pms-Trazodone

pms-Trazodone

trazodone

Manufacturer:

Pharmascience

Distributor:

T-BOMA
Full Prescribing Info
Contents
Trazodone hydrochloride.
Description
Each tablet contains trazodone hydrochloride 50 mg or 100 mg respectively equivalent to 45.5 mg and 91 mg trazodone base.
Proper name: Trazodone Hydrochloride.
Chemical name: 2-{3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-1,2,4-triazolo-[4,3-a]pyridin-3(2H)-one monohydrochloride.
Molecular formula: C19H22ClN5O·HCl.
Molecular mass: 408.32 g/mol.
Physicochemical properties: White, odorless crystals (plates) with a bitter taste. The melting point for trazodone free base is 96°C. The hydrochloride salt melts with decomposition in the range 222-228°C. Under vacuum decomposition does not occur and a melting range of 231-232.5°C is reported. Trazodone Hydrochloride is sparingly soluble in chloroform and in water. The reported pKa for trazodone in 50% ethanol is 6.14. This value was obtained potentiometrically using a glass-calomel electrode.
Excipients/Inactive Ingredients: croscarmellose sodium, dibasic calcium phosphate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch.
50 mg: FD&C Yellow #6.
Action
Pharmacology: Trazodone's antidepressant mechanism of action in man is not fully understood, but is thought to be related to its potentiation of serotonergic activity in the CNS. It is also called a Serotonin 2A/2C Antagonist and Serotonin Reuptake Inhibitor (SARI).
Preclinical studies have shown that trazodone functions as an antagonist at 5-HT2A and 5-HT2C receptors and as a weak inhibitor of serotonin reuptake.
Trazodone's active metabolite, m-chlorophenylpiperazine (mCPP) functions as a potent 5-HT2C agonist and as a partial agonist at several of the other subtypes of serotonin receptors.
Trazodone is a potent α1-adrenergic receptor antagonist with relatively weak α2-adrenergic receptor activity and its main actions at adrenergic receptors are dominated by antagonism of α1-adrenergic receptor subtypes. Trazodone has weak action at a variety of other neurotransmitter receptors, ion channels and transporters.
Cardiac conduction effects of trazodone in the anesthetized dog are qualitatively dissimilar and quantitatively less pronounced than those seen with tricyclic antidepressants. Trazodone is not a monoamine oxidase inhibitor and, unlike amphetamine-type drugs, does not stimulate the central nervous system.
Clinical Trials: Comparative Bioavailability Studies: A single-dose comparative bioavailability study was conducted between two different formulations of trazodone hydrochloride. The study compared a 100 mg dose (2 x 50 mg tablets) of pms-TRAZODONE (trazodone hydrochloride tablets) manufactured by Pharmascience Inc. versus DESYREL (trazodone hydrochloride tablets) manufactured by Bristol Inc., administered to fourteen healthy volunteers. The pharmacokinetic parameters are summarized as follows: See Table 1.

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Detailed Pharmacology: The pharmacological profile of trazodone differs significantly from that of other known psychopharmacological agents.
Trazodone impedes the membrane uptake of serotonin. Small doses of the drug impede the depletion of brain serotonin, by fenfluramine, but doses of 50 mg/kg do not affect the concentration of serotonin in the rat brain. In experimental studies, trazodone is a weak inhibitor of noradrenalin re-uptake but is practically inactive against 1-dopa, histamine and acetylcholine. It has no known monoamine oxidase inhibiting activity.
Trazodone exhibits CNS depressant properties, causing decreased motor activity in cats, rats and mice and increasing the hexobarbital-induced sleeping time in mice. It also inhibits conditioned avoidance responding in rats at doses which do not influence the unconditioned response (ED50 = 19.5 mg/kg p.o.). Trazodone has no anticonvulsant, anti-reserpine or cataleptogenic effects and its muscle relaxant activity is very weak.
