Bupropion

Bupropion is a prescription medication used to treat depression, prevents seasonal depression, and to quit smoking, depending on the form. Bupropion belongs to a group of drugs called antidepressants, which work by affecting certain natural chemicals in the brain. It is not known how bupropion helps patients quit smoking.

This medication comes in immediate release tablets, sustained-release tablets, and extended-release tablets. The immediate release tablets are usually taken 3 or 4 times daily. The sustained-release tablet is usually taken twice daily. The extended-release tablet is usually taken once daily. 

Common side effects of bupropion include nervousness, constipation, trouble sleeping, headache, and nausea.

Bupropion is part of the drug class:

• Other antidepressants

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For bupropion, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to bupropion or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of bupropion in the pediatric population. However, children are more sensitive to the effects of bupropion than adults when used for treating depression. Use of bupropion to treat depression in children is not recommended. Safety and efficacy of bupropion to help stop smoking have not been established in children.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of bupropion in the elderly. However, elderly patients may be more sensitive to the effects of bupropion and are more likely to have age-related kidney or liver problems, which may require caution and an adjustment in the dose for patients receiving bupropion.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking bupropion, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using bupropion with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Bromopride
• Furazolidone
• Iproniazid
• Isocarboxazid
• Linezolid
• Methylene Blue
• Metoclopramide
• Moclobemide
• Nialamide
• Phenelzine
• Procarbazine
• Rasagiline
• Selegiline
• Tranylcypromine

