BUPROPION HYDROCHLORIDE TABLETS, USP

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 buproprion 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. Bupropion is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients and PRECAUTIONS: Pediatric Use.)

Bupropion hydrochloride, USP, an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin reuptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The molecular weight is 276.2. The molecular formula is C₁₃H₁₈ClNO•HCl. Bupropion hydrochloride powder is white or almost white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The structural formula is:

Bupropion Hydrochloride Tablets, USP for oral administration, are available containing 75 mg or 100 mg of bupropion hydrochloride. Each tablet also contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, crospovidone, hydrochloric acid, hypromellose, microcrystalline cellulose, polydextrose, polyethylene glycol, stearic acid and titanium dioxide. In addition, the 75 mg tablets contain synthetic red iron oxide, synthetic yellow iron oxide and triacetin and the 100 mg tablets contain FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake and triacetin.

The neurochemical mechanism of the antidepressant effect of bupropion is not known. Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine, and does not inhibit monoamine oxidase or the reuptake of seritonin.

Bupropion produces dose related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule controlled operant behavior tasks, and, at high doses, induction of mild stereotyped behavior.

Bupropion causes convulsions in rodents and dogs at doses approximately 10-fold the dose recommended as the human antidepressant dose.

Bupropion is a racemic mixture. The pharmacological activity and pharmacokinetics of the individual enantiomers have not been studied. In humans, following oral administration of bupropion, peak plasma bupropion concentrations are usually achieved within 2 hours, followed by a biphasic decline. The terminal phase has a mean half-life of 14 hours, with a range of 8 to 24 hours. The distribution phase has a mean half-life of 3 to 4 hours. The mean elimination half-life (± SD) of bupropion after chronic dosing is 21 (± 9) hours, and steady-state plasma concentrations of bupropion are reached within 8 days. Plasma bupropion concentrations are dose proportional following single doses of 100 to 250 mg; however, it is not known if the proportionality between dose and plasma level is maintained in chronic use.

Factors or conditions altering metabolic capacity (e.g., liver disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be expected to influence the degree and extent of accumulation of the active metabolites of bupropion. The elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic function because they are moderately polar compounds and are likely to undergo further metabolism or conjugation in the liver prior to urinary excretion.

Bupropion Hydrochloride Tablets are indicated for the treatment of major depressive disorder. A physician considering bupropion for the management of a patient's first episode of depression should be aware that the drug may cause generalized seizures in a dose dependent manner with an approximate incidence of 0.4% (4/1,000). This incidence of seizures may exceed that of other marketed antidepressants by as much as 4-fold. This relative risk is only an approximate estimate because no direct comparative studies have been conducted (see WARNINGS).

The efficacy of bupropion has been established in three placebo-controlled trials, including 2 of approximately 3 weeks' duration in depressed inpatients and one of approximately 6 weeks' duration in depressed outpatients. The depressive disorder of the patients studied corresponds most closely to the Major Depression category of the APA Diagnostic and Statistical Manual III.

Major Depression implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include 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.

Effectiveness of bupropion in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use bupropion for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Bupropion is contraindicated in patients with a seizure disorder.

Bupropion is contraindicated in patients treated with ZYBAN^®Zyban^® is a registered trademark of GlaxoSmithKline. (bupropion hydrochloride) Sustained-Release Tablets, or any other medications that contain bupropion because the incidence of seizure is dose dependent.

Bupropion is contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures noted in such patients treated with bupropion.

Bupropion is contraindicated in patients undergoing abrupt discontinuation of alcoholor sedatives (including benzodiazepines).

The concurrent administration of bupropion and a monoamine oxidase (MAO) inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with bupropion.

Bupropion is contraindicated in patients who have shown an allergic response to bupropion or the other ingredients that make up bupropion hydrochloride tablets.

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 to 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 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 nine 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 healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for bupropion should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

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 bupropion is not approved for use in treating bipolar depression.

Patients should be made aware that bupropion hydrochloride tablets contain the same active ingredient found in ZYBAN^®, used as an aid to smoking cessation treatment, and that bupropion hydrochloride tablets should not be used in combination with ZYBAN^®, or any other medications that contain bupropion.

