CATEGORIES: Depression; Pregnancy Category C; FDA Approved December 1981
Drug Classes: Antidepressants, miscellaneous
BRAND NAMES: Desyrel; Desyrel Dividose
FOREIGN BRAND AVAILABILITY:
Azonz (Finland);
Beneficat (Argentina);
Bimaran (Argentina);
Deprax (Spain);
Depresil (Philippines);
Depyrel (Israel);
Desirel (Thailand);
Manegan (Argentina);
Molipaxin (England, Ireland, South Africa);
Pragmarel (France);
Reslin (Japan);
Taxagon (Argentina);
Thombran (Germany);
Trazodil (Israel);
Trazolan (Belgium, India, Netherlands);
Trazone (Indonesia, Portugal, Taiwan);
Trittico (Austria, Colombia, Greece, Hong Kong, Italy, Peru, Switzerland)
COST OF THERAPY:
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Trazodone HCl, is an antidepressant chemically unrelated to tricyclic, tetracyclic, or other known antidepressant agents. It is a triazolopyridine derivative designated as 2-[3-{4 -(m- Chlorophenyl)-1-piperazinyl} propyl]s-triazolo[4,3-a]-pyridin-3(2H)-one monohydrochloride. Trazodone HCl is a white to off-white crystalline powder which is sparingly soluble in chloroform and water. Its molecular weight is 408.3. The empirical formula is C19H22ClN5O·HCl.
Trazodone HCl is supplied for oral administration in 50 mg, 100 mg, 150 mg, and 300 mg tablets.
Trazodone HCl tablets, 50 mg, contain the following inactive ingredients: dibasic calcium phosphate, castor oil, microcrystalline cellulose, ethylcellulose, FD&C yellow no. 6 (aluminum lake), lactose, magnesium stearate, povidone, sodium starch glycolate, and starch (corn).
Trazodone HCl tablets, 100 mg, contain the following inactive ingredients: dibasic calcium phosphate, castor oil, microcrystalline cellulose, ethylcellulose, lactose, magnesium stearate, povidone, sodium starch glycolate, and starch (corn).
Trazodone HCl tablets, 150 mg, contain the following in active ingredients: microcrystalline cellulose, FD&C yellow no. 6 (aluminum lake), magnesium stearate, pre-gelatinized starch, and stearic acid.
Trazodone HCl tablets, 300 mg, contain the following inactive ingredients: microcrystalline cellulose, yellow ferric oxide, magnesium stearate, sodium starch glycolate, pregelatinized starch, and stearic acid.
Storage
Store at controlled room temperature 15-30°C (59-86°F).
Dispense in tight, light-resistant container with a child-resistant closure.
The mechanism of trazodone HCl's antidepressant action in man is not fully understood. In animals, trazodone HCl selectively inhibits serotonin uptake by brain synaptosomes and potentiates the behavioral changes induced by the serotonin precursor, 5-hydroxytryptophan. Cardiac conduction effects of trazodone HCl in the anesthetized dog are qualitatively dissimilar and quantitatively less pronounced than those seen with tricyclic antidepressants. Trazodone HCl is not a monoamine oxidase inhibitor and, unlike amphetamine-type drugs, does not stimulate the central nervous system.
In man, trazodone HCl is well absorbed after oral administration without selective localization in any tissue. When trazodone HCl 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 1 hour after dosing when trazodone HCl tablets are taken on an empty stomach or 2 hours after dosing when taken with food. Elimination of trazodone HCl is biphasic, consisting of an initial phase (half-life 3-6 hours) followed by a slower phase (half-life 5-9 hours), and is unaffected by the presence or absence of food. Since the clearance of trazodone HCl from the body is sufficiently variable, is some patients trazodone HCl may accumulate in the plasma.
For those patients who responded to trazodone HCl, one-third of the inpatients and one-half of the outpatients had a significant therapeutic response by the end of the first week of treatment. Three-fourths of all responders demonstrated a significant therapeutic effect by the end of the second week. One-fourth of responders required 2-4 weeks for a significant therapeutic response.
Trazodone HCl is indicated for the treatment of depression. The efficacy of trazodone HCl has been demonstrated in both inpatient and outpatient settings and for depressed patients with and without prominent anxiety. The depressive illness of patients studied corresponds to the Major Depressive Episode criteria of the American Psychiatric Association's Diagnostic and Statistical Manual, III. 1
Major Depressive Episode implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least four of the following eight symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigability, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and suicidal ideation or attempts.