Using bupropion with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acetophenazine
• Aclidinium
• Acrivastine
• Alcaftadine
• Amantadine
• Ambenonium
• Amdinocillin
• Amdinocillin Pivoxil
• Amiloride
• Amineptine
• Aminophylline
• Amitriptyline
• Amitriptylinoxide
• Amoxapine
• Amphetamine
• Ampicillin
• Anisotropine
• Antazoline
• Aripiprazole
• Astemizole
• Atomoxetine
• Atropine
• Azatadine
• Azelastine
• Azlocillin
• Bacampicillin
• Belladonna Alkaloids
• Benperidol
• Benzphetamine
• Bepotastine
• Betamethasone
• Brexpiprazole
• Bromodiphenhydramine
• Bromperidol
• Brompheniramine
• Buclizine
• Budesonide
• Bupivacaine
• Butriptyline
• Butylscopolamine
• Carbamazepine
• Carbenicillin
• Carbimazole
• Carbinoxamine
• Carvedilol
• Chlorambucil
• Chlorotrianisene
• Chlorpheniramine
• Chlorphenoxamine
• Cimetidine
• Cimetropium
• Cinnarizine
• Citalopram
• Clemastine
• Clemizole
• Clidinium
• Clobetasone
• Clomipramine
• Clopidogrel
• Cloxacillin
• Clozapine
• Codeine
• Conjugated Estrogens
• Corticotropin
• Cortisone
• Cosyntropin
• Cyclacillin
• Cyclizine
• Cyclosporine
• Cyproheptadine
• Danazol
• Darifenacin
• Deflazacort
• Delavirdine
• Demecarium
• Desipramine
• Desonide
• Desvenlafaxine
• Deutetrabenazine
• Dexamethasone
• Dexbrompheniramine
• Dexchlorpheniramine
• Dextroamphetamine
• Dextromethorphan
• Dibenzepin
• Dicloxacillin
• Dicyclomine
• Dienestrol
• Diethylstilbestrol
• Dimenhydrinate
• Diphenhydramine
• Diphenylpyraline
• Distigmine
• Donepezil
• Dopamine
• Dothiepin
• Doxepin
• Doxorubicin
• Doxorubicin Hydrochloride Liposome
• Doxylamine
• Droperidol
• Duloxetine
• Ebastine
• Echothiophate
• Edrophonium
• Efavirenz
• Eliglustat
• Emedastine
• Enflurane
• Epinastine
• Escitalopram
• Esterified Estrogens
• Estradiol
• Estramustine
• Estriol
• Estrone
• Estropipate
• Ethinyl Estradiol
• Famotidine
• Fesoterodine
• Flavoxate
• Flecainide
• Floxacillin
• Fludrocortisone
• Flunarizine
• Flunisolide
• Fluoxetine
• Fluticasone
• Fluvoxamine
• Fosphenytoin
• Galantamine
• Glycopyrrolate
• Guanidine
• Haloperidol
• Hetacillin
• Homatropine
• Hydrocortisone
• Hydroxyzine
• Hyoscyamine
• Imipramine
• Indalpine
• Iobenguane I 123
• Isoflurophate
• Isoniazid
• Isopropamide
• Ketamine
• Ketotifen
• Levocabastine
• Levodopa
• Levomilnacipran
• Lidocaine
• Lindane
• Lisdexamfetamine
• Lofepramine
• Lopinavir
• Loxapine
• Mebeverine
• Mebhydrolin
• Meclizine
• Memantine
• Mepenzolate
• Mestranol
• Metformin
• Methamphetamine
• Methantheline
• Methdilazine
• Methenolone
• Methicillin
• Methimazole
• Methixene
• Methylphenidate
• Methylprednisolone
• Methyltestosterone
• Metronidazole
• Mexiletine
• Mezlocillin
• Milnacipran
• Mizolastine
• Nafcillin
• Nalidixic Acid
• Nandrolone
• Nebivolol
• Nefazodone
• Neostigmine
• Niaprazine
• Nortriptyline
• Olopatadine
• Ondansetron
• Opipramol
• Ospemifene
• Oxacillin
• Oxaliplatin
• Oxandrolone
• Oxatomide
• Oxybutynin
• Oxymetholone
• Paramethasone
• Paroxetine
• Penicillin G
• Penicillin V
• Phenindamine
• Pheniramine
• Phenobarbital
• Phenyltoloxamine
• Phenytoin
• Physostigmine
• Pimozide
• Pinaverium
• Pindolol
• Piperacillin
• Pirenzepine
• Pivampicillin
• Pizotyline
• Polyestradiol Phosphate
• Prasugrel
• Prednisolone
• Prednisone
• Procainamide
• Procaine
• Promestriene
• Promethazine
• Propafenone
• Propantheline
• Propicillin
• Propiverine
• Propizepine
• Propranolol
• Protriptyline
• Pyrilamine
• Quinestrol
• Ranitidine
• Regorafenib
• Rimexolone
• Risperidone
• Ritonavir
• Rivastigmine
• Scopolamine
• Sertraline
• Sibutramine
• Solifenacin
• Sorafenib
• Stanozolol
• Sultamicillin
• Tacrine
• Terfenadine
• Testosterone
• Theophylline
• Thioridazine
• Thiotepa
• Thonzylamine
• Tibolone
• Ticarcillin
• Ticlopidine
• Timiperone
• Tiotropium
• Tolterodine
• Tramadol
• Trimeprazine
• Trimipramine
• Tripelennamine
• Triprolidine
• Tropicamide
• Trospium
• Umeclidinium
• Valbenazine
• Valethamate
• Varenicline
• Venlafaxine
• Vortioxetine

Using bupropion with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aripiprazole Lauroxil
• Digoxin
• Isavuconazonium Sulfate
• St John's Wort
• Tipranavir
• Zolpidem

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using bupropion with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use bupropion, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of bupropion. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol use, if stopped suddenly, or
• Eating disorders (eg, anorexia, bulimia), history of or
• Seizures, history of or
• Seizure medicine use, if stopped suddenly (eg, carbamazepine (Tegretol®), phenobarbital, phenytoin (Dilantin®)), or
• Sleeping or anxiety medicine use, if stopped suddenly (eg, alprazolam (Xanax®), lorazepam (Ativan®), temazepam (Restoril®), triazolam (Halcion®))—Should not be used in patients with these conditions.

• Arteriovenous malformation (circulation problem) or
• Brain tumor or infection or
• Diabetes or
• Drug or alcohol abuse or
• Head injury, severe or
• Hypoglycemia (low blood sugar) or
• Hyponatremia (low sodium in the blood) or
• Hypoxia (low oxygen in the blood) or
• Liver disease, severe
• Stroke, history of—May increase the risk of seizures.

