Oleptro

Oleptro™
(Oh-LEP-troe)
(trazodone hydrochloride) Extended-release Tablets

Read the Medication Guide that comes with Oleptro before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk to your healthcare provider or pharmacist if there is something you do not understand or you want to learn about Oleptro.

What is the most important information I should know about Oleptro?

Antidepressant medicines, depression or other serious mental illnesses, and suicidal thoughts or actions:

Talk to your healthcare provider about:

• All risks and benefits of treatment with antidepressant medicines
• All treatment choices for depression or other serious mental illnesses

1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a higher risk of having suicidal thoughts or actions. These include people who have or have a family history of bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions?
   • Pay close attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
   • Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts or feelings.
   • Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Call a healthcare provider right away if you have any of the following symptoms, especially if they are new, worse, or worry you:

• Thoughts about suicide or dying
• Attempts to commit suicide
• New or worse depression
• New or worse anxiety
• Feeling very agitated or restless
• Panic attacks
• Trouble sleeping (insomnia)
• New or worse irritability
• Acting aggressive, being angry or violent
• Acting on dangerous impulses
• An extreme increase in activity and talking (mania)
• Other unusual changes in behavior or mood

What else do I need to know about antidepressant medicines?

• Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to your healthcare provider about the side effects of your medicines.
• Antidepressant medicines can interact with other medicines. Know all of the medicines that you take. Keep a list of all medicines to show your healthcare provider. Do not start new medicines without first checking with your healthcare provider.

4. Oleptro is not approved for use in children. Talk to your healthcare provider for more information.

What is Oleptro?

Oleptro is a prescription medicine taken 1 time a day to treat major depressive disorder in adults.

Who should not take Oleptro?

• If you take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
• Do not take an MAOI within 2 weeks of stopping Oleptro unless directed to do so by your physician.
• Do not start Oleptro if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.

What should I tell my healthcare provider before taking Oleptro?

Before you take Oleptro, tell your healthcare provider if you:

• Have heart problems, including QT prolongation or a family history of it
• Have ever had a heart attack
• Have bipolar disorder
• Have liver or kidney problems
• Have other serious medical conditions
• Are pregnant or plan to become pregnant. Oleptro may harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
• Are breastfeeding or plan to breastfeed. It is not known if Oleptro passes into your breast milk. You and your healthcare provider should decide if you will take Oleptro or breastfeed.
• Have taken a Monoamine Oxidase Inhibitor (MAOI) or if you have stopped taking an MAOI in the last 2 weeks.

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.

Using Oleptro with certain other medicines can affect each other causing serious side effects.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take Oleptro?

• Take Oleptro exactly as your healthcare provider tells you.
• Oleptro should be taken 1 time a day.
• Oleptro should be taken at the same time each day in the late evening, if possible at bedtime, on an empty stomach.
• Do not stop taking Oleptro without talking to your healthcare provider.
• Oleptro should be swallowed whole or broken in half along the score line. Do not chew or crush Oleptro. Tell your healthcare provider if you cannot swallow Oleptro either whole or as a half tablet

What should I avoid while taking Oleptro?

• Do not drive, operate heavy machinery, or do other dangerous activities until you know how Oleptro affects you. Oleptro can slow your thinking and motor skills.
• Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking Oleptro until you talk with your healthcare provider. Oleptro may make your sleepiness or dizziness worse if you take it with alcohol or other medicines that cause sleepiness or dizziness.

What are the possible side effects of Oleptro?

Oleptro can cause serious side effects or death. See “What is the most important information I should know about Oleptro?”

Serious side effects include:

• Serotonin syndrome. Symptoms of serotonin syndrome include: agitation, hallucinations, problems with coordination, fast heartbeat, tight muscles, trouble walking, nausea, vomiting, diarrhea.
• Visual problems
  • eye pain
  • changes in vision
  • swelling or redness in or around the eye

Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

• Feeling high or in a very good mood, then becoming irritable, or having too much energy, feeling like you have to keep talking or do not sleep (Mania).
• Irregular or fast heartbeat or faint (QT prolongation).
• Low blood pressure. You feel dizzy or faint when you change positions (go from sitting to standing).
• Unusual bruising or bleeding.
• Erection lasting for more than 6 hours (Priapism).
• Low sodium in your blood (Hyponatremia). Symptoms of hyponatremia include: headache, feeling weak, feeling confused, trouble concentrating, memory problems and feeling unsteady when you walk.

Get medical help right away, if you have any of the symptoms listed above.

The most common side effects of Oleptro include:

• Sleepiness
• Dizziness
• Constipation
• Blurry vision

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Oleptro. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800FDA-1088.

How should I store Oleptro?

• Store Oleptro between 59oF to 86oF (15oC to 30oC)
• Keep in tight container
• Keep out of the light

Keep Oleptro and all medicines out of the reach of children.

