BUPROPION HYDROCHLORIDE

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Overview

What is BUPROPION HYDROCHLORIDE?

Bupropion hydrochloride extended-release tablets (SR), an antidepressant of the aminoketone class, are chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake 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 CHClNO•HCl. Bupropion hydrochloride powder is 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 extended-release tablets (SR) are supplied for oral administration as 100 mg, 150 mg, and 200 mg white to off-white, film-coated, extended-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the following inactive ingredients: hydroxypropyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, stearic acid, magnesium stearate, and diluted hydrochloric acid. The film coating contains lactose monohydrate, hydroxypropyl cellulose, titanium dioxide, and polyethylene glycol.

What does BUPROPION HYDROCHLORIDE look like?

What are the available doses of BUPROPION HYDROCHLORIDE?

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What should I talk to my health care provider before I take BUPROPION HYDROCHLORIDE?

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How should I use BUPROPION HYDROCHLORIDE?

Bupropion hydrochloride extended-release tablets (SR) are indicated for the treatment of major depressive disorder.

The efficacy of bupropion in the treatment of a major depressive episode was established in two 4-week controlled trials of depressed inpatients and in one 6-week controlled trial of depressed outpatients whose diagnoses corresponded most closely to the Major Depression category of the APA Diagnostic and Statistical Manual (DSM) (see ).

A major depressive episode (DSM-IV) implies the presence of 1) depressed mood or 2) loss of interest or pleasure; in addition, at least 5 of the following symptoms have been present during the same 2-week period and represent a change from previous functioning: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.

The efficacy of bupropion in maintaining an antidepressant response for up to 44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial (see ). Nevertheless, the physician who elects to use bupropion hydrochloride extended-release tablets (SR) for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

General Dosing Considerations:

Initial Treatment:

Increasing the Dosage Above 300 mg/day:

Maintenance Treatment:

Dosage Adjustment for Patients with Impaired Hepatic Function:

Dosage Adjustment for Patients with Impaired Renal Function:

What interacts with BUPROPION HYDROCHLORIDE?

Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients with a seizure disorder.

Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients treated with Zyban (bupropion hydrochloride) Sustained-Release Tablets; Wellbutrin (bupropion hydrochloride), the immediate-release formulation; Wellbutrin XL (bupropion hydrochloride), the extended-release formulation; or any other medications that contain bupropion because the incidence of seizure is dose dependent.

Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures noted in patients treated for bulimia with the immediate-release formulation of bupropion. Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients undergoing abrupt discontinuation of alcohol or sedatives (including benzodiazepines).

The concurrent administration of bupropion hydrochloride extended-release tablets (SR) 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 hydrochloride extended-release tablets (SR).

Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients who have shown an allergic response to bupropion or the other ingredients that make up bupropion hydrochloride extended-release tablets (SR).

What are the warnings of BUPROPION HYDROCHLORIDE?

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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 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 healthcare providers. Such monitoring should include daily observation by families and caregivers.

Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment:

(see BOXED WARNING, ADVERSE REACTIONS). These have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide.

These events have occurred in patients with and without pre-existing psychiatric disease; some have experienced worsening of their psychiatric illnesses. All patients being treated with bupropion as part of smoking cessation treatment should be observed for neuropsychiatric symptoms or worsening of pre-existing psychiatric illness.

Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the pre-marketing studies of Zyban®*.

Advise patients and caregivers that the patient using bupropion for smoking cessation should stop taking bupropion and contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after discontinuation of Zyban®* was reported, although in some cases the symptoms persisted, therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.

The risks of using bupropion for smoking cessation should be weighed against the benefits of its use. Zyban®*has been demonstrated to increase the likelihood of abstinence from smoking for as long as six months compared to treatment with placebo. The health benefits of quitting smoking are immediate and substantial.

Screening Patients for Bipolar Disorder:

Bupropion-Containing Products:

, used as an aid to smoking cessation treatment, and that bupropion hydrochloride extended-release tablets should not be used in combination with Zyban

, or any other medications that contain bupropion, such as Wellbutrin

(bupropion hydrochloride), the immediate-release formulation or Wellbutrin XL

(bupropion hydrochloride), the extended-release formulation.