In mice, responses to painful stimuli are suppressed by doses at which motor activity is unaffected (10 mg/kg p.o.), and oxotremorine-, clonidine- and nicotine-induced tremors are significantly inhibited by 12.5 mg/kg i.p. Trazodone protects grouped mice against amphetamine-induced toxicity, but does not inhibit the stereotyped behaviour due to amphetamine or apomorphine.
In rats, infusion of trazodone produces first a fall in mean blood pressure, followed by ECG changes only as a consequence of the hypotension produced. In anesthetized dogs, graded doses between 1 and 30 mg/kg i.v. demonstrated no effect on the bundle of His conduction and no evidence of heart block or rhythm disturbance other than the slowing of normal sinus rhythm, while 0.5 to 5 mg/kg imipramine slowed impulse conduction as well as atrial transmission. The effect of trazodone on the sleep-wakefulness cycle in rats was comparable to that of similar doses of imipramine: 10 mg/kg p.o. reduced and 160 mg/kg completely suppressed REM sleep.
Pharmacokinetics: Absorption: Trazodone hydrochloride is well absorbed after oral administration with peak plasma levels obtained within one-half to two hours after ingestion. Absorption is somewhat delayed and enhanced by food.
Distribution: Trazodone is 89-95% protein bound in vitro at concentrations attained with therapeutic doses.
Metabolism: In vitro studies in human liver microsomes show that trazodone is metabolized to an active metabolite, mCPP, by cytochrome P450 3A4 (CYP3A4). Other metabolic pathways that may be involved in 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.
Elimination: Approximately 60-70% of 14C-labelled trazodone was found to be excreted in the urine within two days and 9-29% in feces over 60-100 hours. In some patients trazodone may accumulate in the plasma.
Special Populations and Conditions: Pediatrics (< 18 years of age): The safety and efficacy of trazodone in patients below the age of 18 years have not been evaluated.
Geriatrics (> 65 years of age): pms-TRAZODONE should be used with caution in geriatric patients (see Recommended Dose and Dosage Adjustment: Geriatrics (>65 years of age) under Dosage & Administration).
Hepatic Insufficiency: pms-TRAZODONE has not been studied in patients with hepatic impairment and should be used with caution in this population.
Renal Insufficiency: pms-TRAZODONE has not been studied in patients with renal insufficiency and should be used with caution in this population.
Toxicology: Acute Toxicity: The acute toxicity of trazodone has been examined in the mouse, rat, rabbit and dog. Summarized LD50 values are presented in the following table. (See Table 2.)

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Signs of toxicity included dyspnea, salivation, ptosis, aggressivity, hypoactivity, prostration and clonic convulsions.
Subacute and Chronic Toxicity: In several subacute studies in rats, 100 to 450 mg/kg/day p.o. for one to four months produced a decrease in body weight gain and slight liver enlargement in males as the main toxic effects. The highest dose also caused some deaths. In dogs, 50 and 100 mg/kg/day p.o. for one month produced tremors, vomiting and clonic convulsions.
One of two dogs receiving 100 mg/kg died after 3 weeks. In a 6-month rat study, administration of approximately 250 mg/kg/day in the diet resulted in significantly greater liver weights than in control rats and in slightly lower weight gain in males. Dogs receiving 5 and 25 mg/kg/day for 6 months showed no toxic effects.
An eighteen-month study was carried out in rats using doses of 0, 30, 100 and 300 mg/kg/day p.o. A decrease in body weight gain was seen in all treated groups and males at the highest dose level showed significantly reduced food intake. No behavioral or pathologic effects were observed at the lowest dose level, while rats at the 100 mg/kg dose exhibited some lethargy and salivation immediately following dosing. At the highest dose level, there was excessive salivation and the animals became inactive, assuming a prone position for approximately 3 hours after dosing. Occasional body tremors were also seen. Tolerance developed to all these reactions within 30 weeks.