• Bipolar disorder (type of depression), or risk of or
• Glaucoma, angle closure or
• Hypertension (high blood pressure) or
• Mania or hypomania (type of mental disease), history of or
• Psychosis (type of mental disease) or
• Schizophrenia (type of mental disease)—Use with caution. May make these conditions worse.

• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

General Instructions for Use

To minimize the risk of seizure, increase the dose gradually [see Warnings and Precautions (5.3)]. Bupropion hydrochloride extended-release tablets, USP (SR) should be swallowed whole and not crushed, divided, or chewed. Bupropion hydrochloride extended-release tablets, USP (SR) may be taken with or without food.

The usual adult target dose for Bupropion hydrochloride extended-release tablets, USP (SR) is 300 mg per day, given as 150 mg twice daily. Initiate dosing with 150 mg per day given as a single daily dose in the morning. After 3 days of dosing, the dose may be increased to the 300 mg per day target dose, given as 150 mg twice daily. There should be an interval of at least 8 hours between successive doses. A maximum of 400 mg per day, given as 200 mg twice daily, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg per day. To avoid high peak concentrations of Bupropion and/or its metabolites, do not exceed 200 mg in any single-dose.

It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether the dose of Bupropion hydrochloride extended-release tablets, USP (SR) needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment.

Dose Adjustment in Patients with Hepatic Impairment

In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of Bupropion hydrochloride extended-release tablets, USP (SR) is 100 mg per day or 150 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Use in Specific Populations (8.7),Clinical Pharmacology (12.3)].

Dose Adjustment in Patients with Renal Impairment

Consider reducing the dose and/or frequency of Bupropion hydrochloride extended-release tablets, USP (SR) in patients with renal impairment (Glomerular Filtration Rate less than 90 mL per min) [see Use in Specific Populations (8.6),Clinical Pharmacology (12.3)].

Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant

At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with Bupropion hydrochloride extended-release tablets, USP (SR). Conversely, at least 14 days should be allowed after stopping Bupropion hydrochloride extended-release tablets, USP (SR) before starting an MAOI antidepressant [see Contraindications (4), Drug Interactions (7.6)].

Use of Bupropion Hydrochloride Extended-Release Tablets, USP (SR) with Reversible MAOIs Such as Linezolid or Methylene Blue

Do not start Bupropion hydrochloride extended-release tablets, USP (SR) in a patient who is being treated with a reversible MAOI such as linezolid or intravenous methylene blue. Drug interactions can increase the risk of hypertensive reactions. In a patient who requires more urgent treatment of a psychiatric condition, non-pharmacological interventions, including hospitalization, should be considered [see Contraindications (4),Drug Interactions (7.6)].

In some cases, a patient already receiving therapy with Bupropion hydrochloride extended-release tablets, USP (SR) may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of hypertensive reactions in a particular patient, Bupropion hydrochloride extended-release tablets, USP (SR)should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Bupropion hydrochloride extended-release tablets, USP (SR) may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg per kg with Bupropion hydrochloride extended-release tablets, USP (SR) is unclear. The clinician should, nevertheless, be aware of the possibility of a drug interaction with such use [see Contraindications (4), Drug Interactions (7.6)].

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Suicidal thoughts and behaviors in adolescents and young adults [see Boxed Warning, Warnings and Precautions (5.1)]
• Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see Warnings and Precautions (5.2)]
• Seizure [see Warnings and Precautions (5.3)]
• Hypertension [see Warnings and Precautions (5.4)]
• Activation of mania or hypomania [see Warnings and Precautions (5.5)]
• Psychosis and other neuropsychiatric reactions [see Warnings and Precautions (5.6)]
• Angle-closure glaucoma [see Warnings and Precautions (5.7)]
• Hypersensitivity reactions [see Warnings and Precautions (5.8)]

Clinical Trials Experience

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

Adverse Reactions Leading to Discontinuation of Treatment
In placebo-controlled clinical trials, 4%, 9%, and 11% of the placebo, 300 mg per day, and 400 mg per day groups, respectively, discontinued treatment due to adverse reactions. The specific adverse reactions leading to discontinuation in at least 1% of the 300 mg per day or 400 mg per day groups and at a rate at least twice the placebo rate are listed in Table 2. 