General information about Oleptro.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Oleptro for a condition for which it was not prescribed. Do not give Oleptro to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Oleptro. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Oleptro that is written for health professionals.

For more information, go to www.oleptro.com or call 1-877-345-6177.

What are the ingredients in Oleptro?

Active ingredient: trazodone hydrochloride

Inactive ingredients: hydroxypropyl distarch phosphate (Contramid®), hypromellose, sodium stearyl fumarate, colloidal silicon dioxide, iron oxide yellow, iron oxide red, talc, polyethylene glycol 3350, titanium dioxide, polyvinyl alcohol, black ink (food grade).

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Many medicines can interact with Oleptro. Talk to your doctor if you take one of the following medicines:

• antifungal medicine (ketoconazole, itraconazole, fluconazole)
• warfarin (coumadin)
• antidepressants
• MAO inhibitors
• digoxin
• phenytoin
• carbamazepine
• HIV medicines

These are not all the possible drug interactions with Oleptro. Ask your doctor or pharmacist for more information.

You should not use trazodone if you are allergic to it, or if you are being treated with methylene blue injection.

Do not use trazodone if you have taken an MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include isocarboxazid, linezolid, phenelzine, rasagiline, selegiline, and tranylcypromine. After you stop taking trazodone, you must wait at least 14 days before you start taking an MAOI.

To make sure trazodone is safe for you, tell your doctor if you have:

• liver or kidney disease;

• heart disease;

• a bleeding or blood clotting disorder;

• seizures or epilepsy;

• narrow-angle glaucoma;

• bipolar disorder (manic depression);

• a history of Long QT syndrome;

• a history of drug abuse or suicidal thoughts; or

• if you have recently had a heart attack.

Some young people have thoughts about suicide when first taking an antidepressant. Your doctor will need to check your progress at regular visits while you are using trazodone. Your family or other caregivers should also be alert to changes in your mood or symptoms.

Taking an SSRI antidepressant during pregnancy may cause serious lung problems or other complications in the baby. However, you may have a relapse of depression if you stop taking your antidepressant. Tell your doctor right away if you become pregnant while taking trazodone. Do not start or stop taking this medicine during pregnancy without your doctor's advice.

It is not known whether trazodone passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Do not give this medicine to anyone younger than 18 years old without the advice of a doctor. Trazodone is not approved for use in children.

Stop taking trazodone and call your doctor at once if you have a penis erection that is painful or lasts 6 hours or longer. This is a medical emergency and could lead to a serious condition that must be corrected with surgery.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Call your doctor at once if you have:

• blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;

• headache with chest pain and severe dizziness, fainting, fast or pounding heartbeats;

• chest pain or pressure, tight feeling in your neck or jaw, sweating, pain spreading to your arm or shoulder;

• high levels of serotonin in the body--agitation, hallucinations, fever, fast heart rate, overactive reflexes, nausea, vomiting, diarrhea, loss of coordination, fainting;

• low levels of sodium in the body--headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady; or

• severe nervous system reaction--very stiff (rigid) muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, feeling like you might pass out.

Common side effects may include:

• drowsiness, dizziness;

• vision changes;

• constipation; or

• dry mouth, altered sense of taste.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take on an empty stomach.
• Swallow whole. Do not chew or crush.
• Long-acting tablets may be broken in half.
• If you feel sleepy after taking Oleptro, talk with your doctor. Your doctor may change your dose or when you take this medicine.
• To gain the most benefit, do not miss doses.
• Keep taking Oleptro as you have been told by your doctor or other health care provider, even if you feel well.
• It may take several weeks to see the full effects.
• Do not stop taking this medicine all of a sudden without calling your doctor. You may have a greater risk of side effects. If you need to stop Oleptro, you will want to slowly stop it as ordered by your doctor.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

Oleptro™ is indicated for the treatment of major depressive disorder (MDD) in adults. The efficacy of Oleptro has been established in a trial of outpatients with MDD as well as in trials with the immediate release formulation of trazodone [see Clinical Studies (14)].

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 (ages 18 – 24) with 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 analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 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 1,000 patients treated) are provided in Table 1.

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 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 Oleptro should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Oleptro, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of Oleptro with MAOIs intended to treat psychiatric disorders is contraindicated. Oleptro should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Oleptro. Oleptro should be discontinued before initiating treatment with the MAOI. [see Contraindications (4.1) and Dosage and Administration (2.3 and 2.4)].

If concomitant use of Oleptro with other serotonergic drugs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with Oleptro and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

5.3 Angle Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including Oleptro may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania

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 for clinical worsening and suicide risk 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 Oleptro is not approved for use in treating bipolar depression.