Beagle dogs were given oral doses of 0, 10 and 40 mg/kg/day for one year; however, after 8 weeks the highest dose was reduced to 30 mg/kg/day following the death of 3/10 animals in the group. No abnormal signs were observed at the 10 mg/kg level. In the 20 mg/kg group, one animal was found prostrate and panting on one occasion and another was unexpectedly found dead near the end of the study. 40 mg/kg produced occasional transient ataxia, excessive salivation and convulsions. Following the three deaths and the reduction of dosage to 30 mg/kg, a fourth death occurred 16 weeks later, subsequent to convulsions. A fifth animal became hypersensitive to touch and aggressive during the final 6 months of the study. Hematological and biochemical analyses were normal apart from one case of transient anemia in the 20 mg/kg group and slightly elevated SGPT values in 2/6 high dose dogs during the final 3 months.
Groups of 6 rhesus monkeys received 0, 20, 40, and 80 mg/kg/day of trazodone by gavage for one year. The only effects noted were a slight dose-related decrease in activity and tremors in 3 high dose monkeys. Both effects decreased during the study.
Reproductive Studies: A number of reproductive studies were performed. Fertility and general reproductive performance of male and female rats were not affected by doses of up to 250 mg/kg/day. At 300 mg/kg, the birth weight of pups was significantly reduced.
In one rat study, 100 and 210 mg/kg/day p.o. was given during days 10-15 and 6-15 of gestation respectively, and another study, 150 to 450 mg/kg/day p.o. during days 9-14 of gestation. At 100 mg/kg only a sedative effect on dams was noted. 150 mg/kg and higher doses produced increased sedation, decreased maternal and fetal weights, and retarded ossification. 300 and 450 mg/kg resulted in a significant increase in resorption and stillborn feti in addition to retarded fetal growth. Also noted were isolated cases of branched rib, separated thoracic arch, umbilical hernia, and exencephalia.
Peri-and postnatal effects of up to 300 mg/kg/day of trazodone were examined in rats. The only effects observed were reduced birth and weaning weights of offspring in the highest dosage group.
When doses approximately 30 - 50 times the proposed maximum human dose were administered to rats, trazodone was shown to cause increased fetal resorption and other adverse effects on the fetus. There was also an increase in congenital anomalies in one of three rabbit studies at approximately 15 - 50 times the maximum human dose.
Carcinogenicity Studies: A two-year carcinogenicity study was performed in rats at dose levels of 0, 40 and 80 mg/kg/day. Larger numbers of female rats in both treatment groups died sooner than controls and most deaths were related to the presence of pituitary tumors. The incidence of palpable masses (mammary tumors, cysts, etc.) also was increased in both treatment groups at 12, 13, and 14 months. The observations may be related to the effects of trazodone on prolactin secretion. (Acute administration caused an increase in prolactin blood levels; chronic administration did not; however, turnover was not studied. A neuroleptic, used as a positive control, produced similar results). The relative incidences of male rats with pituitary tumors were reversed; however, early deaths due to nephritis and other causes might have influenced these observations.
Indications/Uses
pms-TRAZODONE (trazodone hydrochloride) is of value in the symptomatic relief of depressive illness.
Geriatrics (> 65 years of age): Use with caution in geriatric patients. See Use in the Elderly under Precautions.
Pediatrics (< 18 years of age): Safety and efficacy have not been established in patients below 18 years of age. pms-TRAZODONE is not indicated in this age group.
Dosage/Direction for Use
Dosing Considerations: Dosage should be initiated at a low level and increased gradually. It should be kept in mind that there may be a lag in the therapeutic response. Increasing the dosage rapidly does not normally shorten this latent period and may increase the incidence of side effects.
