg per day in divided doses .
- Trazodone hydrochloride tablets should be taken shortly after a meal or light snack .
- Tablets should be swallowed whole or broken in half along the score line, and should not be chewed or crushed .
- When discontinued, gradual dose reduction is recommended .
2.1 Dose SelectionAn initial dose of 150 mg/day in divided doses is suggested. The dosage should be initiated at a low-dose and increased gradually, noting the clinical response and any evidence of intolerance. Occurrence of drowsiness may require the administration of a major portion of the daily dose at bedtime or a reduction of dosage.
The dose may be increased by 50 mg/day every 3 to 4 days. The maximum dose for outpatients usually should not exceed 400 mg/day in divided doses. Inpatients (i.e., more severely depressed patients) may be given up to but not in excess of 600 mg/day in divided doses.
Once an adequate response has been achieved, dosage may be gradually reduced, with subsequent adjustment depending on therapeutic response.2.2 Important Administration InstructionsTrazodone hydrochloride tablets can be swallowed whole or administered as a half tablet by breaking the tablet along the score line. Trazodone hydrochloride tablets should be taken shortly after a meal or light snack.
2.3 Screen for Bipolar Disorder Prior to Starting Trazodone Hydrochloride TabletsPrior to initiating treatment with trazodone hydrochloride tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania
[see Warnings and Precautions (5.7)].2.4 Switching to or from Monoamine Oxidase Inhibitor AntidepressantAt least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of trazodone hydrochloride tablets. In addition, at least 14 days must elapse after stopping trazodone hydrochloride tablets before starting an MAOI antidepressant
[see Contraindications (4), Warnings and Precautions (5.2)].2.5 Dosage Recommendations for Concomitant Use with Strong CYP3A4 Inhibitors or InducersCoadministration with Strong CYP3A4 Inhibitors
Consider reducing trazodone hydrochloride tablets dose based on tolerability when trazodone hydrochloride tablets are coadministered with a strong CYP3A4 inhibitor[see Drug Interactions (7.1)].Coadministration with Strong CYP3A4 Inducers
Consider increasing trazodone hydrochloride tablets dose based on therapeutic response when trazodone hydrochloride tablets are coadministered with a strong CYP3A4 inducer[see Drug Interactions (7.1)].2.6 Discontinuation of Treatment with Trazodone Hydrochloride TabletsAdverse reactions may occur upon discontinuation of trazodone hydrochloride tablets
[See Warnings and Precautions (5.8)]. Gradually reduce the dosage rather than stopping trazodone hydrochloride tablets abruptly whenever possible. - Tablets should be swallowed whole or broken in half along the score line, and should not be chewed or crushed ().2 DOSAGE AND ADMINISTRATION
- Starting dose: 150 mg in divided doses daily. May be increased by 50 mg per day every three to four days. Maximum dose: 400 mg per day in divided doses .
- Trazodone hydrochloride tablets should be taken shortly after a meal or light snack .
- Tablets should be swallowed whole or broken in half along the score line, and should not be chewed or crushed .
- When discontinued, gradual dose reduction is recommended .
2.1 Dose SelectionAn initial dose of 150 mg/day in divided doses is suggested. The dosage should be initiated at a low-dose and increased gradually, noting the clinical response and any evidence of intolerance. Occurrence of drowsiness may require the administration of a major portion of the daily dose at bedtime or a reduction of dosage.
The dose may be increased by 50 mg/day every 3 to 4 days. The maximum dose for outpatients usually should not exceed 400 mg/day in divided doses. Inpatients (i.e., more severely depressed patients) may be given up to but not in excess of 600 mg/day in divided doses.
Once an adequate response has been achieved, dosage may be gradually reduced, with subsequent adjustment depending on therapeutic response.2.2 Important Administration InstructionsTrazodone hydrochloride tablets can be swallowed whole or administered as a half tablet by breaking the tablet along the score line. Trazodone hydrochloride tablets should be taken shortly after a meal or light snack.
2.3 Screen for Bipolar Disorder Prior to Starting Trazodone Hydrochloride TabletsPrior to initiating treatment with trazodone hydrochloride tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania
[see Warnings and Precautions (5.7)].2.4 Switching to or from Monoamine Oxidase Inhibitor AntidepressantAt least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of trazodone hydrochloride tablets. In addition, at least 14 days must elapse after stopping trazodone hydrochloride tablets before starting an MAOI antidepressant
[see Contraindications (4), Warnings and Precautions (5.2)].2.5 Dosage Recommendations for Concomitant Use with Strong CYP3A4 Inhibitors or InducersCoadministration with Strong CYP3A4 Inhibitors
Consider reducing trazodone hydrochloride tablets dose based on tolerability when trazodone hydrochloride tablets are coadministered with a strong CYP3A4 inhibitor[see Drug Interactions (7.1)].Coadministration with Strong CYP3A4 Inducers
Consider increasing trazodone hydrochloride tablets dose based on therapeutic response when trazodone hydrochloride tablets are coadministered with a strong CYP3A4 inducer[see Drug Interactions (7.1)].2.6 Discontinuation of Treatment with Trazodone Hydrochloride TabletsAdverse reactions may occur upon discontinuation of trazodone hydrochloride tablets
[See Warnings and Precautions (5.8)]. Gradually reduce the dosage rather than stopping trazodone hydrochloride tablets abruptly whenever possible. - When discontinued, gradual dose reduction is recommended ().2 DOSAGE AND ADMINISTRATION
- Starting dose: 150 mg in divided doses daily. May be increased by 50 mg per day every three to four days. Maximum dose: 400 mg per day in divided doses .