QT Prolongation and Risk of Sudden Death

Trazodone is known to prolong the QT/QTc interval. Some drugs that prolong the QT/QTc interval can cause Torsades de Pointes with sudden, unexplained death. The relationship of QT prolongation is clearest for larger increases (20 msec and greater), but it is possible that smaller QT/QTc prolongations may also increase risk, especially in susceptible individuals, such as those with hypokalemia, hypomagnesemia, or a genetic predisposition to prolonged QT/QTc.

Although Torsades de Pointes has not been observed with the use of Oleptro at recommended doses in premarketing trials, experience is too limited to rule out an increased risk. However, there have been postmarketing reports of Torsades de Pointes with the immediate-release form of trazodone (in the presence of multiple confounding factors), even at doses of 100 mg per day or less.

Use in Patients with Heart Disease

Trazodone hydrochloride is not recommended for use during the initial recovery phase of myocardial infarction.

Caution should be used when administering Oleptro to patients with cardiac disease and such patients should be closely monitored, since antidepressant drugs (including trazodone hydrochloride) may cause cardiac arrhythmias.

QT prolongation has been reported with trazodone therapy [see Warnings and Precautions (5.5)]. Clinical studies in patients with pre-existing cardiac disease indicate that trazodone hydrochloride may be arrhythmogenic in some patients in that population. Arrhythmias identified include isolated PVCs, ventricular couplets, tachycardia with syncope, and Torsades de Pointes. Postmarketing events have been reported at doses of 100 mg or less with the immediate-release form of trazodone.

Concomitant administration of drugs that prolong the QT interval or that are inhibitors of CYP3A4 may increase the risk of cardiac arrhythmia.

Orthostatic Hypotension and Syncope

Hypotension, including orthostatic hypotension and syncope has been reported in patients receiving trazodone hydrochloride. Concomitant use with an antihypertensive may require a reduction in the dose of the antihypertensive drug.

Abnormal Bleeding

Postmarketing data have shown an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal (GI) bleeding. While no association between trazodone and bleeding events, in particular GI bleeding, was shown, 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. Other bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

Interaction with MAOIs

In patients receiving serotonergic drugs in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal reactions including hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuation in vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued antidepressant treatment and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Furthermore, limited animal data on the effects of combined use of serotonergic antidepressants and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. Therefore, it is recommended that Oleptro should not be used in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping Oleptro before starting an MAOI.

Priapism

Rare cases of priapism (painful erections greater than 6 hours in duration) were reported in men receiving trazodone. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Men who have an erection lasting greater than 6 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention [see Adverse Reactions (6.2) and Overdosage (10)].

Trazodone should be used with caution in men who have conditions that might predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia), or in men with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie's disease).

Hyponatremia

Hyponatremia may occur as a result of treatment with antidepressants. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with antidepressants. Also, patients taking diuretics or who are otherwise volume-depleted can be at greater risk. Discontinuation of Oleptro should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

Potential for Cognitive and Motor Impairment

Oleptro may cause somnolence or sedation and may impair the mental and/or physical ability required for the performance of potentially hazardous tasks. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.

Discontinuation Symptoms

Withdrawal 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.

The following serious adverse reactions are described elsewhere in the labeling:

• Clinical Worsening and Suicide Risk [see Boxed Warning and Warnings and Precautions (5.1)]
• Serotonin Syndrome or NMS-like Reactions [see Warnings and Precautions (5.2)]
• QT Prolongation and Risk of Sudden Death [see Warnings and Precautions (5.5)]
• Orthostatic Hypotension [see Warnings and Precautions (5.7)]
• Abnormal bleeding events [see Warnings and Precautions (5.8)]
• Priapism [see Warnings and Precautions (5.10)]
• Hyponatremia [see Warnings and Precautions (5.11)]
• Cognitive and Motor Impairment [see Warnings and Precautions (5.12)]
• Discontinuation symptoms [see Warnings and Precautions (5.13)]

The most common adverse reactions (reported in ≥5% and at twice the rate of placebo) are: somnolence/sedation, dizziness, constipation, vision blurred.

Table 2 presents the summary of adverse events (AEs) leading to discontinuation of Oleptro treatment with an incidence of at least 1% and at least twice that for placebo.

Clinical Studies Experience

The data described below reflects exposure in a clinical trial of 406 patients, including 204 exposed to placebo and 202 exposed to Oleptro. Patients were between 18-80 years of age and 69.3% and 67.5% of patients had at least one previous episode of depression in the last 24 months in the placebo and active-treated group, respectively. In individual patients, doses were flexible and ranged from 150 to 375 mg per day. The mean daily dose during the 6-week treatment period was 310 mg. The tablets were administered orally and were given once a day for a total duration of 8 weeks, including the titration period.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 3 presents the summary of all treatment emergent AEs that occurred at an incidence of ≥ 5% in the Oleptro group, whether considered by the clinical investigator to be related to the study drug or not.