Recommended Dose and Dosage Adjustment: Adults: The recommended initial dose is 150-200 mg daily, in two or three divided doses. pms-TRAZODONE should be taken shortly after a meal or light snack in order to reduce the incidence of adverse reactions. The dose may be increased according to tolerance and response by increments of 50 mg, usually up to 300 mg daily in divided doses. In some patients, doses up to 400 mg daily and, rarely, up to 600 mg daily, may be required. Occurrence of drowsiness may require the administration of a major portion of the daily dose at bedtime or a reduction of dosage.
Once an adequate response has been achieved, the dosage may be gradually reduced, with adjustment depending on therapeutic response. During prolonged maintenance therapy the dosage should be kept at the lowest effective level.
Discontinuation of Treatment: Patients should be monitored for discontinuation symptoms when discontinuing treatment with pms-TRAZODONE. The dose should be gradually reduced whenever possible.
Geriatrics (>65 years of age): If used in the elderly, doses not exceeding half the recommended adult dosage should be used, with adjustments made depending on tolerance and response.
Pediatrics: pms-TRAZODONE is not indicated for use in children under 18 years of age.
Overdosage
Fatal overdoses have occurred mostly in patients ingesting trazodone and other CNS depressant drugs concurrently (alcohol; chloral hydrate; diazepam; amobarbital; chlordiazepoxide; or meprobamate).
The most severe reactions reported with overdose of trazodone alone have been priapism, respiratory arrest, coma, seizures, ECG changes (including QTc prolongation and torsade de pointes) and death. The reactions reported most frequently have been drowsiness and vomiting. Also reported were bradycardia, transient first-degree heart block, ataxia and hyponatremia. Overdosage may cause an increase in incidence or severity of any of the reported adverse reactions.
Treatment of Overdosage: There is no specific antidote for trazodone. Treatment should be symptomatic and supportive. Ensure adequate airway, oxygenation and ventilation. Continuous ECG and vital signs monitoring are recommended. Monitor fluids and electrolyte status in symptomatic patients. Induction of emesis is not recommended. Any patient suspected of having taken a potentially life-threatening overdose should have the stomach emptied by gastric lavage, with appropriate airway protection, if it can be performed soon after ingestion. Forced diuresis may be useful in facilitating elimination of the drug.
Contraindications
Patients who are hypersensitive to trazodone or to any ingredient in the formulation. For a complete listing, see Description.
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.
Use In Pregnancy & Lactation
Pregnant Women: There are no adequate and well-controlled studies in pregnant women. In two studies using the rat, trazodone has been shown to cause increased fetal resorption and other adverse effects on the fetus when given at dose levels approximately 30 - 50 times the proposed maximum human dose. There was also an increase in congenital anomalies in one of three rabbit studies at approximately 15 - 50 times the maximum human dose. pms-TRAZODONE should not be used in women of childbearing potential unless, in the opinion of the physician, the expected benefits justify the potential risk to the fetus.
Trazodone Hydrochloride Treatment during Pregnancy - Effects on Newborns: Postmarketing reports indicate that some neonates exposed to trazodone, SSRIs or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Most often, such complications begin immediately or soon (< 24 hours) after delivery. When treating a pregnant woman with pms-TRAZODONE during later stages of pregnancy, the physician should carefully consider the potential risks and benefits of treatment.
Nursing Women: Trazodone and its metabolites have been detected in the milk of lactating animals; it should not be administered to nursing mothers unless the potential benefits justify the possible risks to the child.
Adverse Reactions
The following adverse reactions are listed alphabetically by body system or organ class.
Blood and the lymphatic system disorders: Blood dyscrasias (agranulocytosis, leucopenia, anemia).
Cardiac disorders: Orthostatic hypotension, syncope, hypertension, tachycardia, bradycardia, palpitations, shortness of breath, apnea, arrhythmias (including Torsade de Pointes, PVCs, ventricular couplets, ventricular tachycardia), prolonged P-R interval, atrial fibrillation, myocardial infarction, cardiac arrest and conduction block.
Endocrine disorders: Syndrome of Inappropriate Antidiuretic Hormone Secretion.