Commonly Observed Adverse Reactions
Adverse reactions from Table 3 occurring in at least 5% of subjects treated with Bupropion hydrochloride extended-release tablets (SR) and at a rate at least twice the placebo rate are listed below for the 300 and 400 mg per day dose groups.

Bupropion hydrochloride extended-release tablets, USP (SR) 300 mg per day: Anorexia, dry mouth, rash, sweating, tinnitus, and tremor.

Bupropion hydrochloride extended-release tablets, USP (SR) 400 mg per day: Abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency.

Adverse reactions reported in placebo-controlled trials are presented in Table 3. Reported adverse reactions were classified using a COSTART-based Dictionary.

Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of subjects.

Other Adverse Reactions Observed during the Clinical Development of Bupropion
In addition to the adverse reactions noted above, the following adverse reactions have been reported in clinical trials with the sustained-release formulation of Bupropion in depressed subjects and in nondepressed smokers, as well as in clinical trials with the immediate-release formulation of Bupropion.

Adverse reaction frequencies represent the proportion of subjects who experienced a treatment-emergent adverse reaction on at least one occasion in placebo-controlled trials for depression (n = 987) or smoking cessation (n = 1,013), or subjects who experienced an adverse reaction requiring discontinuation of treatment in an open-label surveillance trial with Bupropion hydrochloride extended-release tablets (SR)(n = 3,100). All treatment-emergent adverse reactions are included except those listed in Table 3, those listed in other safety-related sections of the prescribing information, those subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those not reasonably associated with the use of the drug, and those that were not serious and occurred in fewer than 2 subjects.

Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions of frequency: Frequent adverse reactions are defined as those occurring in at least 1/100 subjects. Infrequent adverse reactions are those occurring in 1/100 to 1/1,000 subjects, while rare events are those occurring in less than 1/1,000 subjects.

Body (General): Infrequent were chills, facial edema, and photosensitivity. Rare was malaise.

Cardiovascular:  Infrequent were postural hypotension, stroke, tachycardia, and vasodilation. Rare were syncope and myocardial infarction.

Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of tongue.

Hemic and Lymphatic: Infrequent was ecchymosis.

Metabolic and Nutritional: Infrequent were edema and peripheral edema.

Musculoskeletal: Infrequent were leg cramps.

Nervous System: Infrequent were abnormal coordination, decreased libido, depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia, suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania.

Respiratory: Rare was bronchospasm.

Special Senses: Infrequent were accommodation abnormality and dry eye.

Urogenital: Infrequent were impotence, polyuria, and prostate disorder.

Changes in Body Weight
In placebo-controlled trials, subjects experienced weight gain or weight loss as shown in Table 4.

In clinical trials conducted with the immediate-release formulation of Bupropion, 35% of subjects receiving tricyclic antidepressants gained weight, compared with 9% of subjects 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.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Bupropion hydrochloride extended-release tablets (SR) and are not described elsewhere in the label. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body (General)
Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness [see Warnings and Precautions (5.8)].

Cardiovascular
Complete atrioventricular block, extrasystoles, hypotension, hypertension (in some cases severe), phlebitis, and pulmonary embolism.

Digestive
Colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, pancreatitis, and stomach ulcer.

Endocrine
Hyperglycemia, hypoglycemia, hyponatremia, and syndrome of inappropriate antidiuretic hormone secretion.

Hemic and Lymphatic
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
Glycosuria.

Musculoskeletal
Muscle rigidity/fever/rhabdomyolysis and muscle weakness.

Nervous System
Abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, completed suicide, delirium, delusions, dysarthria, euphoria, extrapyramidal syndrome (dyskinesia, dystonia, hypokinesia, parkinsonism), hallucinations, increased libido, manic reaction, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.

