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TrazodoneDESYREL (trazodone hydrochloride) is an antidepressant chemically unrelated to tricyclic, tetracyclic, or other known antidepressant agents. Trazodone hydrochloride is a triazolopyridine derivative designated as 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazo-lo[4,3-a]pyridin-3(2H)-one hydrochloride. It is a white odorless crystalline powder which is freely soluble in water. Its molecular weight is 408.3. The empirical formula is C19H22CIN5O • HCl DESYREL is supplied for oral administration in 50 mg, 100 mg, 150 mg and 300 mg tablets. DESYREL Tablets,50 mg, contain the following inactive ingredients: dibasic calcium phosphate, castor oil, microcrystalline cellulose, eth-ylcellulose, FD&C Yellow No. 6 (aluminum lake), lactose, magnesium stearate, povidone, sodium starch glycolate, and starch (corn). DESYREL Tablets, 100 mg, contain the following inactive ingredients: dibasic calcium phosphate, castor oil, microcrystalline cellulose, ethylcel-lulose, lactose, magnesium stearate, povidone, sodium starch glycolate, and starch (corn). DESYREL Tablets, 150 mg, contain the following inactive ingredients: microcrystalline cellulose, FD&C Yellow No.6 (aluminum lake),magne-sium stearate, pregelatinized starch, and stearic acid. DESYREL Tablets, 300 mg, contain the following inactive ingredients: microcrystalline cellulose, yellow ferric oxide, magnesium stearate, sodium starch glycolate, pregelatinized starch, and stearic acid. The mechanism of DESYREL’s antidepressant action in man is not fully understood. In animals, DESYREL selectively inhibits serotonin uptake by brain synaptosomes and potentiates the behavioral changes induced by the serotonin precursor, 5-hydroxytryptophan. Cardiac conduction effects of DESYREL in the anesthetized dog are qualitatively dissimilar and quantitatively less pronounced than those seen with tricyclic antidepressants. DESYREL is not a monoamine oxidase inhibitor and, unlike amphetamine-type drugs, does not stimulate the central nervous system. Pharmacokinetics Absorption In humans, DESYREL is well absorbed after oral administration without selective localization in any tissue. When DESYREL 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 one hour after dosing when DESYREL is taken on an empty stomach or two hours after dosing when taken with food. Metabolism In vitro studies in human liver microsomes show that trazodone is metabolized to an active metabolite, m-chlorophenylpiperazine (mCPP) by cytochrome P450 3A4 (CYP3A4). Other metabolic pathways that may be involved in metabolism of trazodone have not been well characterized. Elimination In some patients DESYREL may accumulate in the plasma. Drug-Drug Interactions See also PRECAUTIONS: Drug Interactions. In vitro drug metabolism studies reveal that trazodone is a substrate of the cytochrome P450 3A4 (CYP3A4) enzyme and trazodone metabolism can be inhibited by the CYP3A4 inhibitors ketoconazole, ritonavir, and indi-navir. The effect of short-term administration of ritonavir (200 mg twice daily, 4 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. 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. For those patients who responded to DESYREL, 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. DESYREL is indicated for the treatment of depression. The efficacy of DESYREL 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.a Major Depressive Episode implies a prominent and relatively persistent (nearly every day for at least two 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. 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. DESYREL 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 two weeks. Twenty-five percent of those who respond to DESYREL require more than two weeks (up to four 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 three to four 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 DESYREL beyond six weeks, it is generally recommended that a course of antidepressant drug treatment should be continued for several months. DESYREL® (trazodone hydrochloride) Tablets, 50 mg—round, orange/scored, film-sealed (debossed withDESYREL and MJ 775) NDC 0087-0775-41 Bottles of 100 NDC 0087-0775-43 Bottles of 1000 Tablets, 100 mg—round, white/scored, film-sealed (debossed withDESYREL and MJ 776) NDC 0087-0776-41 Bottles of 100 NDC 0087-0776-43 Bottles of 1000 Tablets, 150 mg—orange, in the Dividose® tablet design (debossed with MJ and 778 on front; "50,""50,""50" on reverse) NDC 0087-0778-43 Bottles of 100 NDC 0087-0778-44 Bottles of 500 Tablets, 300 mg—yellow, in the Dividose® tablet design (debossed with MJ and 796 on front; "100,""100,""100" on reverse) NDC 0087-0796-41 Bottles of 100 Storage Store at room temperature. Protect from temperatures above 104° F (40° C). Dispense in tight,light-resistant container (USP). REFERENCES a. Williams JBW, Ed: Diagnostic and Statistical Manual of Mental Disorders-III, American Psychiatric Association May, 1980. b. Lue TF, Physiology of erection and pathophysiology of impotence. In: Wash PC, Retik AB, Stamey TA, Vaughan ED, eds. Campbell’s Urology. Sixth edition. Philadelphia: W.B.Saunders; 1992:722-725. c. Goldstein I, Krane RJ, Diagnosis and therapy of erectile dysfunction. In: Wash PC, Retik AB, Stamey TA, Vaughan ED, eds. Campbell’s Urology. Sixth edition. Philadelphia: W.B. Saunders; 1992: 3071-3072. d. Yealy DM, Hogya PT: Priapism. Emerg Med Clin North Am. 1988; 6:509-520. e. Banos JE,Bosch F,Farre M,Drug-induced priapism. Its aetiology, inci-dence and treatment. Med Toxicol Adverse Drug Exp. 1989; 4:46-58. f. O’Brien WM,O’Connor KP,Lynch JH.Priapism: current concepts. Ann Emerg Med. 1989:980-983. g. Bardin ED, Krieger JN. Pharmacological priapism: comparison of tra-zodone- and papaverine-associated cases. Int Urol Nephrol. 