Bupropion is associated with seizures in approximately 0.4% (4/1,000) of patients treated at doses up to 450 mg/day. This incidence of seizures may exceed that of other marketed antidepressants by as much as 4-fold. This relative risk is only an approximate estimate because no direct comparative studies have been conducted. The estimated seizure incidence for bupropion hydrochloride tablets increases almost 10-fold between 450 and 600 mg/day, which is twice the usually required daily dose (300 mg) and one and one-third the maximum recommended daily dose (450 mg). Given the wide variability among individuals and their capacity to metabolize and eliminate drugs this disproportionate increase in seizure incidence with dose incrementation calls for caution in dosing.

During the initial development, 25 among approximately 2,400 patients treated with bupropion hydrochloride tablets experienced seizures. At the time of seizure, seven patients were receiving daily doses of 450 mg or below for an incidence of 0.33% (3/1,000) within the recommended dose range. Twelve patients experienced seizures at 600 mg/day (2.3% incidence); six additional patients had seizures at daily doses between 600 and 900 mg (2.8% incidence).

A separate, prospective study was conducted to determine the incidence of seizure during an 8 week treatment exposure in approximately 3,200 additional patients who received daily doses of up to 450 mg. Patients were permitted to continue treatment beyond 8 weeks if clinically indicated. Eight seizures occurred during the initial 8 week treatment period and five seizures were reported in patients continuing treatment beyond 8 weeks, resulting in a total seizure incidence of 0.4%.

The risk of seizure appears to be strongly associated with dose. Sudden and large increments in dose may contribute to increased risk. While many seizures occurred early in the course of treatment, some seizures did occur after several weeks at fixed dose. Bupropion hydrochloride tablets should be discontinued and not restarted in patients who experience a seizure while on treatment.

The risk of seizure is also related to patient factors, clinical situations, and concomitant medications, which must be considered in selection of patients for therapy with bupropion hydrochloride tablets.

• Patient factors: Predisposing factors that may increase the risk of seizure with bupropion use include history of head trauma or prior seizure, central nervous system (CNS) tumor, the presence of severe hepatic cirrhosis, and concomitant medications that lower seizure threshold.
• Clinical situations: Circumstances associated with an increased seizure risk include, among others, excessive use of alcohol or sedatives (including benzodiazepines); addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; and diabetes treated with oral hypoglycemics or insulin.
• Concomitant medications: Many medications (e.g., antipsychotics, antidepressants, theophylline, systemic steroids) are known to lower seizure threshold.

Bupropion hydrochloride should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients a reduced dose and/or frequency is required, as peak bupropion, as well as AUC, levels are substantially increased and accumulation is likely to occur in such patients to a greater extent than usual. The dose should not exceed 75 mg once a day in these patients (see CLINICAL PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

In rats receiving large doses of bupropion chronically, there was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In dogs receiving large doses of bupropion chronically, various histologic changes were seen in the liver, and laboratory tests suggesting mild hepatocellular injury were noted.

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with bupropion 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 bupropion. 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 spans. Patients should be given the opportunity to discuss the spans of the Medication Guide and to obtain answers to any questions they may have. The complete div 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 bupropion.

There are no specific laboratory tests recommended.

Few systemic data have been collected on the metabolism of bupropion following concomitant administration with other drugs or, alternatively, the effect of concomitant administration of bupropion on the metabolism of other drugs.

Because bupropion is extensively metabolized, the coadministration of other drugs may affect its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug interaction between bupropion and drugs that are the substrates or inhibitors of the CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa and cyclophosphamide). In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, and fluvoxamine as well as nelfinavir, ritonavir, and efavirenz inhibit the hydroxylation of bupropion. No clinical studies have been performed to evaluate this finding. The threohydrobupropion metabolite of bupropion does not appear to be produced by the cytochrome P450 isoenzymes. The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers. Following oral administration of two 150 mg sustained-release tablets with and without 800 mg of cimetidine, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and C_max, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.

While not systematically studied, certain drugs may induce the metabolism of bupropion (e.g., carbamazepine, phenobarbital, phenytoin).

Multiple oral doses of bupropion had no statistically significant effects on the single-dose pharmacokinetics of lamotrigine in 12 healthy volunteers.

Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In one study, following chronic administration of bupropion, 100 mg 3 times daily to eight healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism. Nevertheless, there may be the potential for clinically important alterations of blood levels of coadministered drugs.

Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day; lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study.