Sexual Dysfunction

Adverse events related to sexual dysfunction (regardless of causality) were reported by 4.9% and 1.5% of patients treated with Oleptro and placebo, respectively. In the Oleptro group, ejaculation disorders occurred in 1.5% of patients, decreased libido occurred in 1.5% of patients, and erectile dysfunction and abnormal orgasm < 1% of patients.

Vital Signs and Weight

There were no notable changes in vital signs (blood pressure, respiratory rate, pulse) or weight in either treatment group.

Following is a list of treatment-emergent adverse reactions with an incidence of ≥ 1% to < 5% (i.e., less common) in patients treated with Oleptro. This listing is not intended to include reactions (i) already listed in previous tables or elsewhere in the labeling (ii) for which the association with treatment is remote, (iii) which were so general as to be uninformative, and (iv) which were not considered to have significant clinical implications. Reactions are classified by body-system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in less than 1/100 patients.

Ear and Labyrinth Disorders Infrequent: hypoacusis, tinnitus, vertigo

Eye Disorders Frequent: visual disturbance; Infrequent: dry eye, eye pain, photophobia

Gastrointestinal Disorders Frequent: abdominal pain, vomiting; Infrequent: reflux esophagitis

General Disorders and Administration Site Conditions Frequent: edema; Infrequent: gait disturbance

Immune System Disorders Infrequent: hypersensitivity

Musculoskeletal and Connective Tissue Disorders Frequent: musculoskeletal complaints, myalgia; Infrequent: muscle twitching

Nervous System Disorders Frequent: coordination abnormal, dysgeusia, memory impairment, migraine, paraesthesia, tremor; Infrequent: amnesia, aphasia, hypoesthesia, speech disorder

Psychiatric Disorders Frequent: agitation, confusional state, disorientation

Renal and Urinary Disorders Frequent: micturition urgency; Infrequent: bladder pain, urinary incontinence

Respiratory, Thoracic and Mediastinal Disorders Frequent: dyspnea

Skin and Subcutaneous Tissue Disorders Frequent: night sweats; Infrequent: acne, hyperhidrosis, photosensitivity reaction

Vascular Disorders Infrequent: flushing

Postmarketing Experience

Spontaneous reports regarding trazodone hydrochloride received from postmarketing experience include the following: abnormal dreams, agitation, alopecia, anxiety, aphasia, apnea, ataxia, breast enlargement or engorgement, cardiospasm, cerebrovascular accident, chills, cholestasis, 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 (5.10) and Patient Counseling Information (17.1)], 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, ventricular ectopic activity, including ventricular tachycardia and QT prolongation. In postmarketing surveillance, prolonged QT interval, Torsades de Pointes, and ventricular tachycardia have been reported with the immediate-release form of trazodone at doses of 100 mg per day or less [see Warnings and Precautions (5.5)].

Pregnancy

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. Oleptro should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Trazodone 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 Oleptro is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established [see Boxed Warning and Warnings and Precautions (5.1)]. Oleptro should not be used in children or adolescents.

Geriatric Use

Of 202 patients treated with Oleptro in the clinical trial, there were 9 patients older than 65. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical literature and experience with trazodone have not identified differences in responses between elderly and younger patients. However, as experience in the elderly with Oleptro is limited, it should be used with caution in geriatric patients.

Antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.11)].

Renal Impairment

Oleptro has not been studied in patients with renal impairment. Trazodone should be used with caution in this population.

Hepatic Impairment

Oleptro has not been studied in patients with hepatic impairment. Trazodone should be used with caution in this population.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No drug- or dose-related occurrence of carcinogenesis was evident in rats receiving trazodone in daily oral doses up to 300 mg/kg for 18 months.

Oleptro 150 mg is a yellowish-beige, capsule-shaped extended-release tablet, coated and scored on both sides with DDS 080 printed on one side. It is supplied as follows:

Bottles of 30 tablets NDC 43595-080-03

Oleptro 300 mg is a beige-orange, capsule-shaped extended-release tablet, coated and scored on both sides with DDS 081 printed on one side. It is supplied as follows:

Bottles of 30 tablets NDC 43595-081-03

Store at room temperature (15 – 30ºC) in tight, light-resistant containers.

You should not use Oleptro if you are allergic to trazodone, or if you are being treated with methylene blue injection.

Do not use Oleptro if you have taken an MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include isocarboxazid, linezolid, phenelzine, rasagiline, selegiline, and tranylcypromine.

Some young people have thoughts about suicide when first taking an antidepressant. Your doctor will need to check your progress at regular visits while you are using Oleptro. Your family or other caregivers should also be alert to changes in your mood or symptoms.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Do not give this medicine to anyone younger than 18 years old without the advice of a doctor. Oleptro is not approved for use in children.