TRAZODONE HYDROCHLORIDE- trazodone tablet

Trazodone Hydrochloride by

Drug Labeling and Warnings

Trazodone Hydrochloride by is a Prescription medication manufactured, distributed, or labeled by Rebel Distributors Corp.. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

BOXED WARNING

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Suicidality and Antidepressant Drugs

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of trazodone HCl or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Trazodone HCl is not approved for use in pediatric patients. (See Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use

DESCRIPTION

Trazodone HCl is an antidepressant chemically unrelated to tricyclic, tetracyclic, or other known antidepressant agents. Trazodone HCl is a triazolopyridine derivative designated as 2-[3-[4-(m-Chlorophenyl)-1-piperazinyl]propyl]s-triazolo[4,3-a]-pyridin-3 (2H)-one monohydrochloride. It is a white to off-white crystalline powder which is sparingly soluble in chloroform and in water. Its molecular weight is 408.3. The molecular formula is C19H22ClN5OHCl and the structural formula is represented as follows:

Each tablet, for oral administration, contains 50 mg, 100 mg or 150 mg of trazodone hydrochloride, USP. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, anhydrous lactose, magnesium stearate, microcrystalline cellulose and sodium starch glycolate.

CLINICAL PHARMACOLOGY

The mechanism of trazodone HCl’s antidepressant action in man is not fully understood. In animals, trazodone HCl selectively inhibits its 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.

Pharmacokinetics

Absorption

In humans, trazodone is well absorbed after oral administration without selective localization in any tissue. When trazodone 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 trazodone 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 trazodone 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 indinavir. 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 CYP34A. 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 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.

INDICATIONS AND USAGE

Trazodone hydrochloride tablets are 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, lll.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.

CONTRAINDICATIONS

Trazodone hydrochloride tablets are contraindicated in patients hypersensitive to trazodone HCl.

WARNINGS

Clinical Worsening and Suicide Risk

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (aged 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analysis of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders including a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1
Age Range	Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
	Increases Compared to Placebo
<18	14 additional cases
18-24	5 additional cases
	Decreases Compared to Placebo
25-64	1 fewer case
≥65	6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about the drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for trazodone HCl should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that trazodone HCl is not approved for use in treating bipolar depression.

TRAZODONE HAS BEEN ASSOCIATED WITH THE OCCURRENCE OF PRIAPISM. IN MANY OF THE CASES REPORTED, SURGICAL INTERVENTION WAS REQUIRED AND, IN 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 intracavernosal 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.

Trazodone 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 two patients short episodes (3-4 beats) of ventricular tachycardia.

PRECAUTIONS

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 based on the consideration of the physician that the expected benefits of therapy outweigh potential risk factors.

Information for Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with trazodone HCl and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for trazodone HCl. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking trazodone HCl.

Clinical Worsening and Suicide Risk

Patients, their families and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

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 abilities 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.

Drug Interactions

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 intraconazole or nefazadone 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 more 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 trazodone concurrently with either of those two 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.

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, 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

Teratogenic Effects: Pregnancy Category C

Trazodone hydrochloride 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 the pediatric population have not been established (see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk).

Anyone considering the use of trazodone HCl in a child or adolescent must balance the potential risks with the clinical need.

ADVERSE REACTIONS

Because the frequency of adverse drug effects is affected by diverse factors (e.g., drug dose, method 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 2 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 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 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.

Table 2

Treatment Emergent

Symptom Incidence

InpatientsOutpatients

T1 P2 T3 P4

Number of Patients 142 95 157 158

% of Patients Reporting

Allergic

Skin Condition/Edema 2.8 1.1 7.0 1.3

Autonomic

Blurred Vision 6.3 4.2 14.7 3.8

Constipation 7.0 4.2 7.6 5.7

Dry Mouth 14.8 8.4 33.8 20.3

Cardiovascular

Hypertension 2.1 1.1 1.3 *5

Hypotension 7.0 1.1 3.8 0.0

Shortness of Breath *6 1.1 1.3 0.0

Syncope 2.8 2.1 4.5 1.3

Tachycardia/Palpitations 0.0 0.0 7.0 7.0

CNS

Anger/Hostility 3.5 6.3 1.3 2.5

Confusion 4.9 0.0 5.7 7.6

Decreased Concentration 2.8 2.1 1.3 0.0

Disorientation 2.1 0.0 *7 0.0

Dizziness/Lightheadedness 19.7 5.3 28.0 15.2

Drowsiness 23.9 6.3 40.8 19.6

Excitement 1.4 1.1 5.1 5.7

Fatigue 11.3 4.2 5.7 2.5

Headache 9.9 5.3 19.8 15.8

Insomnia 9.9 10.5 6.4 12.0

Impaired Memory 1.4 0.0 *8 *9

Nervousness 14.8 10.5 6.4 8.2

Gastrointestinal

Abdominal/Gastric Disorder 3.5 4.2 5.7 4.4

Bad Taste in Mouth 1.4 0.0 0.0 0.0

Diarrhea 0.0 1.1 4.5 1.9

Nausea/Vomiting 9.9 1.1 12.7 9.5

Musculoskeletal

Musculoskeletal Aches/Pains 5.6 3.2 5.1 2.5

Neurological

Incoordination 4.9 0.0 1.9 0.0

Paresthesia 1.4 0.0 0.0 *10

Tremors 2.8 1.1 5.1 3.8

Sexual Function

Decreased Libido *11 1.1 1.3 *12

Other

Decreased Appetite 3.5 5.3 0.0 *13

Eyes Red/Tired/Itching 2.8 0.0 0.0 0.0

Head Full-Heavy 2.8 0.0 0.0 0.0

Malaise 2.8 0.0 0.0 0.0

Nasal/Sinus Congestion 2.8 0.0 5.7 3.2

Nightmares/Vivid Dreams *14 1.1 5.1 5.7

Sweating/Clamminess 1.4 1.1 *15 *16

Tinnitus 1.4 0.0 0.0 *17

Weight Gain 1.4 0.0 4.5 1.9

Weight Loss *18 3.2 5.7 2.5

1 T=Trazodone HCl

2 P=Placebo

3

4

5 Incidence less than 1%

6

7

8

9

10

11

12

13

14

15

16

17

18

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.

Post Introduction 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: 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, hyperbilirubinemia, increased amylase, increased salivation, insomnia, leukocytosis, 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 intervention), 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, palpitations, bradycardia, atrial fibrillation, myocardial infarction, cardiac arrest, arrhythmia, and ventricular ectopic activity, including ventricular tachycardia (see WARNINGS).