Bupropion produced a borderline positive response (2 to 3 times control mutation rate) in some strains in the Ames bacterial mutagenicity test, and a high oral dose (300 mg/kg, but not 100 or 200 mg/kg) produced a low incidence of chromosomal aberrations in rats. The relevance of these results in estimating the risk of human exposure to therapeutic doses is unknown.

A fertility study was performed in rats; no evidence of impairment of fertility was encountered at oral doses up to 300 mg/kg/day.

The effect of bupropion on labor and delivery in humans is unknown.

Like many other drugs, bupropion and its metabolites are secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from bupropion, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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 bupropion hydrochloride in a child or adolescent must balance the potential risks with the clinical need.

Of the approximately 6,000 patients who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation studies), 275 were 65 and over and 47 were 75 and over. In addition, several hundred patients 65 and over participated in clinical trials using the immediate-release formulation of bupropion (depression studies). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects; however, another pharmacokinetic study, single and multiple-dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites (see CLINICAL PHARMACOLOGY).

Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of toxic reaction to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see PRECAUTIONS: General: Renal Impairment and DOSAGE AND ADMINISTRATION).

(See also WARNINGS and PRECAUTIONS.)

Adverse events commonly encountered in patients treated with bupropion are agitation, dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, and tremor.

Adverse events were sufficiently troublesome to cause discontinuation of treatment with bupropion in approximately 10% of the 2,400 patients and volunteers who participated in clinical trials during the product's initial development. The more common events causing discontinuation include neuropsychiatric disturbances (3%), primarily agitation and abnormalities in mental status; gastrointestinal disturbances (2.1%), primarily nausea and vomiting; neurological disturbances (1.7%), primarily seizures, headaches, and sleep disturbances; and dermatologic problems (1.4%), primarily rashes. It is important to note, however, that many of these events occurred at doses that exceed the recommended daily dose.

Accurate estimates of the incidence of adverse events associated with the use of any drug are difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician judgments, etc. Consequently, Table 2 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 bupropion under relatively similar conditions of daily dosage (300 to 600 mg), setting, and duration (3 to 4 weeks). 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 must 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 as each group of drug trials is conducted under a different set of conditions.

Finally, it is important to emphasize that the tabulation does not reflect the relative severity and/or clinical importance of the events. A better perspective on the serious adverse events associated with the use of bupropion is provided in WARNINGS and PRECAUTIONS.

The conditions and duration of exposure to bupropion varied greatly, and a substantial proportion of the experience was gained in open and uncontrolled clinical settings. During this experience, numerous adverse events were reported; however, without appropriate controls, it is impossible to determine with certainty which events were or were not caused by bupropion. The following enumeration is organized by organ system and describes events in terms of their relative frequency of reporting in the database. Events of major clinical importance are also described in WARNINGS and PRECAUTIONS.

The following definitions of frequency are used: Frequent adverse events are defined as those occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1,000 patients, while rare events are those occurring in less than 1/1,000 patients.

Cardiovascular: Frequent was edema; infrequent were chest pain, electrocardiogram (ECG) abnormalities (premature beats and nonspecific ST-T changes), and shortness of breath/dyspnea; rare were flushing, pallor, phlebitis, and myocardial infarction.

Dermatologic: Frequent were nonspecific rashes; infrequent were alopecia and dry skin; rare were change in hair color, hirsutism, and acne.

Endocrine: Infrequent was gynecomastia; rare were glycosuria and hormone level change.

Gastrointestinal: Infrequent were dysphagia, thirst disturbance, and liver damage/jaundice; rare were rectal complaints, colitis, gastrointestinal bleeding, intestinal perforation, and stomach ulcer.

Genitourinary: Frequent was nocturia; infrequent were vaginal irritation, testicular swelling, urinary tract infection, painful erection, and retarded ejaculation; rare were dysuria, enuresis, urinary incontinence, menopause, ovarian disorder, pelvic infection, cystitis, dyspareunia, and painful ejaculation.

Hematologic/Oncologic: Rare were lymphadenopathy, anemia, and pancytopenia.

Musculoskeletal: Rare was musculoskeletal chest pain.

Neurological: (See WARNINGS.) Frequent were ataxia/incoordination, seizure, myoclonus, dyskinesia, and dystonia; infrequent were mydriasis, vertigo, and dysarthria; rare were electroencephalogram (EEG) abnormality, abnormal neurological exam, impaired attention, sciatica, and aphasia.