1990; 22:147-152. Princeton, NJ 08543-4500, USA, 1138855A1 778DIM-05 Revised September 2003 Because the frequency of adverse drug effects is affected by diverse factors (e.g.,drug dose, method of detection, physician judgment, dis-ease 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 DESYREL. It is impossible to determine precisely what accounts for the differences observed. Clinical Trial Reports The table below 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 DESYREL® (trazodone hydrochloride). 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 DESYREL® (trazodone hydrochloride) 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, numb-ness, and retrograde ejaculation. Post Introduction Reports Although the following adverse reactions have been reported in DESYREL users, the causal association has neither been confirmed nor refuted. Voluntary reports received since market introduction include the following: abnormal dreams, agitation, alopecia, anxiety, aphasia, apnea, ataxia, breast enlargement or engorgement, cardiospasm, cerebrovascular accident, chills, cholestatis, clitorism, congestive heart failure, diplopia, edema, extrapyramidal symptoms, grand mal seizures, hallucinations, hemolytic anemia, hirsutism, hyperbiliru-binemia, increased amylase, increased salivation, insomnia, leukocy-tosis, leukonychia, jaundice, lactation, liver enzyme alterations, methemoglobinemia, nausea/vomiting (most frequently), paresthesia, paranoid reaction, priapism (See WARNINGS and PRECAUTIONS, Information for Patients; some patients have required surgical inter-vention), pruritus, psoriasis, 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, palpi-tations, bradycardia, atrial fibrillation, myocardial infarction, cardiac arrest, arrhythmia, and ventricular ectopic activity, including ventricular tachycardia (see WARNINGS). 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 or nefazodone may lead to substantial increases in trazodone plasma concentrations, with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, a lower dose of trazodone should be considered. Carbamazepine reduced plasma concentrations of trazodone when co-administered. Patients should be closely monitored to see if there is a need for an increased dose of trazodone when taking both drugs. Increased serum digoxin or phenytoin levels have been reported to occur in patients receiving DESYREL concurrently with either of those two drugs. It is not known whether interactions will occur between monoamine oxidase (MAO) inhibitors and DESYREL. Due to the absence of clinical experience, if MAO inhibitors are discontinued shortly before or are to be given concomitantly with DESYREL, therapy should be initiated cautiously with gradual increase in dosage until optimum response is achieved. 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 warfarinized patients who take DESYREL. TRAZODONE HAS BEEN ASSOCIATED WITH THE OCCURRENCE OF PRIAPISM. IN MANY OF THE CASES REPORTED, SURGICAL INTERVENTION WAS REQUIRED AND, IN A SOME 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 has been accomplished by both pharmacologic, e.g., the intracaver-nosal injection of alpha-adrenergic stimulants such as epinephrine and norepinephrine, as well as surgical procedures.b-g Any pharmacologic or surgical procedure utilized in the treatment of priapism 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. DESYREL (trazodone hydrochloride) is not recommended for use during the initial recovery phase of myocardial infarction. Caution should be used when administering DESYREL to patients with cardiac disease, and such patients should be closely monitored, since antidepressant drugs (including DESYREL) have been associated with the occurrence of cardiac arrhythmias. Recent clinical studies in patients with pre-existing cardiac disease indicate that DESYREL may be arrhythmogenic in some patients in that population. Arrhythmias identified include isolated PVCs, ventricular couplets, and in two 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 DESYREL. Concomitant administration of antihypertensive therapy with DESYREL may require a reduction in the dose of the antihypertensive drug. Little is known about the interaction between DESYREL and general anesthetics; therefore, prior to elective surgery, DESYREL should be discontinued for as long as clinically feasible. As with all antidepressants, the use of DESYREL should be based on the consideration of the physician that the expected benefits of therapy outweigh potential risk factors. INFORMATION FOR PATIENTS
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