Gastrointestinal disorders: Nausea, vomiting, dry mouth, increased salivation, constipation, diarrhea, dyspepsia, stomach pain, gastroenteritis, paralytic ileus.
Genitourinary: Priapism (see Priapism under Precautions), decreased libido, increased libido (rarely), retrograde ejaculation, inhibition of ejaculation, menstrual irregularities.
Hepato-biliary disorders: Hepatic function abnormalities (including jaundice and hepatocellular damage), intrahepatic cholestasis.
Immune system disorders: Allergic reactions, including skin rash, itching, edema, and, rarely, hemolytic anemia, methemoglobinemia, liver enzyme alterations, leukocytoclastic vasculitis, purpuric maculopapular eruptions, photosensitivity, fever and obstructive jaundice.
Metabolism and nutrition disorders: Hyponatremia, weight loss, anorexia, increased appetite.
Nervous system disorders: Serotonin syndrome, convulsion, neuroleptic malignant syndrome, dizziness, vertigo, headache, drowsiness, restlessness, decreased alertness, tremor, blurred vision, memory disturbance, myoclonus, aphasia, paresthesia, dystonia, taste altered.
Psychiatric disorders: Suicidal ideation or suicidal behaviours, confusional state, insomnia, disorientation, mania, anxiety, nervousness, agitation (very occasionally exacerbating to delirium), delusion, aggressive reaction, hallucinations, nightmares, withdrawal syndrome.
Respiratory disorders: Nasal congestion, dyspnea.
Skin and subcutaneous tissue disorders: Rash, pruritus, hyperhidrosis.
Drug Interactions
Drug-Drug Interactions: CYP 3A4 Inhibitors and Inducers: In vitro studies reveal that trazodone is a substrate of the cytochrome P450 3A4 enzyme (CYP3A4) and trazodone metabolism can be inhibited by CYP3A4 inhibitors (e.g. ritonavir, ketoconazole). The effect of short-term administration of ritonavir (200 mg twice daily for four doses) on the pharmacokinetics of a single dose of trazodone (50 mg) has been studied in 10 healthy subjects. The Cmax of trazodone increased by 34%, the AUC increased 2.4-fold, the half-life increased by 2.2-fold, and the clearance decreased by 52%. Adverse effects including nausea, hypotension, and syncope were observed when ritonavir and trazodone were co-administered. If trazodone is used with a potent CYP3A4 inhibitor, a lower dose of trazodone should be considered.
Prolongation of the QTc interval by pms-TRAZODONE is anticipated to be increased in the presence of CYP3A4 inhibitors. Drugs that inhibit CYP3A4 include ketoconazole, itraconazole, voriconazole, clarithromycin, erythromycin, atazanavir, indinavir, nelfinavir, ritonavir, saquinavir, and amiodarone. The concomitant use of these drugs with pms-TRAZODONE is discouraged. If used concomitantly with a CYP3A4 inhibitor, pms-TRAZODONE should be started at a low dose and patients monitored closely.
Carbamazepine induces CYP3A4. Following co-administration of carbamazepine 400 mg/day with trazodone 100 mg to 300 mg daily, carbamazepine reduced plasma concentrations of trazodone as well as mCPP by 76 and 60%, respectively, compared to pre-carbamazepine values.