Neuropsychiatric: (See PRECAUTIONS.) Frequent were mania/hypomania, increased libido, hallucinations, decrease in sexual function, and depression; infrequent were memory impairment, depersonalization, psychosis, dysphoria, mood instability, paranoia, formal thought disorder, and frigidity; rare was suicidal ideation.

Oral Complaints: Frequent was stomatitis; infrequent were toothache, bruxism, gum irritation, and oral edema; rare was glossitis.

Respiratory: Infrequent were bronchitis and shortness of breath/dyspnea; rare were epistaxis, rate or rhythm disorder, pneumonia, and pulmonary embolism.

Special Senses: Infrequent was visual disturbance; rare was diplopia.

Nonspecific: Frequent were flu-like symptoms; infrequent was nonspecific pain; rare were body odor, surgically related pain, infection, medication reaction, and overdose.

Voluntary reports of adverse events temporally associated with bupropion that have been received since market introduction and which may have no causal relationship with the drug include the following:

Body (General): arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness (see PRECAUTIONS).

Cardiovascular: hypertension (in some cases severe, see PRECAUTIONS), orthostatic hypotension, third degree heart block

Endocrine: syndrome of inappropriate antidiuretic hormone secretion, hyperglycemia, hypoglycemia

Gastrointestinal: esophagitis, hepatitis, liver damage

Hemic and Lymphatic: ecchymosis, leukocytosis, leukopenia, thrombocytopenia. Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin

Musculoskeletal: arthralgia, myalgia, muscle rigidity/fever/rhabdomyolysis, muscle weakness

Nervous: aggression, coma, delirium, dream abnormalities, paranoid ideation, paresthesia, restlessness, unmasking of tardive dyskinesia

Skin and Appendages: Stevens-Johnson Syndrome, angioedema, exfoliative dermatitis, urticaria

Special Senses: tinnitus, increased intraocular pressure

Controlled clinical studies conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed patients showed some increase in motor activity and agitation/exclient.

In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of bupropion hydrochloride tablets produced mild amphetamine-like activity as compared to placebo on the Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug desirability.

Findings in clinical trials, however, are not known to predict the abuse potential of drugs reliably. Nonetheless, evidence from single-dose studies does suggest that the recommended daily dosage of bupropion when administered in divided doses is not likely to be especially reinforcing to amphetamine or stimulant abusers. However, higher doses, that could not be tested because of the risk of seizure, might be modestly attractive to those who abuse stimulant drugs.

Studies in rodents have shown that bupropion exhibits some pharmacologic actions common to psychostimulants, including increases in locomotor activity and the production of a mild stereotyped behavior and increases in rates of responding in several schedule-controlled behavior paradigms. Drug discrimination studies in rats showed stimulus generalization between bupropion and amphetamine and other psychostimulants. Rhesus monkeys have been shown to self-administer bupropion intravenously.

Overdoses of up to 30 g or more of bupropion have been reported. Seizure was reported in approximately one-third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances or arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses.

Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients.

Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. EEG monitoring is also recommended for the first 48 hours post-ingestion. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients.

Activated charcoal should be administered. There is no experience with the use of forced diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of bupropion overdoses. No specific antidotes for bupropion are known.

Due to the dose related risk of seizures with bupropion, hospitalization following suspected overdose should be considered. Based on studies in animals, it is recommended that seizures be treated with intravenous benzodiazepine administration and other supportive measures, as appropriate.

In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are uled in the Physicians' Desk Reference (PDR).

It is particularly important to administer bupropion hydrochloride tablets in a manner most likely to minimize the risk of seizure (see WARNINGS). Increases in dose should not exceed 100 mg/day in a 3 day period. Gradual escalation in dosage is also important if agitation, motor restlessness, and insomnia, often seen during the initial days of treatment, are to be minimized. If necessary, these effects may be managed by temporary reduction of dose or the short-term administration of an intermediate to long-acting sedative hypnotic. A sedative hypnotic usually is not required beyond the first week of treatment. Insomnia may also be minimized by avoiding bedtime doses. If distressing, untoward effects supervene, dose escalation should be stopped.

No single-dose of bupropion hydrochloride tablets should exceed 150 mg. Bupropion should be administered 3 times daily, preferably with at least 6 hours between successive doses.

