FDA label cd11365f-a504-41dc-8493-69c763ed03b3

WARNING Serious neuropsychiatric events, including but not limited to depression, suicidal ideation, suicide attempt, and completed suicide have been reported in patients taking Bupropion Hydrochloride Extended-Release Tablets, USP (SR) for smoking cessation. Some cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms have occurred in patients taking Bupropion Hydrochloride Extended-Release Tablets, USP (SR) who continued to smoke. All patients being treated with Bupropion Hydrochloride Extended-Release Tablets, USP (SR) should be observed for neuropsychiatric symptoms including changes in behavior, hostility, agitation, depressed mood, and suicide-related events, including ideation, behavior, and attempted suicide. These symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide have been reported in some patients attempting to quit smoking while taking Bupropion Hydrochloride Extended-Release Tablets, USP (SR) in the postmarketing experience. When symptoms were reported, most were during treatment with Bupropion Hydrochloride Extended-Release Tablets, USP (SR), but some were following discontinuation of treatment with Bupropion Hydrochloride Extended-Release Tablets, USP (SR). These events have occurred in patients with and without pre-existing psychiatric disease; some have experienced worsening of their psychiatric illnesses. Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the pre-marketing studies of Bupropion Hydrochloride Extended-Release Tablets, USP (SR). Advise patients and caregivers that the patient should stop taking Bupropion Hydrochloride Extended-Release Tablets, USP (SR) and contact a healthcare provider immediately if agitation, hostility, depressed mood, or changes in thinking or behavior 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 Bupropion Hydrochloride Extended-Release Tablets, USP (SR) was reported, although in some cases the symptoms persisted; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve. The risks of Bupropion Hydrochloride Extended-Release Tablets, USP (SR) should be weighed against the benefits of its use. Bupropion Hydrochloride Extended-Release Tablets, USP (SR) has been demonstrated to increase the likelihood of abstinence from smoking for as long as 6 months compared to treatment with placebo. The health benefits of quitting smoking are immediate and substantial. (See WARNINGS: Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment and PRECAUTIONS: Information for Patients .) Use in Treating Psychiatric Disorders: Although Bupropion Hydrochloride Extended-Release Tablets, USP (SR) is not indicated for treatment of depression, it contains the same active ingredient as the antidepressant medications WELLBUTRIN ® , WELLBUTRIN SR ® , and WELLBUTRIN XL ® . 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 Bupropion Hydrochloride Extended-Release Tablets, USP (SR) 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 Hydrochloride Extended-Release Tablets, USP (SR) is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders , PRECAUTIONS: Information for Patients , and PRECAUTIONS: Pediatric Use .)

WARNINGS Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment: Serious neuropsychiatric symptoms have been reported in patients taking Bupropion Hydrochloride Extended-Release Tablets, USP (SR) for smoking cessation (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 . Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms have occurred in patients taking Bupropion Hydrochloride Extended-Release Tablets, USP (SR) who continued to smoke. When symptoms were reported, most were during treatment with Bupropion Hydrochloride Extended-Release Tablets, USP (SR), but some were following discontinuation of treatment with Bupropion Hydrochloride Extended-Release Tablets, USP (SR) These events have occurred in patients with and without pre-existing psychiatric disease; some patients have experienced worsening of their psychiatric illnesses. All patients being treated with Bupropion Hydrochloride Extended-Release Tablets, USP (SR) 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 Bupropion Hydrochloride Extended-Release Tablets, USP (SR). Advise patients and caregivers that the patient should stop taking Bupropion Hydrochloride Extended-Release Tablets, USP (SR) 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 post-marketing cases, resolution of symptoms after discontinuation of Bupropion Hydrochloride Extended-Release Tablets, USP (SR) was reported, although in some cases the symptoms persisted, therefore, ongoing monitoring and supportive care should be provided until symptoms resolve . The risks of Bupropion Hydrochloride Extended-Release Tablets, USP (SR) should be weighed against the benefits of its use. Bupropion Hydrochloride Extended-Release Tablets, USP (SR) 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. Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders: Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with 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 4. Table 4 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about 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, irritabilit y , 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 Hydrochloride Extended-Release Tablets, USP (SR) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Bupropion Hydrochloride Extended-Release Tablets, USP (SR) are not approved for use in treating bipolar depression. Bupropion-Containing Products: Patients should be made aware that Bupropion Hydrochloride Extended-Release Tablets, USP (SR) contains the same active ingredient found in WELLBUTRIN, WELLBUTRIN SR, and WELLBUTRIN XL used to treat depression, and that Bupropion Hydrochloride Extended-Release Tablets, USP (SR) should not be used in combination with WELLBUTRIN (bupropion hydrochloride), the immediate-release formulation; WELLBUTRIN SR (bupropion hydrochloride), the sustained-release formulation; WELLBUTRIN XL (bupropion hydrochloride), the extended-release formulation; or any other medications that contain bupropion. Seizures: Because the use of bupropion is associated with a dose-dependent risk of seizures, clinicians should not prescribe doses over 300 mg/day for smoking cessation. The risk of seizures is also related to patient factors, clinical situation, and concomitant medications, which must be considered in selection of patients for therapy with Bupropion Hydrochloride Extended-Release Tablets, USP (SR). Bupropion Hydrochloride Extended-Release Tablets, USP (SR) should be discontinued and not restarted in patients who experience a seizure while on treatment. • Dose: For smoking cessation, doses above 300 mg/day should not be used. The seizure rate associated with doses of sustained-release bupropion up to 300 mg/day is approximately 0.1% (1/1,000). This incidence was prospectively determined during an 8-week treatment exposure in approximately 3,100 depressed patients. • Data for the immediate-release formulation of bupropion revealed a seizure incidence of approximately 0.4% (4/1,000) in depressed patients treated at doses in a range of 300 to 450 mg/day. In addition, the estimated seizure incidence increases almost tenfold between 450 and 600 mg/day. • 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. Recommendations for Reducing the Risk of Seizure: Retrospective analysis of clinical experience gained during the development of bupropion suggests that the risk of seizure may be minimized if • the total daily dose of Bupropion Hydrochloride Extended-Release Tablets, USP (SR) does not exceed 300 mg (the maximum recommended dose for smoking cessation), and • the recommended daily dose for most patients (300 mg/day) is administered in divided doses (150 mg twice daily). • No single dose should exceed 150 mg to avoid high peak concentrations of bupropion and/or its metabolites. Bupropion Hydrochloride Extended-Release Tablets, USP (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, antidepressants, theophylline, systemic steroids, etc.) that lower seizure threshold. Hepatic Impairment: Bupropion Hydrochloride Extended-Release Tablets, USP (SR) should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients a reduced frequency of dosing is required, as peak bupropion levels are substantially increased and accumulation is likely to occur in such patients to a greater extent than usual. The dose should not exceed 150 mg every other day in these patients (see CLINICAL PHARMACOLOGY , PRECAUTIONS , and DOSAGE AND ADMINISTRATION ). Potential for Hepatotoxicity: 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.

<table ID="_RefID0ECQAE" width="100%"> <caption> Table 4 </caption> <col width="43%"/> <col width="28%"/> <col width="30%"/> <thead> <tr> <th align="left" valign="bottom"> <content styleCode="bold"> Age Range </content> </th> <th align="left" valign="top"/> <th align="left" valign="top"> <content styleCode="bold">Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated</content> </th> </tr> </thead> <tbody> <tr> <td valign="top"/> <td colspan="2" valign="top"> <paragraph>Increases Compared to Placebo </paragraph> </td> </tr> <tr> <td align="center" valign="top"> <paragraph>&lt;18</paragraph> </td> <td valign="top"/> <td align="center" valign="top"> <paragraph>14 additional cases </paragraph> </td> </tr> <tr> <td align="center" valign="top"> <paragraph>18 to 24</paragraph> </td> <td valign="top"/> <td align="center" valign="top"> <paragraph>5 additional cases </paragraph> </td> </tr> <tr> <td valign="top"/> <td colspan="2" valign="top"> <paragraph>Decreases Compared to Placebo </paragraph> </td> </tr> <tr> <td align="center" valign="top"> <paragraph>25 to 64</paragraph> </td> <td valign="top"/> <td align="center" valign="top"> <paragraph>1 fewer case </paragraph> </td> </tr> <tr> <td align="center" valign="middle"> <paragraph>&#x2265;65</paragraph> </td> <td valign="top"/> <td align="center" valign="top"> <paragraph>6 fewer cases </paragraph> </td> </tr> </tbody> </table>