Respiratory
Pneumonia.

Skin
Alopecia, angioedema, exfoliative dermatitis, hirsutism, and Stevens-Johnson syndrome.

Special Senses
Deafness, increased intraocular pressure, and mydriasis.

Urogenital
Abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.

Potential for Other Drugs to Affect Bupropion Hydrochloride Extended-Release Tablets(SR)

Bupropion is primarily metabolized to hydroxyBupropion by CYP2B6. Therefore, the potential exists for drug interactions between Bupropion hydrochloride extended-release tablets (SR) and drugs that are inhibitors or inducers of CYP2B6.

Inhibitors of CYP2B6
Ticlopidine and Clopidogrel:  Concomitant treatment with these drugs can increase Bupropion exposure but decrease hydroxyBupropion exposure. Based on clinical response, dosage adjustment of Bupropion hydrochloride extended-release tablets (SR) may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see Clinical Pharmacology (12.3)].

Inducers of CYP2B6
Ritonavir, Lopinavir, and Efavirenz:  Concomitant treatment with these drugs can decrease Bupropion and hydroxyBupropion exposure. Dosage increase of Bupropion hydrochloride extended-release tablets (SR) may be necessary when coadministered with ritonavir, lopinavir, or efavirenz [see Clinical Pharmacology (12.3)] but should not exceed the maximum recommended dose.

Carbamazepine, Phenobarbital, Phenytoin:  While not systematically studied, these drugs may induce the metabolism of Bupropion and may decrease Bupropion exposure [see Clinical Pharmacology (12.3)]. If Bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of Bupropion, but the maximum recommended dose should not be exceeded.

Potential for Bupropion Hydrochloride Extended-Release Tablets(SR) to Affect Other Drugs

Drugs Metabolized by CYP2D6

Bupropion and its metabolites (erythrohydroBupropion, threohydroBupropion, hydroxyBupropion) are CYP2D6 inhibitors. Therefore, coadministration of Bupropion hydrochloride extended-release tablets (SR) with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). When used concomitantly with Bupropion hydrochloride extended-release tablets (SR), it may be necessary to decrease the dose of these CYP2D6 substrates, particularly for drugs with a narrow therapeutic index.

Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen) theoretically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as Bupropion. Patients treated concomitantly with Bupropion hydrochloride extended-release tablets (SR) and such drugs may require increased doses of the drug [see Clinical Pharmacology (12.3)].

Digoxin

Coadministration of Bupropion hydrochloride extended-release tablets (SR) with digoxin may decrease plasma digoxin levels. Monitor plasma digoxin levels in patients treated concomitantly with Bupropion hydrochloride extended-release tablets (SR) and digoxin [see Clinical Pharmacology (12.3)].

Drugs that Lower Seizure Threshold

Use extreme caution when coadministering Bupropion hydrochloride extended-release tablets (SR)with other drugs that lower seizure threshold (e.g., other Bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses and increase the dose gradually [see Contraindications (4),Warnings and Precautions (5.3)].

Dopaminergic Drugs (Levodopa and Amantadine)

Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has been reported when Bupropion was coadministered with levodopa or amantadine. Adverse reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use caution when administering Bupropion hydrochloride extended-release tablets (SR) concomitantly with these drugs.

Use with Alcohol

In postmarketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with Bupropion hydrochloride extended-release tablets (SR). The consumption of alcohol during treatment with Bupropion hydrochloride extended-release tablets (SR) should be minimized or avoided.

MAO Inhibitors

Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of MAOIs and Bupropion is contraindicated because there is an increased risk of hypertensive reactions if Bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that the acute toxicity of Bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of treatment with Bupropion hydrochloride extended-release tablets (SR). Conversely, at least 14 days should be allowed after stopping Bupropion hydrochloride extended-release tablets (SR) before starting an MAOI antidepressant [see Dosage and Administration (2.4,2.5), Contraindications(4)].

Drug-Laboratory Test Interactions

False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking Bupropion. This is due to lack of specificity of some screening tests. False-positive test results may result even following discontinuation of Bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish Bupropion from amphetamines.

