pms-Trazodone Special Precautions





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Special Precautions
Potential Association with Behavioural and Emotional Changes, Including Self-Harm: Pediatrics: Placebo-Controlled Clinical Trial Data: Analyses of placebo-controlled clinical trial safety databases from SSRIs and other newer antidepressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.
The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs.
Adults and Pediatrics: Additional data: There are clinical trials and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm and harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.
Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes.
An FDA meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients aged 18 to 24 years with psychiatric disorders showed an increased risk of suicidal behaviours with antidepressants compared to placebo.
Discontinuation Symptoms: At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose, rather than an abrupt cessation, is recommended whenever possible.
QT Prolongation and Risk of Arrhythmias and Sudden Death: pms-TRAZODONE is not recommended for use during the initial recovery phase of myocardial infarction. Caution should be used when administering pms-TRAZODONE to patients with cardiac disease and such patients should be closely monitored.
QT Prolongation: Trazodone is associated with QTc interval prolongation (see Cardiac disorders under Adverse Reactions; Drug-Drug Interactions: Drugs with a QTc prolongation effect under Interactions). Torsade de pointes, ventricular tachycardia, and sudden death have been reported with the immediate-release form of trazodone during post-marketing use.
Torsade de pointes is a polymorphic ventricular tachyarrhythmia. Generally, the risk of torsade de pointes increases with the magnitude of QTc prolongation produced by the drug. Torsade de pointes may be asymptomatic or experienced by the patient as dizziness, palpitations, syncope, or seizures. If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death.
Particular care should be exercised when administering pms-TRAZODONE to patients who are suspected to be at an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging drug.
Risk factors for torsade de pointes in the general population include, but are not limited to: female gender; age 65 years or older; baseline prolongation of the QTc interval; presence of genetic variants affecting cardiac ion channels or regulatory proteins, especially congenital long QT syndromes; family history of sudden cardiac death at <50 years; cardiac disease (e.g., myocardial ischemia, congestive heart failure, left ventricular hypertrophy, cardiomyopathy, conduction system disease); history of arrhythmias (especially ventricular arrhythmias, atrial fibrillation, or recent conversion from atrial fibrillation); electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia); bradycardia; acute neurological events (e.g., intracranial or subarachnoid hemorrhage, stroke, intracranial trauma); nutritional deficits (e.g., eating disorders, extreme diets); diabetes mellitus; autonomic neuropathy.
The concomitant use of pms-TRAZODONE with drugs known to prolong the QTc interval should be avoided (see Drug-Drug Interactions: Drugs with a QTc prolongation effect under Interactions).
Concomitant administration of CYP3A4 inhibitors may increase trazodone plasma levels. The concomitant use of potent CYP3A4 inhibitors with pms-TRAZODONE is discouraged. If used, a lower dose of pms-TRAZODONE should be considered.
When drugs that prolong the QTc interval are prescribed, healthcare professionals should counsel their patients concerning the nature and implications of the ECG changes, underlying diseases and disorders that are considered to represent risk factors, demonstrated and predicted drug-drug interactions, symptoms suggestive of arrhythmia, risk management strategies, and other information relevant to the use of the drug.
Cardiac Disease: Clinical studies in patients with pre-existing cardiac disease indicate that trazodone may be arrhythmogenic in some patients in that population. Arrhythmias identified include isolated PVCs, ventricular couplets, and short episodes of ventricular tachycardia (3-4 beats). There have also been several post-marketing reports of arrhythmias in trazodone-treated patients who had pre-existing cardiac disease and also in some patients who did not have preexisting cardiac disease.
Priapism: Rare cases of priapism (painful erections greater than 4 hours in duration) were reported in patients receiving trazodone. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.
Trazodone should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia), or with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease).
The following additional warnings and precautions are listed alphabetically by body system or organ class: Carcinogenesis and Mutagenesis: See Pharmacology: Toxicology: Carcinogenicity Studies under Actions for animal data.
Cardiovascular: Trazodone may cause hypotension including orthostatic hypotension and syncope; caution is required if it is given to patients receiving antihypertensive drugs and an adjustment in the dose of the antihypertensive medication may be required.
Dependence/Tolerance: Although trazodone has not been systematically studied for its potential for abuse, there is no evidence that trazodone possesses any addictive properties. Physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of trazodone.
Discontinuation symptoms, including anxiety, agitation and sleep disturbances, have been reported with trazodone. Clinical experience suggests that the dose should be gradually reduced before complete discontinuation of the treatment.
Endocrine and Metabolism: Hyperprolactinemia and Breast Tumors: There is sufficient experimental evidence to conclude that chronic administration of those psychotropic drugs, such as trazodone, which increase prolactin secretion has the potential to induce mammary neoplasms in rodents under appropriate conditions. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer.
Although disturbances such as galactorrhea, amenorrhea, gynecomastia and impotence have been reported, the clinical significance of elevated serum prolactin levels or increased secretion and turnover is unknown for most patients. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; available evidence is considered too limited to be conclusive at this time.
Genitourinary: See Priapism as previously mentioned.
Hematologic: Abnormal Bleeding: The use of drugs that interfere with serotonin reuptake, including pms-TRAZODONE, may increase the risk of bleeding events by causing abnormal platelet aggregation. Concomitant use of acetylsalicylic acid (ASA), nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of pms-TRAZODONE and NSAIDs, ASA, or other drugs that affect coagulation (see Drug-Drug Interactions: Drugs that affect coagulation or bleeding under Interactions). Caution is advised in patients with a history of bleeding disorder or predisposing conditions (e.g. thrombocytopenia).