ADVERSE REACTIONS (See also WARNINGS and PRECAUTIONS. ) The information included under ADVERSE REACTIONS is based primarily on data from the dose-response trial and the comparative trial that evaluated Bupropion Hydrochloride Extended-Release Tablets, USP (SR) for smoking cessation (see CLINICAL TRIALS ). Information on additional adverse events associated with the sustained-release formulation of bupropion in depression 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 ). Adverse Events Associated With the Discontinuation of Treatment: Adverse events were sufficiently troublesome to cause discontinuation of treatment in 8% of the 706 patients treated with Bupropion Hydrochloride Extended-Release Tablets, USP (SR) and 5% of the 313 patients treated with placebo. The more common events leading to discontinuation of treatment with Bupropion Hydrochloride Extended-Release Tablets, USP (SR) included nervous system disturbances (3.4%), primarily tremors, and skin disorders (2.4%), primarily rashes. Incidence of Commonly Observed Adverse Events: The most commonly observed adverse events consistently associated with the use of Bupropion Hydrochloride Extended-Release Tablets, USP (SR) were dry mouth and insomnia. The most commonly observed adverse events were defined as those that consistently occurred at a rate of 5 percentage points greater than that for placebo across clinical studies. Dose Dependency of Adverse Events: The incidence of dry mouth and insomnia may be related to the dose of Bupropion Hydrochloride Extended-Release Tablets, USP (SR). The occurrence of these adverse events may be minimized by reducing the dose of Bupropion Hydrochloride Extended-Release Tablets, USP (SR). In addition, insomnia may be minimized by avoiding bedtime doses. Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated With Bupropion Hydrochloride Extended-Release Tablets, USP (SR): Table 5 enumerates selected treatment-emergent adverse events from the dose-response trial that occurred at an incidence of 1% or more and were more common in patients treated with Bupropion Hydrochloride Extended-Release Tablets, USP (SR) compared to those treated with placebo. Table 6 enumerates selected treatment-emergent adverse events from the comparative trial that occurred at an incidence of 1% or more and were more common in patients treated with Bupropion Hydrochloride Extended-Release Tablets, USP (SR), NTS, or the combination of Bupropion Hydrochloride Extended-Release Tablets, USP (SR) and NTS compared to those treated with placebo. Reported adverse events were classified using a COSTART-based dictionary. Table 5. Treatment-Emergent Adverse Event Incidence in the Dose-Response Trial a Bupropion Hydrochloride Extended-Release Tablets, SP (SR) 100 to 300 mg/day Placebo Body System/ (n = 461) (n = 150) Adverse Experience % % a Selected adverse events with an incidence of at least 1% of patients treated with Bupropion Hydrochloride Extended-Release Tablets, USP (SR) and more frequent than in the placebo group. Body (General) Neck pain 2 <1 Allergic reaction 1 0 Cardiovascular Hot flashes 1 0 Hypertension 1 <1 Digestive Dry mouth 11 5 Increased appetite 2 <1 Anorexia 1 <1 Musculoskeletal Arthralgia 4 3 Myalgia 2 1 Nervous system Insomnia 31 21 Dizziness 8 7 Tremor 2 1 Somnolence 2 1 Thinking abnormality 1 0 Respiratory Bronchitis 2 0 Skin Pruritus 3 <1 Rash 3 <1 Dry skin 2 0 Urticaria 1 0 Special senses Taste perversion 2 <1 Table 6. Treatment-Emergent Adverse Event Incidence in the Comparative Trial a Bupropion Bupropion Hydrochloride Nicotine Hydrochloride Extended-Release Transdermal Extended-Release Tablets, USP (SR) System (NTS) Tablets, USP (SR) 300 mg/day 21 mg/day and NTS Placebo Adverse Experience (n = 243) (n = 243) (n = 244) (n = 159) (COSTART Term) % % % % a Selected adverse events with an incidence of at least 1% of patients treated with either Bupropion Hydrochloride Extended-Release Tablets, USP (SR), NTS, or the combination of Bupropion Hydrochloride Extended-Release Tablets, USP (SR) and NTS and more frequent than in the placebo group. b Patients randomized to