Controlled Substance

Bupropion is not a controlled substance.

Abuse

Humans
Controlled clinical trials conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed subjects showed some increase in motor activity and agitation/excitement, often typical of central stimulant activity.

In a population of individuals experienced with drugs of abuse, a single oral dose of 400 mg of Bupropion produced mild amphetamine-like activity as compared with placebo on the Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a score greater than placebo but less than 15 mg of the Schedule II stimulant dextroamphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug liking which are often associated with abuse potential.

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

Bupropion hydrochloride extended-release tablets (SR) are intended for oral use only. The inhalation of crushed tablets or injection of dissolved Bupropion has been reported. Seizures and/or cases of death have been reported when Bupropion has been administered intranasally or by parenteral injection.

Animals
Studies in rodents and primates demonstrated that Bupropion exhibits some pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase locomotor activity, elicit a mild stereotyped behavior response, and increase rates of responding in several schedule-controlled behavior paradigms. In primate models assessing the positive-reinforcing effects of psychoactive drugs, Bupropion was self-administered intravenously. In rats, Bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs.

The efficacy of the immediate-release formulation of Bupropion in the treatment of major depressive disorder was established in two 4-week, placebo-controlled trials in adult inpatients with MDD (Trials 1 and 2 in Table 6) and in one 6-week, placebo-controlled trial in adult outpatients with MDD (Trial 3 in Table 6). In the first trial, the dose range of Bupropion was 300 mg to 600 mg per day administered in divided doses; 78% of subjects were treated with doses of 300 mg to 450 mg per day. This trial demonstrated the effectiveness of the immediate-release formulation of Bupropion by the Hamilton Depression Rating Scale (HDRS) total score, the HDRS depressed mood item (Item 1), and the Clinical Global Impressions severity score (CGI-S). The second trial included 2 doses of the immediate-release formulation of Bupropion (300 and 450 mg per day) and placebo. This trial demonstrated the effectiveness of the immediate-release formulation of Bupropion, but only at the 450 mg per day dose. The efficacy results were significant for the HDRS total score and the CGI-S score, but not for HDRS Item 1. In the third trial, outpatients were treated with 300 mg per day of the immediate-release formulation of Bupropion. This trial demonstrated the efficacy of the immediate-release formulation of Bupropion as measured by the HDRS total score, the HDRS Item 1, the Montgomery-Asberg Depression Rating Scale (MADRS), the CGI-S score, and the CGI-Improvement Scale (CGI-I) score.

n: sample size; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval included for doses that were demonstrated to be effective; NA: not available.

Although there are not as yet independent trials demonstrating the antidepressant effectiveness of the sustained-release formulation of Bupropion, trials have demonstrated the bioequivalence of the immediate-release and sustained-release forms of Bupropion under steady-state conditions, i.e., Bupropion sustained-release 150 mg twice daily was shown to be bioequivalent to 100 mg 3 times daily of the immediate-release formulation of Bupropion, with regard to both rate and extent of absorption, for parent drug and metabolites.

In a longer-term trial, outpatients meeting DSM-IV criteria for major depressive disorder, recurrent type, who had responded during an 8-week open trial on Bupropion hydrochloride extended-release tablets (SR) (150 mg twice daily) were randomized to continuation of their same dose of Bupropion hydrochloride extended-release tablets (SR) or placebo for up to 44 weeks of observation for relapse. Response during the open phase was defined as CGI Improvement score of 1 (very much improved) or 2 (much improved) for each of the final 3 weeks. Relapse during the double-blind phase was defined as the investigator’s judgment that drug treatment was needed for worsening depressive symptoms. Patients receiving continued treatment with Bupropion hydrochloride extended-release tablets (SR) experienced significantly lower relapse rates over the subsequent 44 weeks compared with those receiving placebo.