The usual adult dose is 300 mg/day, given 3 times daily. Dosing should begin at 200 mg/day, given as 100 mg twice daily. Based on clinical response, this dose may be increased to 300 mg/day, given as 100 mg 3 times daily, no sooner than 3 days after beginning therapy (see table below).

As with other antidepressants, the full antidepressant effect of bupropion may not be evident until 4 weeks of treatment or longer. An increase in dosage, up to a maximum of 450 mg/day, given in divided doses of not more than 150 mg each, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg/day. Dosing above 300 mg/day may be accomplished using the 75 or 100 mg tablets. The 100 mg tablet must be administered 4 times daily with at least 4 hours between successive doses, in order not to exceed the limit of 150 mg in a single-dose. Bupropion should be discontinued in patients who do not demonstrate an adequate response after an appropriate period of treatment at 450 mg/day.

The lowest dose that maintains remission is recommended. Although it is not known how long the patient should remain on bupropion, it is generally recognized that acute episodes of depression require several months or longer of antidepressant drug treatment.

Bupropion should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should not exceed 75 mg once a day in these patients. Bupropion should be used with caution in patients with hepatic impairment (including mild to moderate hepatic cirrhosis) and a reduced frequency and/or dose should be considered in patients with mild to moderate hepatic cirrhosis (see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS).

Bupropion should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS).

Bupropion Hydrochloride Tablets, USP are available containing 75 mg or 100 mg of bupropion hydrochloride, USP.

The 75 mg tablets are peach film-coated, round, unscored tablets debossed with M on one side of the tablet and 433 on the other side. They are available as follows:

NDC 0378-0433-01
bottles of 100 tablets

NDC 0378-0433-05
bottles of 500 tablets

The 100 mg tablets are light blue film-coated, round, unscored tablets debossed withM on one side of the tablet and 435 on the other side. They are available as follows:

NDC 0378-0435-01
bottles of 100 tablets

NDC 0378-0435-05
bottles of 500 tablets

Bupropion Hydrochloride Tablets, USP

Read this information completely before you start taking bupropion. Read the information each time you get more medicine. There may be something new. This leaflet provides a summary about bupropion. It does not include everything there is to know about your medicine. This information should not take the place of discussions with your doctor about your medical condition or bupropion.

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

• At a dose of up to 450 mg each day, there is a chance that approximately 4 out of every 1000 people taking bupropion hydrochloride, the active ingredient in bupropion hydrochloride tablets, will have a seizure. The chance of seizures further increases with doses above 450 mg a day. Seizures are also called convulsions. They can cause you to fall with uncontrolled shaking.
• You may have an increased risk of seizures while taking bupropion if you have certain medical problems. Be sure to tell your doctor about all of your medical problems.
• You may have an increased risk of seizures while taking bupropion if you take certain medicines. Be sure to tell your doctor about all the medicines you take, including non-prescription medicines and herbal or natural supplements.

For more information, see the section "Who should not take bupropion hydrochloride tablets?"

If you have a seizure while taking bupropion, stop taking the tablets and call your doctor right away. Do not take bupropion again if you have a seizure.

What is the important information I should know and share with my family about taking antidepressants?

Patients and their families should watch out for worsening depression or thoughts of suicide. Also watch out for sudden or severe changes in feelings such as feeling anxious, agitated, panicky, irritable, hostile, aggressive, impulsive, severely restless, overly excited and hyperactive, or not being able to sleep. If this happens, especially at the beginning of antidepressant treatment or after a change in dose, call your doctor.

A patient Medication Guide will be provided to you with each prescription of Bupropion Hydrochloride Tablets that is entitled "About Using Antidepressants in Children and Teenagers." Bupropion Hydrochloride Tablets are not approved for the use in children and teenagers.

What is bupropion?

Bupropion is a prescription medicine used to treat depression. Bupropion is thought to treat depression by correcting an imbalance of certain chemicals in your brain.

Who should not take bupropion hydrochloride tablets?