Bupropion Hydrochloride Extended-Release Tablets, USP (SR) or placebo received placebo patches. Body Abdominal pain 3 4 1 1 Accidental injury 2 2 1 1 Chest pain <1 1 3 1 Neck pain 2 1 <1 0 Facial edema <1 0 1 0 Cardiovascular Hypertension 1 <1 2 0 Palpitations 2 0 1 0 Digestive Nausea 9 7 11 4 Dry mouth 10 4 9 4 Constipation 8 4 9 3 Diarrhea 4 4 3 1 Anorexia 3 1 5 1 Mouth ulcer 2 1 1 1 Thirst <1 <1 2 0 Musculoskeletal Myalgia 4 3 5 3 Arthralgia 5 3 3 2 Nervous system Insomnia 40 28 45 18 Dream abnormality 5 18 13 3 Anxiety 8 6 9 6 Disturbed concentration 9 3 9 4 Dizziness 10 2 8 6 Nervousness 4 <1 2 2 Tremor 1 <1 2 0 Dysphoria <1 1 2 1 Respiratory Rhinitis 12 11 9 8 Increased cough 3 5 <1 1 Pharyngitis 3 2 3 0 Sinusitis 2 2 2 1 Dyspnea 1 0 2 1 Epistaxis 2 1 1 0 Skin Application site reaction b 11 17 15 7 Rash 4 3 3 2 Pruritus 3 1 5 1 Urticaria 2 0 2 0 Special Senses Taste perversion 3 1 3 2 Tinnitus 1 0 <1 0 Bupropion Hydrochloride Extended-Release Tablets, USP (SR) was well-tolerated in the long-term maintenance trial that evaluated chronic administration of Bupropion Hydrochloride Extended-Release Tablets, USP (SR) for up to 1 year and in the COPD trial that evaluated patients with mild-to-moderate COPD for a 12-week period. Adverse events in both studies were quantitatively and qualitatively similar to those observed in the dose-response and comparative trials. 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 sustained-release tablets (n = 3,100). All treatment-emergent adverse events are included except those listed in Tables 5 and 6, those events listed in other safety-related sections of the outsert, those adverse events subsumed under COSTART terms that are either overly general or excessively specified 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 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 Hydrochloride Extended-Release Tablets, USP (SR) is unknown. Body (General): Frequent were asthenia, fever, and headache. Infrequent were back pain, chills, inguinal hernia, musculoskeletal chest pain, pain, and photosensitivity. Rare was malaise. Also observed were arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness (see PRECAUTIONS ). Cardiovascular: Infrequent were flushing, migraine, postural hypotension, stroke, tachycardia, and vasodilation. Rare was syncope. Also observed were cardiovascular disorder, complete AV block, extrasystoles, hypotension, hypertension (in some cases severe, see PRECAUTIONS ), myocardial infarction, phlebitis, and pulmonary embolism. Digestive: Frequent were dyspepsia, flatulence, and vomiting. Infrequent were abnormal liver function, bruxism, dysphagia, gastric reflux, gingivitis, glossitis, jaundice, and stomatitis. Rare was edema of tongue. Also observed were colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, increased salivation, intestinal perforation, liver damage, pancreatitis, stomach ulcer, and stool abnormality. Endocrine: Also observed were hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone. Hemic and Lymphatic: Infrequent was ecchymosis. Also observed were anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin. Metabolic and Nutritional: Infrequent were edema, increased weight, and peripheral edema. Also observed was glycosuria. Musculoskeletal: Infrequent were leg cramps and twitching. Also observed were arthritis and muscle rigidity/fever/rhabdomyolysis, and muscle weakness. Nervous System: Frequent were agitation, depression, and irritability. Infrequent were abnormal coordination, CNS stimulation, confusion, decreased libido, decreased memory, depersonalization, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia, paresthesia, suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania. Also observed were abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, completed suicide, delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hallucinations, hypokinesia, increased libido, manic reaction, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia. Respiratory: Rare was bronchospasm. Also observed was pneumonia. Skin: Frequent was sweating. Infrequent was acne and dry skin. Rare was maculopapular rash. Also observed were alopecia, angioedema, exfoliative dermatitis, and hirsutism. Special Senses: Frequent was blurred vision or diplopia. Infrequent were accommodation abnormality and dry eye. Also observed were deafness, increased intraocular pressure, and mydriasis. Urogenital: Frequent was urinary frequency. Infrequent were impotence, polyuria, and urinary urgency. Also observed were abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, prostate disorder, salpingitis, urinary incontinence, urinary retention, urinary tract disorder, and vaginitis.