Hepatic/Biliary/Pancreatic: pms-TRAZODONE has not been studied in patients with hepatic impairment and should be used with caution in this population.
Interactions with Medications that Alter CYP3A4 Metabolism: Concomitant use of pms-TRAZODONE with CYP3A4 inhibitors may increase trazodone plasma levels (see QT Prolongation and Risk of Arrhythmias and Sudden Death as previously mentioned; Drug-Drug Interactions: CYP 3A4 Inhibitors and Inducers under Interactions). The concomitant use of potent CYP3A4 inhibitors with pms-TRAZODONE is discouraged. If used, a lower dose of pms-TRAZODONE should be considered.
In vitro drug metabolism studies suggest that there is a potential for drug interactions when trazodone is given with CYP3A4 inhibitors. Ritonavir, a potent CYP3A4 inhibitor, increased the Cmax, AUC, and elimination half-life, and decreased clearance of trazodone after administration of ritonavir twice daily for 2 days. Adverse effects including nausea, hypotension, and syncope were observed when ritonavir and trazodone were co-administered. It is likely that ketoconazole, indinavir and other CYP3A4 inhibitors such as itraconazole may also lead to substantial increases in trazodone plasma concentrations with a potential for adverse effects.
Carbamazepine, a CYP3A4 inducer, reduced plasma concentrations of trazodone when coadministered. Patients should be closely monitored to see if there is a need for an increased dose of trazodone when taking both drugs (see Drug-Drug Interactions: CYP 3A4 Inhibitors and Inducers under Interactions).
Laboratory Tests: It is recommended that white blood cell and differential counts should be performed in patients who develop sore throat, fever or other signs of infection or blood dyscrasia. Trazodone should be discontinued if the white blood cell or absolute neutrophil count falls below normal.
Neurologic: Serotonin Syndrome: On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occurred in association with trazodone treatment, particularly when given in combination with other serotonergic or neuroleptic and antipsychotic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with pms-TRAZODONE should be discontinued if patients develop a combination of symptoms possibly including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs and mental status changes (confusion, irritability, extreme agitation progressing to delirium and coma). Supportive symptomatic treatment should be initiated. Due to the risk of serotonergic syndrome or neuroleptic malignant syndrome, pms-TRAZODONE should not be used in combination with MAO inhibitors or serotonin precursors (such as L-tryptophan, oxitriptan) and should be used with caution in patients receiving other serotonergic drugs (e.g., triptans, lithium, tramadol, St. John's Wort, SSRIs, most tricyclic antidepressants) or neuroleptics/antipsychotics (see Drug-Drug Interactions: Serotonergic drugs under Interactions).
Seizures: Episodes of grand mal seizures have been reported in a small number of patients. The majority of these patients were already receiving anticonvulsant therapy for a seizure disorder. As with other antidepressants, pms-TRAZODONE should be introduced cautiously in patients who have a history of seizures or in patients with unstable epilepsy. Treatment should be discontinued in any patient who develops seizures or for whom there is an increase in seizure frequency.
Cognitive and motor disturbances: Trazodone may impair the mental or physical abilities required for performance of potentially hazardous tasks, such as operating an automobile or machinery. Patients should be cautioned not to engage in such activities until they are reasonably certain that pms-TRAZODONE does not affect them adversely.
CNS Depressants: Trazodone may enhance the response to alcohol and the effects of barbiturates and other CNS depressants and patients should be cautioned accordingly.
Psychiatric: Suicide: The possibility of a suicide attempt is inherent in major depressive disorder and may persist until significant remission occurs. Close supervision of patients should accompany initial drug therapy, and consideration should be given to the need for hospitalization of high risk patients. The risk of suicide attempt must be considered, especially in depressed patients; the smallest quantity of drug, consistent with good patient management, should be provided to reduce the risk of overdose with this drug (see Potential Association with Behavioural and Emotional Changes, Including Self-Harm as previously mentioned).
Activation of Mania/Hypomania: pms-TRAZODONE should be used with caution in patients with a history of mania/hypomania and should be discontinued in any patient entering a manic phase. Depression may be the initial presentation of bipolar disorder. Patients with bipolar disorder may be at an increased risk of experiencing manic episodes when treated with antidepressants alone. Therefore, the decision to initiate symptomatic treatment of depression should only be made after patients have been adequately assessed to determine if they are at risk for bipolar disorder.
Renal: Hyponatremia: Hyponatremia has been reported with the use of antidepressants, probably due to syndrome of inappropriate antidiuretic hormone secretion (SIADH). Elderly patients and patients taking diuretics or who are otherwise volume-depleted may be at greater risk of developing hyponatremia. Discontinuation of pms-TRAZODONE should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Symptoms may include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.
Renal Impairment: pms-TRAZODONE has not been studied in patients with renal impairment and should be used with caution in this population.
Sexual Function/Reproduction: See Priapism as previously mentioned.
Use in Children: The safety and effectiveness of trazodone in children below the age of 18 have not been established. pms-TRAZODONE should not be used in that population.
Use in the Elderly: Trazodone should be used with caution in geriatric patients and lower initial and maintenance doses should be considered (see Recommended Dose and Dosage Adjustment: Geriatrics (>65 years of age) under Dosage & Administration).
Elderly patients receiving antidepressants may be at increased risk of clinically significant hyponatremia.
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