Seizures: Bupropion is associated with a dose-related risk of seizures. The risk of seizures is also related to patient factors, clinical situations, and concomitant medications, which must be considered in selection of patients for therapy with bupropion hydrochloride extendedrelease tablets (SR). Bupropion hydrochloride extended-release tablets (SR) should be discontinued and not restarted in patients who experience a seizure while on treatment.

Retrospective analysis of clinical experience gained during the development of bupropion suggests that the risk of seizure may be minimized if

Bupropion hydrochloride extended-release tablets (SR) should be administered with extreme caution to patients with a history of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients treated with other agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that lower seizure threshold.

Hepatic Impairment: Bupropion hydrochloride extended-release tablets (SR) should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients a reduced frequency and/or dose 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 100 mg every day or 150 mg every other day in these patients (see

,

, and

).

Potential for Hepatotoxicity:

**Table 1**
Age Range	Drug-Placebo Difference inNumber of Cases of Suicidalityper 1,000 Patients Treated
<18	14 additional cases
18 to 24	5 additional cases
25 to 64	1 fewer case
≥65	6 fewer cases

What are the precautions of BUPROPION HYDROCHLORIDE?

General:

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Agitation and Insomnia:

In clinical studies, these symptoms were sometimes of sufficient magnitude to require treatment with sedative/hypnotic drugs.

Symptoms were sufficiently severe to require discontinuation of treatment in 1% and 2.6% of patients treated with 300 and 400 mg/day, respectively, of bupropion hydrochloride extended-release tablets (SR) and 0.8% of patients treated with placebo.

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Psychosis, Confusion, and Other Neuropsychiatric Phenomena:

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Activation of Psychosis and/or Mania:

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Altered Appetite and Weight:

In studies conducted with the immediate-release formulation of bupropion, 35% of patients receiving tricyclic antidepressants gained weight, compared to 9% of patients treated with the immediate-release formulation of bupropion. If weight loss is a major presenting sign of a patient’s depressive illness, the anorectic and/or weight-reducing potential of bupropion hydrochloride extended-release tablets (SR) should be considered.

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Allergic Reactions:

Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity have been reported in association with bupropion. These symptoms may resemble serum sickness.

**Table 2. Incidence of Agitation, Anxiety, and Insomnia in Placebo-Controlled Trials**
Adverse Event Term	Bupropion Hydrochloride Sustained-Release Formulation300 mg/day(n=376)	Bupropion HydrochlorideSustained-Release Formulation400 mg/day(n=114)	Placebo(n=385)
AgitationAnxietyInsomnia	3%5%11%	9%6%16%	2%3%6%
WeightChange	Bupropion HydrochlorideSustained-Release Formulation300 mg/day(n=339)	Bupropion HydrochlorideSustained-Release Formulation400 mg/day(n=112)	Placebo(n=347)
Gained>5 lbsLost>5 lbs	3% 14%	2% 19%	4% 6%

Cardiovascular Effects:

In clinical practice, hypertension, in some cases severe, requiring acute treatment, has been reported in patients receiving bupropion alone and in combination with nicotine replacement therapy. These events have been observed in both patients with and without evidence of preexisting hypertension.

Data from a comparative study of the sustained-release formulation of bupropion (Zyban Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this study, 6.1% of patients treated with the combination of sustained-release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of patients treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these patients had evidence of preexisting hypertension. Three patients (1.2%) treated with the combination of Zyban and NTS and 1 patient (0.4%) treated with NTS had study medication discontinued due to hypertension compared to none of the patients treated with Zyban or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.

There is no clinical experience establishing the safety of bupropion hydrochloride extended-release tablets (SR) in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care should be exercised if it is used in these groups. Bupropion was well tolerated in depressed patients who had previously developed orthostatic hypotension while receiving tricyclic antidepressants, and was also generally well tolerated in a group of 36 depressed inpatients with stable congestive heart failure (CHF). However, bupropion was associated with a rise in supine blood pressure in the study of patients with CHF, resulting in discontinuation of treatment in 2 patients for exacerbation of baseline hypertension.