<table ID="_RefID0E3GAG" width="100%"> <caption>Table 5. Treatment-Emergent Adverse Event Incidence in the Dose-Response Trial^a </caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <thead> <tr> <th align="left" valign="bottom"/> <th align="center" valign="top"> <content styleCode="bold">Bupropion Hydrochloride</content> </th> <th align="left" valign="top"/> </tr> <tr> <th align="left" valign="bottom"/> <th align="center" valign="top"> <content styleCode="bold">Extended-Release Tablets, </content> </th> <th align="left" valign="top"/> </tr> <tr> <th align="left" valign="bottom"/> <th align="center" valign="top"> <content styleCode="bold">SP (SR) 100 to 300 mg/day</content> </th> <th align="center" valign="top"> <content styleCode="bold">Placebo</content> </th> </tr> <tr> <th align="center" valign="bottom"> <content styleCode="bold">Body System/</content> </th> <th align="center" valign="top"> <content styleCode="bold">(n = 461)</content> </th> <th align="center" valign="top"> <content styleCode="bold">(n = 150)</content> </th> </tr> <tr> <th align="center" valign="bottom"> <content styleCode="bold">Adverse Experience</content> </th> <th align="center" valign="top"> <content styleCode="bold"> %</content> </th> <th align="center" valign="top"> <content styleCode="bold"> %</content> </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3" styleCode="Botrule" valign="top"> ^aSelected adverse events with an incidence of at least 1% of patients treated with Bupropion Hydrochloride Extended-Release Tablets, USP (SR) and more frequent than in the placebo group. </td> </tr> </tfoot> <tbody> <tr> <td valign="top"> <paragraph>Body (General) </paragraph> </td> <td valign="bottom"/> <td valign="bottom"/> </tr> <tr> <td valign="top"> <paragraph> Neck pain </paragraph> </td> <td align="center" valign="bottom"> <paragraph>2</paragraph> </td> <td align="center" valign="bottom"> <paragraph>&lt;1</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> Allergic reaction </paragraph> </td> <td align="center" valign="bottom"> <paragraph>1</paragraph> </td> <td align="center" valign="bottom"> <paragraph>0</paragraph> </td> </tr> <tr> <td valign="bottom"> <paragraph>Cardiovascular </paragraph> </td> <td valign="middle"/> <td valign="middle"/> </tr> <tr> <td valign="bottom"> <paragraph> Hot flashes </paragraph> </td> <td align="center" valign="middle"> <paragraph>1</paragraph> </td> <td align="center" valign="middle"> <paragraph>0</paragraph> </td> </tr> <tr> <td valign="bottom"> <paragraph> Hypertension </paragraph> </td> <td align="center" valign="middle"> <paragraph>1</paragraph> </td> <td align="center" valign="middle"> <paragraph>&lt;1</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph>Digestive </paragraph> </td> <td valign="middle"/> <td valign="middle"/> </tr> <tr> <td valign="top"> <paragraph> Dry mouth </paragraph> </td> <td align="center" valign="middle"> <paragraph>11</paragraph> </td> <td align="center" valign="middle"> <paragraph>5</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> Increased appetite </paragraph> </td> <td align="center" valign="middle"> <paragraph>2</paragraph> </td> <td align="center" valign="middle"> <paragraph>&lt;1</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> Anorexia </paragraph> </td> <td align="center" valign="middle"> <paragraph>1</paragraph> </td> <td align="center" valign="middle"> <paragraph>&lt;1</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph>Musculoskeletal </paragraph> </td> <td valign="bottom"/> <td valign="bottom"/> </tr> <tr> <td valign="top"> <paragraph> Arthralgia</paragraph> </td> <td align="center" valign="bottom"> <paragraph>4</paragraph> </td> <td align="center" valign="bottom"> <paragraph>3</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> Myalgia </paragraph> </td> <td align="center" valign="bottom"> <paragraph>2</paragraph> </td> <td align="center" valign="bottom"> <paragraph>1</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph>Nervous system </paragraph> </td> <td valign="bottom"/> <td valign="bottom"/> </tr> <tr> <td valign="top"> <paragraph> Insomnia</paragraph> </td> <td align="center" valign="bottom"> <paragraph>31</paragraph> </td> <td align="center" valign="bottom"> <paragraph>21</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> Dizziness</paragraph> </td> <td align="center" valign="bottom"> <paragraph>8</paragraph> </td> <td align="center" valign="bottom"> <paragraph>7</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> Tremor </paragraph> </td> <td align="center" valign="bottom"> <paragraph>2</paragraph> </td> <td align="center" valign="bottom"> <paragraph>1</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> Somnolence </paragraph> </td> <td align="center" valign="top"> <paragraph>2</paragraph> </td> <td align="center" valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> Thinking abnormality </paragraph> </td> <td align="center" valign="top"> <paragraph>1</paragraph> </td> <td align="center" valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph>Respiratory </paragraph> </td> <td valign="bottom"/> <td valign="bottom"/> </tr> <tr> <td