Do not take bupropion hydrochloride tablets if you:

• have or have ever had a seizure disorder such as epilepsy.
• are taking ZYBAN^®Zyban^® is a registered trademark of GlaxoSmithKline. (used to help people stop smoking) or any other medicines that contain bupropion hydrochloride, the active ingredient in bupropion hydrochloride tablets.
• are abruptly discontinuing use of alcohol or sedatives (including benzodiazepines).
• have taken within the last 14 days one of the medicines for depression known as a monoamine oxidase inhibitor (MAOI), such as Nardil^®Nardil^® is a registered trademark of Parke-Davis. (phenelzine sulfate), Parnate^®Parnate^® is a registered trademark of GlaxoSmithKline. (tranylcypromine sulfate), or Marplan^®Marplan^® is a registered trademark of Oxford Pharm. (isocarboxazid).
• have or have ever had an eating disorder, such as anorexia nervosa or bulimia.
• are allergic to the active ingredient, bupropion, or to any of the inactive ingredients. Your doctor and pharmacist have a ul of the inactive ingredients.

What should I tell my doctor before using bupropion?

• Tell your doctor about your medical conditions. Tell your doctor if you
  • are pregnant or plan to become pregnant. It is not known if bupropion can harm the unborn baby.
  • are breastfeeding. Bupropion passes through your milk. It is not known whether bupropion in breast milk can harm the baby.
  • have liver or kidney problems
  • have an eating disorder, such as anorexia nervosa or bulimia
  • have had a head injury
  • have had a seizure
  • have a tumor in your nervous system
  • recently had a heart attack, have heart problems, or have high blood pressure
  • are a diabetic taking insulin or other medicines to control your blood sugar
  • are a heavy drinker of alcoholic beverages
  • use tranquilizers or sedatives frequently
• Tell your doctor about all the medicines you take, including non-prescription medicines and herbal or natural remedies. Some may increase your chance of getting seizures or other side effects if you take bupropion.

How should I take bupropion?

• Take bupropion at the same time each day exactly as prescribed by your doctor. You may take bupropion with or without food.
• It may take 4 weeks or more for you to feel that bupropion is working. Once you feel better, it is important to keep taking bupropion as directed by your doctor.
• Take your doses at least 6 hours apart.
• If you miss a dose, do not take an extra tablet to make up for the dose you forgot. Wait and take your next tablet at the regular time. This is important so you do not increase your chance of having a seizure.

What should I avoid while taking bupropion?

• Limit the amount of alcohol you drink while taking bupropion. If you usually drink a lot of alcohol, talk with your doctor before suddenly stopping. If you suddenly stop drinking alcohol, you may increase your risk of seizures.
• Do not drive a car or use heavy machinery until you know if bupropion affects your ability to perform these tasks.

What are possible side effects of bupropion?

• Seizures. Some patients get seizures while taking bupropion. If you have a seizure while taking bupropion, stop taking the tablets and call your doctor right away. Do not take bupropion again if you have a seizure.
• Hypertension (high blood pressure). Some patients get high blood pressure, sometimes severe, while taking bupropion. The chance of high blood pressure may be increased if you also use nicotine replacement therapy (for example a nicotine patch) to help you stop smoking.

Call your doctor right away if you get a rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, swelling of the lips or tongue, or have trouble breathing. These could be signs of a serious allergic reaction.

The most common side effects of bupropion are nervousness, constipation, trouble sleeping, dry mouth, headache, nausea, vomiting, and shakiness (tremor).

If you have nausea, you may want to take your medicine with food. If you have difficulty sleeping, avoid taking your medicine too close to bedtime.

These are not all the side effects of bupropion. For a complete ul, ask your doctor or pharmacist. Tell your doctor right away about any side effects that bother you. Do not change your dose or stop taking bupropion without talking with your doctor first.

General Information about bupropion hydrochloride tablets.

• Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use bupropion hydrochloride tablets for a condition for which it was not prescribed. Do not give bupropion hydrochloride tablets to other people, even if they have the same symptoms you have. It may harm them. Keep bupropion hydrochloride tablets out of the reach of children.
• Store bupropion hydrochloride tablets at room temperature, out of direct sunlight. Keep bupropion in a tightly closed container.

This leaflet summarizes the most important information about bupropion. For more information, talk with your doctor or pharmacist. They can give you information about bupropion that is written for health professionals.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

REVISED MAY 2005
PL:BUPR:R4

Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions

Read the Medication Guide that comes with you or your family member's antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member's, healthcare provider about:

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

What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?

• 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 particularly high 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 in myself or a family member?
  • 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 the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
  • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call a healthcare provider right away if you or your family member has 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. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a ul of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child's healthcare provider for more information.

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

Revised 8/2007