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Hepatic Impairment:

All patients with hepatic impairment should be closely monitored for possible adverse effects that could indicate high drug and metabolite levels (see , , and ).

Renal Impairment:

There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An inter-study comparison between normal subjects and patients with end-stage renal failure demonstrated that the parent drug C and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. A second study, comparing normal subjects and patients with moderate-to-severe renal impairment (GFR 30.9 ± 10.8 mL/min) showed that exposure to a single 150 mg dose of sustained-release bupropion was approximately 2-fold higher in patients with impaired renal function while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. Bupropion hydrochloride extended-release tablets (SR) should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered as bupropion and the metabolites of bupropion may accumulate in such patients to a greater extent than usual. The patient should be closely monitored for possible adverse effects that could indicate high drug or metabolite levels.

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 bupropion hydrochloride extended-release tablets (SR) and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions” “Quitting Smoking, Quit-Smoking Medication, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information Should I Know About bupropion hydrochloride extended-release tablets (SR)?" is available for bupropion hydrochloride extended-release tablets (SR). 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 bupropion hydrochloride extended-release tablets (SR).

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Clinical Worsening and Suicide Risk :

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Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment:

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Bupropion-Containing Products:

As dose is increased during initial titration to doses above 150 mg/day, patients should be instructed to take bupropion hydrochloride extended-release tablets (SR) in 2 divided doses, preferably with at least 8 hours between successive doses, to minimize the risk of seizures.

Patients should be told that bupropion hydrochloride extended-release tablets (SR) should be discontinued and not restarted if they experience a seizure while on treatment.

Patients should be told that any CNS-active drug like bupropion hydrochloride extended-release tablets (SR) may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Consequently, until they are reasonably certain that bupropion hydrochloride extended-release tablets (SR) do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.

Patients should be told that the excessive use or abrupt discontinuation of alcohol or sedatives (including benzodiazepines) may alter the seizure threshold. Some patients have reported lower alcohol tolerance during treatment with bupropion hydrochloride extended-release tablets (SR). Patients should be advised that the consumption of alcohol should be minimized or avoided.

Patients should be advised to inform their physicians if they are taking or plan to take any prescription or over-the-counter drugs. Concern is warranted because bupropion hydrochloride extended-release tablets (SR) and other drugs may affect each other’s metabolism.

Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy.

Patients should be advised to swallow bupropion hydrochloride extended-release tablets (SR) whole so that the release rate is not altered. Do not chew, divide, or crush tablets, as this may lead to an increased risk of adverse effects, including seizures.

Laboratory Tests:

There are no specific laboratory tests recommended.

Drug Interactions:

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. 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 substrates of or inhibitors/inducers of the CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa, cyclophosphamide, ticlopidine, and clopidogrel). In addition, studies suggest that paroxetine, sertraline, norfluoxetine, and fluvoxamine as well as nelfinavir 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 bupropion hydrochloride extended-release tablets (SR) 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, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.

In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir 100 mg plus lopinavir (KALETRA) 400 mg twice daily reduced the exposure of bupropion and its major metabolites in a dose dependent manner by approximately 20% to 80%. This effect is thought to be due to the induction of bupropion metabolism. Patients receiving ritonavir may need increased doses of bupropion, but the maximum recommended dose of bupropion should not be exceeded (see CLINICAL PHARMACOLOGY: ).

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 8 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.

in vitro

Therefore, coadministration of bupropion with drugs that are metabolized by CYP2D6 isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication. If bupropion is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original medication should be considered, particularly for those concomitant medications with a narrow therapeutic index. Although citalopram is not primarily metabolized by CYP2D6, in one study bupropion increased the C and AUC of citalopram by 30% and 40%, respectively. Citalopram did not affect the pharmacokinetics of bupropion and its three metabolites.