valign="top"> <paragraph> Bronchitis </paragraph> </td> <td align="center" valign="bottom"> <paragraph>2</paragraph> </td> <td align="center" valign="bottom"> <paragraph>0</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph>Skin </paragraph> </td> <td valign="bottom"/> <td valign="bottom"/> </tr> <tr> <td valign="top"> <paragraph> Pruritus </paragraph> </td> <td align="center" valign="bottom"> <paragraph>3</paragraph> </td> <td align="center" valign="bottom"> <paragraph>&lt;1</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> Rash</paragraph> </td> <td align="center" valign="bottom"> <paragraph>3</paragraph> </td> <td align="center" valign="bottom"> <paragraph>&lt;1</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> Dry skin </paragraph> </td> <td align="center" valign="bottom"> <paragraph>2</paragraph> </td> <td align="center" valign="bottom"> <paragraph>0</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> Urticaria </paragraph> </td> <td align="center" valign="bottom"> <paragraph>1</paragraph> </td> <td align="center" valign="bottom"> <paragraph>0</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph>Special senses </paragraph> </td> <td valign="bottom"/> <td valign="bottom"/> </tr> <tr> <td valign="top"> <paragraph> Taste perversion </paragraph> </td> <td align="center" valign="bottom"> <paragraph>2</paragraph> </td> <td align="center" valign="bottom"> <paragraph>&lt;1</paragraph> </td> </tr> </tbody> </table>

<table ID="_RefID0EWRAG" width="100%"> <caption> Table 6. Treatment-Emergent Adverse Event Incidence in the Comparative Trial^a </caption> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <thead> <tr> <th align="left" valign="bottom"/> <th align="center" valign="bottom"> <content styleCode="bold">Bupropion </content> </th> <th align="left" valign="middle"/> <th align="center" valign="bottom"> <content styleCode="bold">Bupropion </content> </th> <th align="left" valign="bottom"/> </tr> <tr> <th align="left" valign="bottom"/> <th align="center" valign="bottom"> <content styleCode="bold">Hydrochloride</content> </th> <th align="center" valign="middle"> <content styleCode="bold">Nicotine</content> </th> <th align="center" valign="bottom"> <content styleCode="bold">Hydrochloride</content> </th> <th align="left" valign="bottom"/> </tr> <tr> <th align="left" valign="bottom"/> <th align="center" valign="bottom"> <content styleCode="bold">Extended-Release</content> </th> <th align="center" valign="middle"> <content styleCode="bold">Transdermal</content> </th> <th align="center" valign="bottom"> <content styleCode="bold">Extended-Release</content> </th> <th align="left" valign="bottom"/> </tr> <tr> <th align="left" valign="bottom"/> <th align="center" valign="bottom"> <content styleCode="bold">Tablets, USP (SR)</content> </th> <th align="center" valign="middle"> <content styleCode="bold">System (NTS)</content> </th> <th align="center" valign="bottom"> <content styleCode="bold">Tablets, USP (SR)</content> </th> <th align="left" valign="bottom"/> </tr> <tr> <th align="left" valign="bottom"/> <th align="center" valign="bottom"> <content styleCode="bold">300 mg/day </content> </th> <th align="center" valign="middle"> <content styleCode="bold">21 mg/day </content> </th> <th align="center" valign="bottom"> <content styleCode="bold">and NTS</content> </th> <th align="center" valign="bottom"> <content styleCode="bold">Placebo</content> </th> </tr> <tr> <th align="left" valign="bottom"> <content styleCode="bold"> Adverse Experience </content> </th> <th align="center" valign="bottom"> <content styleCode="bold">(n = 243)</content> </th> <th align="center" valign="middle"> <content styleCode="bold">(n = 243)</content> </th> <th align="center" valign="bottom"> <content styleCode="bold">(n = 244)</content> </th> <th align="center" valign="bottom"> <content styleCode="bold">(n = 159) </content> </th> </tr> <tr> <th align="left" valign="bottom"> <content styleCode="bold"> (COSTART Term) </content> </th> <th align="center" valign="bottom"> <content styleCode="bold"> %</content> </th> <th align="center" valign="middle"> <content styleCode="bold"> %</content> </th> <th align="center" valign="bottom"> <content styleCode="bold"> %</content> </th> <th align="center" valign="bottom"> <content styleCode="bold"> %</content> </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="8" styleCode="Botrule" valign="top"> ^aSelected adverse events with an incidence of at least 1% of patients treated with either Bupropion Hydrochloride Extended-Release Tablets, USP (SR), NTS, or the combination of Bupropion Hydrochloride Extended-Release Tablets, USP (SR) and NTS and more frequent than in the placebo group.