Drugs with a QTc prolongation effect: The concomitant use of pms-TRAZODONE with another QTc-prolonging drug is discouraged. If used concomitantly with these drugs, pms-TRAZODONE should be started at a low dose and patients monitored closely. Drugs that have been associated with QTc interval prolongation or torsade de pointes include, but are not limited to, the examples in the following list. Drugs classes are listed if some class members have been implicated in QTc prolongation or torsade de pointes: Class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide); Class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide); Class 1C antiarrhythmics (e.g., flecainide, propafenone); antipsychotics (e.g., chlorpromazine, pimozide, haloperidol, droperidol, ziprasidone); antidepressants (e.g., SSRI, venlafaxine, tricyclic/tetracyclic antidepressants); opioids (e.g., methadone); macrolide antibiotics and analogues (e.g., erythromycin, clarithromycin, tacrolimus); quinolone antibiotics (e.g., moxifloxacin, levofloxacin, ciprofloxacin); pentamidine; antimalarials (e.g., quinine, chloroquine); azole antifungals (e.g., ketoconazole, fluconazole, voriconazole); domperidone; 5-hydroxytryptamine receptor antagonists (e.g., dolasetron, ondansetron); tyrosine kinase inhibitors (e.g., sunitinib, nilotinib, lapatinib); histone deacetylase inhibitors (e.g., vorinostat); beta-2 agonists (e.g., salmeterol, formoterol).
Drugs with effect on electrolytes: The use of pms-TRAZODONE is discouraged with drugs that can disrupt electrolyte levels, including: loop, thiazide, and related diuretics; laxatives and enemas; amphotericin B; high dose corticosteroids. If used concomitantly with these drugs, pms-TRAZODONE should be started at a low dose and patients monitored closely.
Digoxin and Phenytoin: Increased serum digoxin or phenytoin levels have been reported to occur in patients receiving trazodone concurrently with either of these drugs.
Serotonergic drugs: Based on the mechanism of action of trazodone and the potential for serotonin syndrome, pms-TRAZODONE should not be used in combination with a MAO inhibitor or within 14 days of discontinuing treatment with a MAO inhibitor; similarly, at least 14 days should be allowed after stopping pms-TRAZODONE before starting treatment with a MAO inhibitor. Caution is advised when pms-TRAZODONE is co-administered with other drugs that may affect neurotransmitter systems, such as tryptophan, triptans, SSRIs, lithium, fentanyl, tramadol, or St. John's Wort (see Neurologic: Serotonin Syndrome under Precautions).
Drugs that affect coagulation or bleeding: Due to a possible association between serotonin modulating drugs and gastrointestinal bleeding, patients should be cautioned about potential risk of bleeding associated with the concomitant use of trazodone and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding (see Hematologic: Abnormal Bleeding under Precautions).
Warfarin: There have been reports of increased and decreased prothrombin time occurring in warfarinized patients who take trazodone.
CNS depressants: Trazodone may enhance the response to alcohol and the effects of barbiturates and other CNS depressants and patients should be cautioned accordingly.
General anesthetics: Little is known about the interaction between trazodone and general anesthetics. As a precaution, pms-TRAZODONE should be discontinued for as long as clinically feasible prior to elective surgery.
Drug-Non-drug Therapy Interactions: Electroconvulsive therapy (ECT): The efficacy and safety of the concurrent use of pms-TRAZODONE and ECT have not been studied.
Drug-Food Interactions: Grapefruit, grapefruit juice, and products containing grapefruit extracts should not be used during treatment with pms-TRAZODONE because of the potential to inhibit CYP3A4 and increase plasma levels of trazodone.
Drug-Herb Interactions: Pharmacodynamic interactions between trazodone and St. John's Wort may occur and may result in an increase in undesirable effects (see Neurologic: Serotonin Syndrome under Precautions).
Drug-Laboratory Interactions: Interactions with laboratory tests have not been established.
Drug-Lifestyle Interactions: Trazodone may enhance the response to alcohol and the effects of barbiturates and other CNS depressants and patients should be cautioned accordingly.
Storage
Store below 25°C. Protect from light.
MIMS Class
ATC Classification
N06AX05 - trazodone ; Belongs to the class of other antidepressants.
Presentation/Packing
Tab 50 mg (salmon, round, biconvex, debossed with "TRAZO" over "50" on one side and a score line on the other side) x 100's, 500's. 100 mg (white, round, biconvex, debossed with "TRAZO" over "100" on one side and a score line on the other side) x 100's, 500's.
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