- Trazodone hydrochloride tablets should be taken shortly after a meal or light snack .
- Tablets should be swallowed whole or broken in half along the score line, and should not be chewed or crushed .
- When discontinued, gradual dose reduction is recommended .
2.1 Dose SelectionAn initial dose of 150 mg/day in divided doses is suggested. The dosage should be initiated at a low-dose and increased gradually, noting the clinical response and any evidence of intolerance. Occurrence of drowsiness may require the administration of a major portion of the daily dose at bedtime or a reduction of dosage.
The dose may be increased by 50 mg/day every 3 to 4 days. The maximum dose for outpatients usually should not exceed 400 mg/day in divided doses. Inpatients (i.e., more severely depressed patients) may be given up to but not in excess of 600 mg/day in divided doses.
Once an adequate response has been achieved, dosage may be gradually reduced, with subsequent adjustment depending on therapeutic response.2.2 Important Administration InstructionsTrazodone hydrochloride tablets can be swallowed whole or administered as a half tablet by breaking the tablet along the score line. Trazodone hydrochloride tablets should be taken shortly after a meal or light snack.
2.3 Screen for Bipolar Disorder Prior to Starting Trazodone Hydrochloride TabletsPrior to initiating treatment with trazodone hydrochloride tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania
[see Warnings and Precautions (5.7)].2.4 Switching to or from Monoamine Oxidase Inhibitor AntidepressantAt least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of trazodone hydrochloride tablets. In addition, at least 14 days must elapse after stopping trazodone hydrochloride tablets before starting an MAOI antidepressant
[see Contraindications (4), Warnings and Precautions (5.2)].2.5 Dosage Recommendations for Concomitant Use with Strong CYP3A4 Inhibitors or InducersCoadministration with Strong CYP3A4 Inhibitors
Consider reducing trazodone hydrochloride tablets dose based on tolerability when trazodone hydrochloride tablets are coadministered with a strong CYP3A4 inhibitor[see Drug Interactions (7.1)].Coadministration with Strong CYP3A4 Inducers
Consider increasing trazodone hydrochloride tablets dose based on therapeutic response when trazodone hydrochloride tablets are coadministered with a strong CYP3A4 inducer[see Drug Interactions (7.1)].2.6 Discontinuation of Treatment with Trazodone Hydrochloride TabletsAdverse reactions may occur upon discontinuation of trazodone hydrochloride tablets
[See Warnings and Precautions (5.8)]. Gradually reduce the dosage rather than stopping trazodone hydrochloride tablets abruptly whenever possible.
Trazodone hydrochloride tablets, USP are available in the following strengths:
• 50 mg: White to off white, round, biconvex shaped functionally scored tablets, debossed with ‘L’ bisect ‘2’ on one side and plain on other side.
• 100 mg: White to off white, round, biconvex shaped functionally scored tablets, debossed with ‘L’ bisect ‘3’ on one side and plain on other side.
• 150 mg: White to off white, oval, flat faced bevelled edge functionally scored tablets with one full bisect and two partial trisects debossed with “L” and “4” on one side and two full trisects debossed with “50” “50” “50” on each part on other side.
• 300 mg: White to off white, oval, flat faced bevelled edge functionally scored tablets with one full bisect and two partial trisects debossed with “L” and “5” on one side and two full trisects debossed with “100” “100” “100” on each part with middle “100’’ perpendicular to the other “100”s on other side.
Published prospective cohort studies, case series, and case reports over several decades with trazodone hydrochloride tablets use in pregnant women have not identified any drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes
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 7.3 to 11 times the maximum recommended human dose (MRHD) of 400 mg/day in adults on a mg/m
2 basis. There was also an increase in congenital anomalies in the rabbit at approximately 7.3 to 22 times the MRHD on a mg/m
2 basis
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression that women who continued antidepressants. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.
While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association with trazodone use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. All available studies have methodological limitations, including small sample size and inconsistent comparator groups.