Non-FDA Approved Indications
Preliminary data suggest trazodone may also be effective in reducing the three primary clusters of symptoms of posttraumatic stress disorder. However, this use is not approved by the FDA and further clinical testing is needed.
Trazodone HCl is contraindicated in patients hypersensitive to the drug substance.
TRAZODONE HAS BEEN ASSOCIATED WITH THE OCCURRENCE OF PRIAPISM. IN APPROXIMATELY 1/3 OF THE CASES REPORTED, SURGICAL INTERVENTION WAS REQUIRED AND, IN A PORTION OF THESE CASES, PERMANENT IMPAIRMENT OF ERECTILE FUNCTION OR IMPOTENCE RESULTED. MALE PATIENTS WITH PROLONGED OR INAPPROPRIATE ERECTIONS SHOULD IMMEDIATELY DISCONTINUE THE DRUG AND CONSULT THEIR PHYSICIAN.
The detumescence of priapism and drug-induced penile erections by the intracavernosal injection of alpha-adrenergic stimulants such as epinephrine and metaraminol has been reported. 2 - 7 For one case of priapism (of some 12-24 hours' duration) in a trazodone HCl treated patient in whom the intracavernosal injection of epinephrine was accomplished, prompt detumescence occurred with return of normal erectile activity.
This procedure should be performed under the supervision of a urologist or a physician familiar with the procedure and should not be initiated without urologic consultation if the priapism has persisted for more than 24 hours.
Trazodone HCl is not recommended for use during the initial recovery phase of myocardial infarction.
Caution should be used when administering trazodone HCl to patients with cardiac disease, and such patients should be closely monitored, since antidepressant drugs (including trazodone HCl) have been associated with the occurrence of cardiac arrhythmias. Recent clinical studies in patients with pre-existing cardiac disease indicate that trazodone HCl may be arrhythmogenic in some patients in that population. Arrhythmias identified include isolated PVCs, ventricular couplets, and in 2 patients short episodes (3-4 beats) of ventricular tachycardia.
General
The possibility of suicide in seriously depressed patients is inherent in the illness and may persist until significant remission occurs. Therefore, prescriptions should be written for the smallest number of tablets consistent with good patient management.
Hypotension, including orthostatic hypotension and syncope, has been reported to occur in patients receiving trazodone HCl. Concomitant administration of antihypertensive therapy with trazodone HCl may require a reduction in the dose of the antihypertensive drug.
Little is known about the interaction between trazodone HCl and general anesthetics; therefore, prior to elective surgery, trazodone HCl should be discontinued for as long as clinically feasible.
As with all antidepressants, the use of trazodone HCl should be given on the consideration of the physician that the expected benefits of therapy outweigh potential risk factors.
Information for the Patient
Because priapism has been reported to occur in patients receiving trazodone HCl, patients with prolonged or inappropriate penile erection should immediately discontinue the drug and consult with the physician (see WARNINGS).
Antidepressants may impair the mental and/or physical ability required for the performance of potentially hazardous tasks, such as operating an automobile or machinery; the patient should be cautioned accordingly.
Trazodone HCl may enhance the response to alcohol, barbiturates, and other CNS depressants.
Trazodone HCl should be given shortly after a meal or light snack. Within any individual patient, total drug absorption may be up to 20% higher when the drug is taken with food rather than on an empty stomach. The risk of dizziness/lightheadedness may increase under fasting conditions.
Laboratory Tests
Occasional low white blood cell and neutrophil counts have been noted in patients receiving trazodone HCl. These were not considered clinically significant and did not necessitate discontinuation of the drug; however, the drug should be discontinued in any patient whose white blood cell count or absolute neutrophil count falls below normal levels. White blood cell and differential counts are recommended for patients who develop fever and sore throat (or other signs of infection) during therapy.
Therapeutic Interactions
Concurrent administration with electroshock therapy should be avoided because of the absence of experience in this area.
There have been reports of increased and decreased prothrombin time occurring in patients taking warfarin and trazodone HCl.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
No drug- or dose-related occurrence of carcinogenesis was evident in rats receiving trazodone HCl in daily oral doses up to 300 mg/kg for 18 months.
Pregnancy Category C
Trazodone HCl has been shown to cause increased fetal resorption and other adverse effects on the fetus in two studies using the rat 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. There are no adequate and well-controlled studies in pregnant women. Trazodone HCl should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Trazodone HCl 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 HCl is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in children below the age of 18 have not been established.
Increased serum digoxin or phenytoin levels have been reported to occur in patients receiving trazodone HCl concurrently with either of those 2 drugs.