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MAO Inhibitors:

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Levodopa and Amantadine:

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Drugs That Lower Seizure Threshold:

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Nicotine Transdermal System:

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Alcohol:

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. These doses are approximately 7 and 2 times the maximum recommended human dose (MRHD), respectively, on a mg/m basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the MRHD on a mg/m basis); 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 positive response (2 to 3 times control mutation rate) in 2 of 5 strains in the Ames bacterial mutagenicity test and an increase in chromosomal aberrations in 1 of 3 rat bone marrow cytogenetic studies.

A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired fertility.

Pregnancy:

Pregnancy Category C. In studies conducted in rats and rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively (approximately 11 and 7 times the maximum recommended human dose [MRHD], respectively, on a mg/m basis), during the period of organogenesis. No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m basis) and greater. Decreased fetal weights were seen at 50 mg/kg and greater.

When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.

One study has been conducted in pregnant women. This retrospective, managed-care database study assessed the risk of congenital malformations overall, and cardiovascular malformations specifically, following exposure to bupropion in the first trimester compared to the risk of these malformations following exposure to other antidepressants in the first trimester and bupropion outside of the first trimester. This study included 7,005 infants with antidepressant exposure during pregnancy, 1,213 of whom were exposed to bupropion in the first trimester. The study showed no greater risk for congenital malformations overall, or cardiovascular malformations specifically, following first trimester bupropion exposure compared to exposure to all other antidepressants in the first trimester, or bupropion outside of the first trimester. The results of this study have not been corroborated. Bupropion hydrochloride extended-release tablets (SR) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery:

The effect of bupropion hydrochloride extended-release tablets (SR) on labor and delivery in humans is unknown.

Nursing Mothers:

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 hydrochloride extended-release tablets (SR), 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.

Pediatric Use:

Safety and effectiveness in the pediatric population have not been established (see and ). Anyone considering the use of bupropion in a child or adolescent must balance the potential risks with the clinical need.

Geriatric Use:

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 ).

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 and ).

What are the side effects of BUPROPION HYDROCHLORIDE?

(See also and .)

The information included under the Incidence in Controlled Trials subsection of ADVERSE REACTIONS is based primarily on data from controlled clinical trials with bupropion hydrochloride extended-release tablets (SR). Information on additional adverse events associated with the sustained-release formulation of bupropion in smoking cessation trials, as well as the immediate-release formulation of bupropion, is included in a separate section (see Other Events Observed During the Clinical Development and Postmarketing Experience of Bupropion).

Incidence in Controlled Trials With Bupropion:

Adverse Events Associated With Discontinuation of Treatment Among Patients Treated With Bupropion Hydrochloride Extended-Release Tablets (SR):

Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated With Bupropion Hydrochloride Extended-Release Tablets (SR):

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. 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 differ from those that 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 hydrochloride extended-release tablets (SR) is provided in the WARNINGS and PRECAUTIONS sections.

Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials:

Bupropion Extended-release Tablets (SR) 300 mg/day:

Bupropion Extended-release Tablets (SR) 400 mg/day:

Other Events Observed During the Clinical Development and Postmarketing Experience of Bupropion:

In addition to the adverse events noted above, the following events have been reported in clinical trials and postmarketing experience with the sustained-release formulation of bupropion in depressed patients and in nondepressed smokers, as well as in clinical trials and postmarketing clinical experience with the immediate-release formulation of bupropion.

Adverse events for which frequencies are provided below occurred in clinical trials with the sustained-release formulation of bupropion. The frequencies represent the proportion of patients who experienced a treatment-emergent adverse event on at least one occasion in placebo-controlled studies for depression (n = 987) or smoking cessation (n = 1,013), or patients who experienced an adverse event requiring discontinuation of treatment in an open-label surveillance study with bupropion hydrochloride extended-release tablets (SR) (n = 3,100). All treatment-emergent adverse events are included except those listed in Tables 2 through 5, those events listed in other safety-related sections, those adverse events subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those events not reasonably associated with the use of the drug, and those events that were not serious and occurred in fewer than 2 patients. Events of major clinical importance are described in the WARNINGS and PRECAUTIONS sections of the labeling.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions of frequency: 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.

Adverse events for which frequencies are not provided occurred in clinical trials or postmarketing experience with bupropion. Only those adverse events not previously listed for sustained-release bupropion are included. The extent to which these events may be associated with bupropion is unknown.