</td> </tr> <tr> <td align="left" colspan="8" styleCode="Botrule" valign="top"> ^bPatients randomized to Bupropion Hydrochloride Extended-Release Tablets, USP (SR) or placebo received placebo patches. </td> </tr> </tfoot> <tbody> <tr> <td valign="middle"> <paragraph>Body</paragraph> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td valign="middle"> <paragraph> Abdominal pain </paragraph> </td> <td align="center" valign="middle"> <paragraph>3 </paragraph> </td> <td align="center" valign="middle"> <paragraph>4 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Accidental injury</paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Chest pain </paragraph> </td> <td align="center" valign="middle"> <paragraph>&lt;1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>3 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Neck pain</paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>&lt;1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>0 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Facial edema </paragraph> </td> <td align="center" valign="middle"> <paragraph>&lt;1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>0 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>0 </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph>Cardiovascular </paragraph> </td> <td valign="bottom"/> <td valign="bottom"/> <td valign="bottom"/> <td valign="bottom"/> </tr> <tr> <td valign="top"> <paragraph> Hypertension </paragraph> </td> <td align="center" valign="bottom"> <paragraph>1 </paragraph> </td> <td align="center" valign="bottom"> <paragraph>&lt;1 </paragraph> </td> <td align="center" valign="bottom"> <paragraph>2 </paragraph> </td> <td align="center" valign="bottom"> <paragraph>0 </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> Palpitations </paragraph> </td> <td align="center" valign="bottom"> <paragraph>2 </paragraph> </td> <td align="center" valign="bottom"> <paragraph>0 </paragraph> </td> <td align="center" valign="bottom"> <paragraph>1 </paragraph> </td> <td align="center" valign="bottom"> <paragraph>0 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph>Digestive</paragraph> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td valign="middle"> <paragraph> Nausea </paragraph> </td> <td align="center" valign="middle"> <paragraph>9 </paragraph> </td> <td align="center" valign="middle"> <paragraph>7 </paragraph> </td> <td align="center" valign="middle"> <paragraph>11 </paragraph> </td> <td align="center" valign="middle"> <paragraph>4 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Dry mouth </paragraph> </td> <td align="center" valign="middle"> <paragraph>10 </paragraph> </td> <td align="center" valign="middle"> <paragraph>4 </paragraph> </td> <td align="center" valign="middle"> <paragraph>9 </paragraph> </td> <td align="center" valign="middle"> <paragraph>4 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Constipation </paragraph> </td> <td align="center" valign="middle"> <paragraph>8 </paragraph> </td> <td align="center" valign="middle"> <paragraph>4 </paragraph> </td> <td align="center" valign="middle"> <paragraph>9 </paragraph> </td> <td align="center" valign="middle"> <paragraph>3 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Diarrhea</paragraph> </td> <td align="center" valign="middle"> <paragraph>4 </paragraph> </td> <td align="center" valign="middle"> <paragraph>4 </paragraph> </td> <td align="center" valign="middle"> <paragraph>3 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Anorexia </paragraph> </td> <td align="center" valign="middle"> <paragraph>3 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>5 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Mouth ulcer </paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Thirst </paragraph> </td> <td align="center" valign="middle"> <paragraph>&lt;1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>&lt;1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> <td align="center" valign="middle"> <paragraph>0 </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph>Musculoskeletal </paragraph> </td> <td valign="bottom"/> <td valign="bottom"/> <td valign="bottom"/> <td valign="bottom"/> </tr> <tr> <td valign="top"> <paragraph> Myalgia </paragraph> </td> <td align="center" valign="bottom"> <paragraph>4 </paragraph> </td> <td align="center" valign="bottom"> <paragraph>3</paragraph> </td> <td align="center" valign="bottom"> <paragraph>5 </paragraph> </td> <td align="center" valign="bottom"> <paragraph>3 </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> Arthralgia </paragraph> </td> <td align="center" valign="bottom"> <paragraph>5 </paragraph> </td> <td align="center" valign="bottom"> <paragraph> 3 </paragraph> </td> <td align="center" valign="bottom"> <paragraph>3 </paragraph> </td> <td align="center" valign="bottom"> <paragraph>2 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph>Nervous system </paragraph> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td valign="middle"> <paragraph> Insomnia</paragraph> </td> <td align="center" valign="middle"> <paragraph>40 </paragraph> </td> <td align="center" valign="middle"> <paragraph>28 </paragraph> </td> <td align="center" valign="middle"> <paragraph>45 </paragraph> </td> <td align="center" valign="middle"> <paragraph>18 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Dream abnormality</paragraph> </td> <td align="center" valign="middle"> <paragraph>5 </paragraph> </td> <td align="center" valign="middle"> <paragraph>18 </paragraph> </td> <td align="center" valign="middle"> <paragraph>13 </paragraph> </td> <td align="center" valign="middle"> <paragraph>3 