NDC 47335-736-86
Bupropion Hydrochloride Extended-release Tablets, USP (SR)
100 mg
Twice-A-Day
Warning: Do not use in combination with ZYBAN®, or any other medicines that contain Bupropion hydrochloride.
Rx only
60 Tablets
SUN PHARMA
PHARMACIST: Please dispense with Medication Guide provided separately to each patient.

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral, as hydrochloride:

Wellbutrin: 75 mg [DSC], 100 mg [DSC]

Generic: 75 mg, 100 mg

Tablet Extended Release 12 Hour, Oral, as hydrochloride:

Budeprion SR: 100 mg [DSC] [contains tartrazine (fd&c yellow #5)]

Budeprion SR: 150 mg [DSC]

Buproban: 150 mg [DSC]

Wellbutrin SR: 100 mg, 150 mg, 200 mg

Zyban: 150 mg

Generic: 100 mg, 150 mg, 200 mg

Tablet Extended Release 24 Hour, Oral, as hydrobromide:

Aplenzin: 174 mg, 348 mg, 522 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

Forfivo XL: 450 mg

Wellbutrin XL: 150 mg, 300 mg

Generic: 150 mg, 300 mg

Major depressive disorder (Aplenzin, Bupropion immediate release, Forfivo XL, Wellbutrin SR, Wellbutrin XL): Treatment of major depressive disorder (MDD).

Seasonal affective disorder (Aplenzin, Wellbutrin XL): Prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder (SAD).

Smoking cessation (Zyban): As an aid to smoking cessation treatment.

You should not take bupropion if you have seizures or an eating disorder, or if you have suddenly stopped using alcohol, seizure medication, or sedatives. If you take Wellbutrin for depression, do not also take Zyban to quit smoking.

Do not use bupropion within 14 days before or 14 days after you have used a MAO inhibitor, such as isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, or tranylcypromine.

Some young people have thoughts about suicide when first taking an antidepressant. Stay alert to changes in your mood or symptoms. Report any new or worsening symptoms to your doctor.

Bupropion may cause seizures, especially in people with certain medical conditions or when using certain drugs. Tell your doctor about all of your medical conditions and the drugs you use.

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

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

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

Call your doctor at once if you have:

• a seizure (convulsions);

• unusual changes in mood or behavior;

• a manic episode - racing thoughts, increased energy, reckless behavior, feeling extremely happy or irritable, talking more than usual, severe problems with sleep;

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

• fast heartbeats; or

• severe skin reaction, fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common bupropion side effects may include:

• dry mouth, stuffy nose;

• nausea, constipation;

• sleep problems (insomnia);

• feeling anxious;

• dizziness; or

• joint pain.

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

Usual Adult Dose for Depression:

Immediate release tablets:
Initial dose: 100 mg orally twice a day.
Maintenance dose: The dosage may be increased in 75 to 100 mg/day increments not more often than every 3 days up to the usual maintenance dose of 100 mg orally 3 times a day. The maximum dose is 450 mg/day, given in 4 divided doses; bupropion should be discontinued if there is not an adequate response to this dose. Single doses should not exceed 150 mg.

Sustained release tablets:
Initial dose: 150 mg orally once a day in the morning.
Maintenance dose: After at least 4 days, the dose may be increased to 100 to 150 mg twice a day. If there is not adequate improvement after several weeks, the dose may be increased to a maximum of 200 mg twice a day.

Extended release tablets (Wellbutrin XL):
Initial dose: 150 mg orally once a day in the morning.
Maintenance dose: After at least 4 days, the dose may be increased to 300 mg once a day. If there is not adequate improvement after several weeks, the dose may be increased to a maximum of 450 mg once a day in the morning.

Extended release tablets (Aplenzin):
Initial dose: 174 mg orally once a day in the morning (equivalent to 150 mg bupropion HCl).
Maintenance dose: After at least 4 days, the dose may be increased to 348 mg once a day (equivalent to 300 mg bupropion HCl). If there is not adequate improvement after several weeks, the dose may be increased to a maximum of 522 mg once a day in the morning (equivalent to 450 mg bupropion HCl).

Usual Adult Dose for Seasonal Affective Disorder:

Initiate treatment for seasonal affective disorder in the autumn prior to onset of symptoms.