Body (General):

Cardiovascular:

Digestive:

Endocrine:

Hemic and Lymphatic:

Metabolic and Nutritional:

Musculoskeletal:

Nervous System:

Respiratory:

Skin:

Special Senses:

Urogenital:

**Table 4. Treatment Discontinuations Due to Adverse Events in Placebo-Controlled Trials**
Adverse Event Term	Bupropion Hydrochloride Sustained-Release Formulation300 mg/day(n=376)	Bupropion Hydrochloride Sustained-Release Formulation400 mg/day(n=114)	Placebo(n=385)
RashNauseaAgitationMigraine	2.4%0.8%0.3%0.0%	0.9%1.8%1.8%1.8%	0.0%0.3%0.3%0.3%
* Adverse events that occurred in at least 1% of patients treated with either 300 or 400 mg/day of bupropion hydrochloride extended-release tablets (SR), but equally or more frequently in the placebo group, were: abnormal dreams, accidental injury, acne, appetite increased, back pain, bronchitis, dysmenorrhea, dyspepsia, flatulence, flu syndrome, hypertension, neck pain, respiratory disorder, rhinitis, and tooth disorder.
Incidence based on the number of female patients.
- Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of patients.
Body System/Adverse Event	BupropionHydrochlorideSustained-ReleaseFormulation300 mg/day(n=376)	BupropionHydrochlorideSustained-ReleaseFormulation400 mg/day(n=114)	Placebo(n=385)
Body (General)
Headache	26%	25%	23%
Infection	8%	9%	6%
Abdominal pain	3%	9%	2%
Asthenia	2%	4%	2%
Chest pain	3%	4%	1%
Pain	2%	3%	2%
Fever	1%	2%	-
Cardiovascular
Palpitation	2%	6%	2%
Flushing	1%	4%	-
Migraine	1%	4%	1%
Hot flashes	1%	3%	1%
Digestive
Dry mouth	17%	24%	7%
Nausea	13%	18%	8%
Constipation	10%	5%	7%
Diarrhea	5%	7%	6%
Anorexia	5%	3%	2%
Vomiting	4%	2%	2%
Dysphagia	0%	2%	0%
Musculoskeletal
Myalgia	2%	6%	3%
Arthralgia	1%	4%	1%
Arthritis	0%	2%	0%
Twitch	1%	2%	-
Nervous system
Insomnia	11%	16%	6%
Dizziness	7%	11%	5%
Agitation	3%	9%	2%
Anxiety	5%	6%	3%
Tremor	6%	3%	1%
Nervousness	5%	3%	3%
Somnolence	2%	3%	2%
Irritability	3%	2%	2%
Memory decreased	-	3%	1%
Paresthesia	1%	2%	1%
Central nervous
system stimulation	2%	1%	1%
Respiratory
Pharyngitis	3%	11%	2%
Sinusitis	3%	1%	2%
Increased cough	1%	2%	1%
Skin
Sweating	6%	5%	2%
Rash	5%	4%	1%
Pruritus	2%	4%	2%
Urticaria	2%	1%	0%
Special senses
Tinnitus	6%	6%	2%
Taste perversion	2%	4%	-
Blurred vision or diplopia	3%	2%	2%
Urogenital
Urinary frequency	2%	5%	2%
Urinary urgency	-	2%	0%
Vaginal hemorrhage	0%	2%	-
Urinary tract infection	1%	0%	-

What should I look out for while using BUPROPION HYDROCHLORIDE?

Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients with a seizure disorder.

Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients treated with Zyban (bupropion hydrochloride) Sustained-Release Tablets; Wellbutrin (bupropion hydrochloride), the immediate-release formulation; Wellbutrin XL (bupropion hydrochloride), the extended-release formulation; or any other medications that contain bupropion because the incidence of seizure is dose dependent.

Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures noted in patients treated for bulimia with the immediate-release formulation of bupropion. Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients undergoing abrupt discontinuation of alcohol or sedatives (including benzodiazepines).