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Anxiety</paragraph> </td> <td align="center" valign="middle"> <paragraph>8 </paragraph> </td> <td align="center" valign="middle"> <paragraph>6 </paragraph> </td> <td align="center" valign="middle"> <paragraph>9 </paragraph> </td> <td align="center" valign="middle"> <paragraph>6 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Disturbed concentration</paragraph> </td> <td align="center" valign="middle"> <paragraph>9 </paragraph> </td> <td align="center" valign="middle"> <paragraph>3 </paragraph> </td> <td align="center" valign="middle"> <paragraph>9 </paragraph> </td> <td align="center" valign="middle"> <paragraph>4 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Dizziness</paragraph> </td> <td align="center" valign="middle"> <paragraph>10 </paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> <td align="center" valign="middle"> <paragraph>8 </paragraph> </td> <td align="center" valign="middle"> <paragraph>6 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Nervousness </paragraph> </td> <td align="center" valign="middle"> <paragraph>4 </paragraph> </td> <td align="center" valign="middle"> <paragraph>&lt;1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Tremor </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>&lt;1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> <td align="center" valign="middle"> <paragraph>0 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Dysphoria </paragraph> </td> <td align="center" valign="middle"> <paragraph>&lt;1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph>Respiratory</paragraph> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td valign="middle"> <paragraph> Rhinitis </paragraph> </td> <td align="center" valign="middle"> <paragraph>12 </paragraph> </td> <td align="center" valign="middle"> <paragraph>11 </paragraph> </td> <td align="center" valign="middle"> <paragraph>9 </paragraph> </td> <td align="center" valign="middle"> <paragraph>8 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Increased cough </paragraph> </td> <td align="center" valign="middle"> <paragraph>3 </paragraph> </td> <td align="center" valign="middle"> <paragraph>5 </paragraph> </td> <td align="center" valign="middle"> <paragraph>&lt;1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Pharyngitis </paragraph> </td> <td align="center" valign="middle"> <paragraph>3 </paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> <td align="center" valign="middle"> <paragraph>3 </paragraph> </td> <td align="center" valign="middle"> <paragraph>0 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Sinusitis </paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Dyspnea </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>0 </paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Epistaxis </paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>0 </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph>Skin </paragraph> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td valign="top"> <paragraph> Application site reaction^b </paragraph> </td> <td align="center" valign="middle"> <paragraph>11 </paragraph> </td> <td align="center" valign="middle"> <paragraph>17 </paragraph> </td> <td align="center" valign="middle"> <paragraph>15 </paragraph> </td> <td align="center" valign="middle"> <paragraph>7 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Rash </paragraph> </td> <td align="center" valign="middle"> <paragraph>4 </paragraph> </td> <td align="center" valign="middle"> <paragraph>3 </paragraph> </td> <td align="center" valign="middle"> <paragraph>3 </paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Pruritus </paragraph> </td> <td align="center" valign="middle"> <paragraph>3 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> <td align="center" valign="middle"> <paragraph>5 </paragraph> </td> <td align="center" valign="middle"> <paragraph>1 </paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> Urticaria </paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> <td align="center" valign="middle"> <paragraph>0 </paragraph> </td> <td align="center" valign="middle"> <paragraph>2 </paragraph> </td> <td align="center" valign="middle"> <paragraph>0 </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph>Special Senses </paragraph> </td> <td valign="bottom"/> <td valign="bottom"/> <td valign="bottom"/> <td valign="bottom"/> </tr> <tr> <td valign="top"> <paragraph> Taste perversion </paragraph> </td> <td align="center" valign="bottom"> <paragraph>3 </paragraph> </td> <td align="center" valign="bottom"> <paragraph>1</paragraph> </td> <td align="center" valign="bottom"> <paragraph>3 </paragraph> </td> <td align="center" valign="bottom"> <paragraph>2 </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> Tinnitus </paragraph> </td> <td align="center" valign="bottom"> <paragraph>1 </paragraph> </td> <td align="center" valign="bottom"> <paragraph> 0 </paragraph> </td> <td align="center" valign="bottom"> <paragraph>&lt;1 </paragraph> </td> <td align="center" valign="bottom"> <paragraph>0 </paragraph> </td> </tr> </tbody> </table>