Wellbutrin XL (R):
Initial: 150 mg orally once a day in the morning
Titration: If tolerated, after 7 days dose may be increased to maximum dose of 300 mg once a day administered in the morning. Patients who are unable to tolerate this increase in dose should be reduced back to 150 mg orally once a day.

Aplenzin (R):
Initial: 174 mg once daily (equivalent to 150 mg bupropion) in the morning
Titration: If tolerated, after 7 days dose may be increased to 348 mg once daily (equivalent to 300 mg bupropion) in the morning through the winter season.

Usual Adult Dose for Smoking Cessation:

Initial Dose: 150 mg orally once a day.
Maintenance: Based on clinical response, this dosage may be increased to 300 mg/day, given as 150 mg twice a day, no sooner than 3 days after beginning therapy.

Commonly reported side effects of bupropion include: insomnia, nausea, pharyngitis, weight loss, constipation, dizziness, headache, and xerostomia. Other side effects include: abdominal pain, agitation, arthralgia, chest pain, migraine, skin rash, urinary frequency, anxiety, asthenia, confusion, diarrhea, hostility, hypertension, lack of concentration, myalgia, nervousness, palpitations, pruritus, tinnitus, tremor, vomiting, anorexia, diaphoresis, dysgeusia, flushing, and abnormal dreams. See below for a comprehensive list of adverse effects.

Bupropion hydrochloride:
Extended-release tablets (Wellbutrin XL (R)):
Initial dose: 150 mg orally once a day in the morning, increased if necessary after 7 days to 300 mg orally once a day
Maintenance dose: 150 to 300 mg orally once a day
Maximum dose: 300 mg orally once a day

Bupropion hydrobromide:
Extended-release tablets (Aplenzin (R)):
Initial dose: 174 mg orally once a day, increased if necessary after 7 days to 348 mg orally once a day
Maintenance dose: 348 mg orally once a day
Maximum dose: 348 mg orally once a day

Comments:
-Treatment should be initiated in the autumn prior to the onset of depressive symptoms, continued through the winter season, and discontinued in early spring.
-If bupropion hydrochloride (Wellbutrin (R)) 300 mg orally per day is not tolerated, it should be reduced to 150 mg once a day.
-Patients taking bupropion hydrochloride 300 mg orally per day during the autumn-winter season should have their dose tapered to 150 mg once a day for 2 weeks prior to discontinuation.
-When discontinuing bupropion hydrobromide (Aplenzin (R)) in patients treated with 348 mg orally once a day, the dose should be reduced to 174 mg once a day prior to discontinuation.
-The timing of initiation and treatment duration for seasonal affective disorder should be individualized according to the patient's historical pattern of seasonal major depressive episodes.

-Dose adjustments should be made gradually to minimize the risk of seizure.
-Consider reducing the dose and/or frequency in elderly patients.
-Dose adjustment may be necessary when bupropion is coadministered with CYP450 2B6 inhibitors.
-Dosage increase of bupropion may be necessary when coadministered with ritonavir, lopinavir, or efavirenz.
-If bupropion is used concomitantly with a CYP450 inducer, it may be necessary to increase the dose of bupropion.

• Bupropion is an antidepressant that may also be used to help people quit smoking.
• Experts aren't exactly sure how bupropion works in depression but presume it is due to its ability to inhibit the reuptake of two neurotransmitters, norepinephrine, and dopamine (although this reuptake inhibition is weak). Bupropion does not affect the reuptake of serotonin or inhibit monoamine oxidase.
• Bupropion is thought to be effective for smoking cessation because of its ability to increase dopamine levels in the nerve synapse by inhibiting the reuptake of dopamine. This replaces the dopamine deficiency experienced during nicotine withdrawal (nicotine causes a release of dopamine which enhances the pleasure-seeking pathways in the brain; reducing nicotine intake means these pathways are no longer being stimulated; bupropion counteracts this effect).
• Bupropion is an aminoketone antidepressant and is chemically unrelated to any other type of antidepressant.