The concurrent administration of bupropion hydrochloride extended-release tablets (SR) 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 hydrochloride extended-release tablets (SR).

Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients who have shown an allergic response to bupropion or the other ingredients that make up bupropion hydrochloride extended-release tablets (SR).

What might happen if I take too much BUPROPION HYDROCHLORIDE?

Human Overdose Experience:

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.

Overdosage Management:

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 hydrochloride extended-release tablets (SR), 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 listed in the (PDR).

How should I store and handle BUPROPION HYDROCHLORIDE?

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Keep out of reach of children.Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Keep out of reach of children.Bupropion hydrochloride extended-release tablets (SR), 100 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3540-60).Bupropion hydrochloride extended-release tablets (SR), 150 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3541-60) and 250 tablets (NDC 0591-3541-25).Bupropion hydrochloride extended-release tablets (SR), 200 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3542-60).Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP.Manufactured by: Corona, CA 92880 USADistributed by: Corona, CA 92880 USAIssued: August 2010 172395-2Bupropion hydrochloride extended-release tablets (SR), 100 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3540-60).Bupropion hydrochloride extended-release tablets (SR), 150 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3541-60) and 250 tablets (NDC 0591-3541-25).Bupropion hydrochloride extended-release tablets (SR), 200 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3542-60).Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP.Manufactured by: Corona, CA 92880 USADistributed by: Corona, CA 92880 USAIssued: August 2010 172395-2Bupropion hydrochloride extended-release tablets (SR), 100 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3540-60).Bupropion hydrochloride extended-release tablets (SR), 150 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3541-60) and 250 tablets (NDC 0591-3541-25).Bupropion hydrochloride extended-release tablets (SR), 200 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3542-60).Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP.Manufactured by: Corona, CA 92880 USADistributed by: Corona, CA 92880 USAIssued: August 2010 172395-2Bupropion hydrochloride extended-release tablets (SR), 100 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3540-60).Bupropion hydrochloride extended-release tablets (SR), 150 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3541-60) and 250 tablets (NDC 0591-3541-25).Bupropion hydrochloride extended-release tablets (SR), 200 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3542-60).Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP.Manufactured by: Corona, CA 92880 USADistributed by: Corona, CA 92880 USAIssued: August 2010 172395-2Bupropion hydrochloride extended-release tablets (SR), 100 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3540-60).Bupropion hydrochloride extended-release tablets (SR), 150 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3541-60) and 250 tablets (NDC 0591-3541-25).Bupropion hydrochloride extended-release tablets (SR), 200 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3542-60).Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP.Manufactured by: Corona, CA 92880 USADistributed by: Corona, CA 92880 USAIssued: August 2010 172395-2Bupropion hydrochloride extended-release tablets (SR), 100 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3540-60).Bupropion hydrochloride extended-release tablets (SR), 150 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3541-60) and 250 tablets (NDC 0591-3541-25).Bupropion hydrochloride extended-release tablets (SR), 200 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3542-60).Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP.Manufactured by: Corona, CA 92880 USADistributed by: Corona, CA 92880 USAIssued: August 2010 172395-2Bupropion hydrochloride extended-release tablets (SR), 100 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3540-60).Bupropion hydrochloride extended-release tablets (SR), 150 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3541-60) and 250 tablets (NDC 0591-3541-25).Bupropion hydrochloride extended-release tablets (SR), 200 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3542-60).Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP.Manufactured by: Corona, CA 92880 USADistributed by: Corona, CA 92880 USAIssued: August 2010 172395-2Bupropion hydrochloride extended-release tablets (SR), 100 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3540-60).Bupropion hydrochloride extended-release tablets (SR), 150 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3541-60) and 250 tablets (NDC 0591-3541-25).Bupropion hydrochloride extended-release tablets (SR), 200 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with over in bottles of 60 tablets (NDC 0591-3542-60).Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP.Manufactured by: Corona, CA 92880 USADistributed by: Corona, CA 92880 USAIssued: August 2010 172395-2

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Pharmacodynamics:

Pharmacokinetics:

Absorption:

In vitro

tert-

In vitro

Because bupropion is extensively metabolized, there is the potential for drug-drug interactions, particularly with those agents that are metabolized by or which inhibit/induce the cytochrome P450IIB6 (CYP2B6) isoenzyme, such as ritonavir. In a healthy volunteer study, ritonavir at a dose of 100 mg twice daily reduced the AUC and C of bupropion by 22% and 21%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the threohydrobupropion decreased by 38% and the erythrohydrobupropion decreased by 48%.