It is not known whether interactions will occur between monoamine oxidase (MAO) inhibitors and trazodone HCl. Due to the absence of clinical experience, if MAO inhibitors are discontinued shortly before or are to be given concomitantly with trazodone HCl, therapy should be initiated cautiously with gradual increase in dosage until optimum response is achieved.
Because the frequency of adverse drug effects is affected by diverse factors (e.g., drug dose, methods of detection, physician judgment, disease under treatment, etc.) a single meaningful estimate of adverse event incidence is difficult to obtain. This problem is illustrated by the variation in adverse event incidence observed and reported from the inpatients and outpatients treated with trazodone HCl. It is impossible to determine precisely what accounts for the differences observed.
Clinical Trial Reports
TABLE 1 is presented solely to indicate the relative frequency of adverse events reported in representative controlled clinical studies conducted to evaluate the safety and efficacy of trazodone HCl.
The figures cited cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors often differ from those which prevailed in the clinical trials. These incidence figures, also, cannot be compared with those obtained from other clinical studies involving related drug products and placebo, as each group of drug trials is conducted under a different set of conditions.
Occasional sinus bradycardia has occurred in long-term studies.
In addition to the relatively common (i.e., greater than 1%) untoward events enumerated above, the following adverse events have been reported to occur in association with the use of trazodone HCl in the controlled clinical studies: akathisia, allergic reaction, anemia, chest pain, delayed urine flow, early menses, flatulence, hallucinations/delusions, hematuria, hypersalivation, hypomania, impaired speech, impotence, increased appetite, increased libido, increased urinary frequency, missed periods, muscle twitches, numbness, and retrograde ejaculation.
Postintroduction Reports
Although the following adverse reactions have been reported in trazodone HCl users, the causal association has neither been confirmed nor refuted.
Voluntary Reports Received Since Market Introduction Include the Following
Agitation, alopecia, apnea, ataxia, breast enlargement or engorgement, diplopia, edema, extrapyramidal symptoms, grand mal seizures, hallucinations, hemolytic anemia, hyperbilirubinemia, leukonychia, jaundice, lactation, liver enzyme alterations, methemoglobinemia, nausea/vomiting (most frequently), paresthesia, priapism (See WARNINGS and PRECAUTIONS, Information for the Patient; some patients may require surgical intervention), pruritus, psychosis, rash, stupor, inappropriate ADH syndrome, tardive dyskinesia, unexplained death, urinary incontinence, urinary retention, urticaria, vasodilation, vertigo, and weakness.
Cardiovascular System Effects Which Have Been Reported Include the Following
Conduction block, orthostatic hypotension and syncope, palpitations, bradycardia, atrial fibrillation, myocardial infarction, cardiac arrest, arrhythmia, and ventricular ectopic activity, including ventricular tachycardia (see WARNINGS).
Animal Oral LD50
The oral LD50 of the drug is 610 mg/kg in mice, 486 mg/kg in rats, and 560 mg/kg rabbits.
Signs and Symptoms
Death from overdose has occurred in patients ingesting trazodone HCl and other drugs concurrently (namely, alcohol; alcohol + chloral hydrate + diazepam; amobarbital; chlordiazepoxide; or meprobamate).
The most severe reactions reported to have occurred with overdose of trazodone HCl alone have been priapism, respiratory arrest, seizures, and EKG changes. The reactions reported most frequently have been drowsiness and vomiting. Overdosage may cause an increase in incidence or severity of any of the reported adverse reactions (see ADVERSE REACTIONS).
Treatment
There is no specific antidote for trazodone HCl. Treatment should be symptomatic and supportive in the case of hypotension or excessive sedation. Any patient suspected of having taken an overdose should have the stomach emptied by gastric lavage. Forced diuresis may be useful in facilitating elimination of the drug.
The dosage should be initiated at a low level 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. Trazodone HCl should be taken shortly after a meal or light snack. Symptomatic relief may be seen during the first week, with optimal antidepressant effects typically evident within 2 weeks. Twenty-five percent (25%) of those who respond to trazodone HCl require more than 2 weeks (up to 4 weeks) of drug administration.
Usual Adult Dosage
An initial dose of 150 mg/day in divided doses is suggested. The dose may be increased by 50 mg/day every 3-4 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.
Maintenance
Dosage during prolonged maintenance therapy should be kept at the lowest effective level. Once an adequate response has been achieved, dosage may be gradually reduced, with subsequent adjustment depending on therapeutic response.
Although there has been no systematic evaluation of the efficacy of trazodone HCl beyond 6 weeks, it is generally recommended that a course of antidepressant drug treatment should be continued for several months.
References
1.
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