No teratogenic effects were observed when trazodone was given to pregnant rats and rabbits during the period of organogenesis at oral doses up to 450 mg/kg/day. This dose is 11 and 22 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 400 mg/day in adults on a mg/m
2 basis. Increased fetal resorption and other adverse effects on the fetus in rats at 7.3 to 11 times the MRHD and increase in congenital anomalies in rabbits at 7.3 to 22 times the MRHD on a mg/m
2 basis were observed. No further details on these studies are available.
Trazodone hydrochloride tablets are contraindicated in:
• Patients taking, or within 14 days of stopping, monoamine oxidase inhibitors (MAOIs), including MAOIs such as linezolid or intravenous methylene blue, because of an increased risk of serotonin syndrome
Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including trazodone hydrochloride tablets, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is
Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
The concomitant use of trazodone hydrochloride tablets with MAOIs is contraindicated. In addition, do not initiate trazodone in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking trazodone hydrochloride tablets, discontinue trazodone hydrochloride tablets before initiating treatment with the MAOI
Monitor all patients taking trazodone hydrochloride tablets for the emergence of serotonin syndrome. Discontinue treatment with trazodone hydrochloride tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of trazodone hydrochloride tablets with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.
Monoamine Oxidase Inhibitors (MAOIs) | |
| Clinical Impact: | The concomitant use of MAOIs and serotonergic drugs including trazodone hydrochloride tablets increases the risk of serotonin syndrome. |
| Intervention: | Trazodone hydrochloride tablets are contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Contraindications (4), Dosage and Administration (2.3, 2.4),and Warnings and Precautions (5.2)] . |
| Examples: | isocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine |
Other Serotonergic Drugs | |
| Clinical Impact: | The concomitant use of serotonergic drugs including trazodone hydrochloride tablets and other serotonergic drugs increases the risk of serotonin syndrome. |
| Intervention: | Monitor patients for signs and symptoms of serotonin syndrome, particularly during trazodone hydrochloride tablets initiation. If serotonin syndrome occurs, consider discontinuation of trazodone hydrochloride tablets and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)] . |
| Examples: | triptans, antidepressants (tricyclic and serotonin uptake inhibitors), fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort |
Antiplatelet Agents and Anticoagulants | |
| Clinical Impact: | Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with trazodone hydrochloride tablets may potentiate the risk of bleeding. |
| Intervention: | Inform patients of the increased risk of bleeding with the concomitant use of trazodone hydrochloride tablets and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing trazodone hydrochloride tablets [see Warnings and Precautions (5.5)] . |
| Examples: | warfarin, rivaroxaban, dabigatran, clopidogrel |
Strong CYP3A4 Inhibitors | |
| Clinical Impact: | The concomitant use of trazodone hydrochloride tablets and strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone hydrochloride tablets alone. |
| Intervention: | If trazodone hydrochloride tablets are used with a potent CYP3A4 inhibitor, the risk of adverse reactions, including cardiac arrhythmias, may be increased and a lower dose of trazodone hydrochloride tablets should be considered [see Dosage and Administration (2.5), Warnings and Precautions (5.3)] . |
| Examples: | itraconazole, ketoconazole, clarithromycin, indinavir |
Strong CYP3A4 Inducers | |
| Clinical Impact: | The concomitant use of trazodone hydrochloride tablets and strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone hydrochloride tablets alone. |
| Intervention: | Patients should be closely monitored to see if there is a need for an increased dose of trazodone hydrochloride tablets when taking CYP3A4 inducers [see Dosage and Administration (2.5)] . |
| Examples: | rifampin, carbamazepine, phenytoin, St. John’s wort |
Digoxin and Phenytoin | |
| Clinical Impact: | Digoxin and phenytoin are narrow therapeutic index drugs. Concomitant use of trazodone hydrochloride tablets can increase digoxin or phenytoin concentrations. |
| Intervention: | Measure serum digoxin or phenytoin concentrations before initiating concomitant use of trazodone hydrochloride tablets. Continue monitoring and reduce digoxin or phenytoin dose as necessary. |
| Examples: | digoxin, phenytoin |
Central Nervous System (CNS) Depressants | |
| Clinical Impact: | Trazodone hydrochloride tablets may enhance the response CNS depressants. |
| Intervention: | Patients should be counseled that trazodone hydrochloride tablets may enhance the response to alcohol, barbiturates, and other CNS depressants. |
| Examples: | alcohol, barbiturates |
QT Interval Prolongation | |
| Clinical Impact: | Concomitant use of drugs that prolong the QT interval may add to the QT effects of trazodone hydrochloride tablets and increase the risk of cardiac arrhythmia. |
| Intervention: | Avoid the use of trazodone hydrochloride tablets in combination with other drugs known to prolong QTc [see Warnings and Precautions (5.3)] . |
| Examples: | Class 1A antiarrhythmics: quinidine, procainamide, disopyramide; Class 3 antiarrhythmics: amiodarone, sotalol; Antipsychotics: ziprasidone, chlorpromazine, thioridazine; Antibiotics: gatifloxacin |