In a second healthy volunteer study, ritonavir at a dose of 600 mg twice daily decreased the AUC and the C of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 78%, the threohydrobupropion decreased by 50% and the erythrohydrobupropion decreased by 68%.

In another healthy volunteer study, KALETRA(lopinavir 400 mg/ritonavir 100 mg twice daily) decreased bupropion AUC and C by 57%. The AUC and C of hydroxybupropion were decreased by 50% and 31%, respectively, (see PRECAUTIONS: Drug Interactions).

Although bupropion is not metabolized by cytochrome P450IID6 (CYP2D6), there is the potential for drug-drug interactions when bupropion is coadministered with drugs metabolized by this isoenzyme (see ).

Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur approximately 6 hours after administration of bupropion hydrochloride extended-release tablets (SR). Peak plasma concentrations of hydroxybupropion are approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours, and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33 (±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively.

Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg/day.

Elimination:

Population Subgroups:

Hepatic:

The second study showed no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in 9 patients with mild-to-moderate hepatic cirrhosis compared to 8 healthy volunteers. However, more variability was observed in some of the pharmacokinetic parameters for bupropion (AUC, C, and T) and its active metabolites (t) in patients with mild-to-moderate hepatic cirrhosis. In addition, in patients with severe hepatic cirrhosis, the bupropion C and AUC were substantially increased (mean difference: by approximately 70% and 3-fold, respectively) and more variable when compared to values in healthy volunteers; the mean bupropion half-life was also longer (29 hours in patients with severe hepatic cirrhosis vs. 19 hours in healthy subjects). For the metabolite hydroxybupropion, the mean C was approximately 69% lower. For the combined amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, the mean C was approximately 31% lower. The mean AUC increased by about 1½-fold for hydroxybupropion and about 2½-fold for threo/erythrohydrobupropion. The median T was observed 19 hours later for hydroxybupropion and 31 hours later for threo/erythrohydrobupropion. The mean half-lives for hydroxybupropion and threo/erythrohydrobupropion were increased 5- and 2-fold, respectively, in patients with severe hepatic cirrhosis compared to healthy volunteers (see , , and ).

Renal:

Left Ventricular Dysfunction:

Age:

Gender:

Smokers:

Non-Clinical Toxicology

Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients with a seizure disorder.

Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients treated with Zyban (bupropion hydrochloride) Sustained-Release Tablets; Wellbutrin (bupropion hydrochloride), the immediate-release formulation; Wellbutrin XL (bupropion hydrochloride), the extended-release formulation; or any other medications that contain bupropion because the incidence of seizure is dose dependent.

Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures noted in patients treated for bulimia with the immediate-release formulation of bupropion. Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients undergoing abrupt discontinuation of alcohol or sedatives (including benzodiazepines).

The concurrent administration of bupropion hydrochloride extended-release tablets (SR) 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 hydrochloride extended-release tablets (SR).

Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients who have shown an allergic response to bupropion or the other ingredients that make up bupropion hydrochloride extended-release tablets (SR).

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. 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 substrates of or inhibitors/inducers of the CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa, cyclophosphamide, ticlopidine, and clopidogrel). In addition, studies suggest that paroxetine, sertraline, norfluoxetine, and fluvoxamine as well as nelfinavir 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 bupropion hydrochloride extended-release tablets (SR) 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, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.

In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir 100 mg plus lopinavir (KALETRA) 400 mg twice daily reduced the exposure of bupropion and its major metabolites in a dose dependent manner by approximately 20% to 80%. This effect is thought to be due to the induction of bupropion metabolism. Patients receiving ritonavir may need increased doses of bupropion, but the maximum recommended dose of bupropion should not be exceeded (see CLINICAL PHARMACOLOGY: ).

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 8 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.

Therefore, coadministration of bupropion with drugs that are metabolized by CYP2D6 isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication. If bupropion is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original medication should be considered, particularly for those concomitant medications with a narrow therapeutic index. Although citalopram is not primarily metabolized by CYP2D6, in one study bupropion increased the C and AUC of citalopram by 30% and 40%, respectively. Citalopram did not affect the pharmacokinetics of bupropion and its three metabolites.

Agitation and Insomnia:

In clinical studies, these symptoms were sometimes of sufficient magnitude to require treatment with sedative/hypnotic drugs.

Symptoms were sufficiently severe to require discontinuation of treatment in 1% and 2.6% of patients treated with 300 and 400 mg/day, respectively, of bupropion hydrochloride extended-release tablets (SR) and 0.8% of patients treated with placebo.

Psychosis, Confusion, and Other Neuropsychiatric Phenomena:

Activation of Psychosis and/or Mania:

Altered Appetite and Weight:

In studies conducted with the immediate-release formulation of bupropion, 35% of patients receiving tricyclic antidepressants gained weight, compared to 9% of patients treated with the immediate-release formulation of bupropion. If weight loss is a major presenting sign of a patient’s depressive illness, the anorectic and/or weight-reducing potential of bupropion hydrochloride extended-release tablets (SR) should be considered.

Allergic Reactions:

Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity have been reported in association with bupropion. These symptoms may resemble serum sickness.

(See also and .)

The information included under the Incidence in Controlled Trials subsection of ADVERSE REACTIONS is based primarily on data from controlled clinical trials with bupropion hydrochloride extended-release tablets (SR). Information on additional adverse events associated with the sustained-release formulation of bupropion in smoking cessation trials, as well as the immediate-release formulation of bupropion, is included in a separate section (see Other Events Observed During the Clinical Development and Postmarketing Experience of Bupropion).

Incidence in Controlled Trials With Bupropion:

Adverse Events Associated With Discontinuation of Treatment Among Patients Treated With Bupropion Hydrochloride Extended-Release Tablets (SR):

Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated With Bupropion Hydrochloride Extended-Release Tablets (SR):

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. 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 differ from those that 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 hydrochloride extended-release tablets (SR) is provided in the WARNINGS and PRECAUTIONS sections.

Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials:

Bupropion Extended-release Tablets (SR) 300 mg/day:

Bupropion Extended-release Tablets (SR) 400 mg/day:

Other Events Observed During the Clinical Development and Postmarketing Experience of Bupropion:

In addition to the adverse events noted above, the following events have been reported in clinical trials and postmarketing experience with the sustained-release formulation of bupropion in depressed patients and in nondepressed smokers, as well as in clinical trials and postmarketing clinical experience with the immediate-release formulation of bupropion.

Adverse events for which frequencies are provided below occurred in clinical trials with the sustained-release formulation of bupropion. The frequencies represent the proportion of patients who experienced a treatment-emergent adverse event on at least one occasion in placebo-controlled studies for depression (n = 987) or smoking cessation (n = 1,013), or patients who experienced an adverse event requiring discontinuation of treatment in an open-label surveillance study with bupropion hydrochloride extended-release tablets (SR) (n = 3,100). All treatment-emergent adverse events are included except those listed in Tables 2 through 5, those events listed in other safety-related sections, those adverse events subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those events not reasonably associated with the use of the drug, and those events that were not serious and occurred in fewer than 2 patients. Events of major clinical importance are described in the WARNINGS and PRECAUTIONS sections of the labeling.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions of frequency: 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.

Adverse events for which frequencies are not provided occurred in clinical trials or postmarketing experience with bupropion. Only those adverse events not previously listed for sustained-release bupropion are included. The extent to which these events may be associated with bupropion is unknown.

Body (General):

Cardiovascular:

Digestive:

Endocrine:

Hemic and Lymphatic:

Metabolic and Nutritional:

Musculoskeletal:

Nervous System:

Respiratory:

Skin:

Special Senses:

Urogenital:

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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