1. WELLBUTRIN SR HISTORY

How was Wellbutrin SR discovered?
Wellbutrin SR is a product of GlaxoSmithKline (GSK) Pharmaceuticals.

GlaxoSmithKline (GSK) is a world leading research-based pharmaceutical company. Glaxo is headquartered in the UK and with operations based in the US; the new company is one of the industry leaders, with an estimated seven per cent of the world's pharmaceutical market.

GSK also has leadership in four major therapeutic areas - anti-infectives, central nervous system (CNS), respiratory and gastro-intestinal/metabolic. In addition, it is a leader in the important area of vaccines and has a growing portfolio of oncology products.

Glaxo also has a Consumer Healthcare portfolio comprising over-the-counter (OTC) medicines; oral care products and nutritional healthcare drinks, all of which are among the market leaders.

Note: World-drugs.net sells generic version of Wellbutrin SR

2. WELLBUTRIN SR FACTS

Wellbutrin SR (Bupropion) belongs to the family of medications known as antidepressants.

Wellbutrin SR is used for the treatment of depression and as an aid for quitting smoking.

Wellbutrin SR works by affecting the balance of chemicals that occur naturally in the brain. For the treatment of depression, the full effects of Wellbutrin SR may not be seen until after several weeks of treatment.

3. ABOUT WELLBUTRIN SR MEDICATION

Wellbutrin SR , a relatively new antidepressant medication, is given to help relieve certain kinds of major depression.

Major depression involves a severely depressed mood (for 2 weeks or more) and loss of interest or pleasure in usual activities accompanied by sleep and appetite disturbances, agitation or lack of energy, feelings of guilt or worthlessness, decreased sex drive, inability to concentrate, and perhaps thoughts of suicide.

Wellbutrin SR contains the active ingredient bupropion hydrochloride, which is a medicine used to help people who are dependant on nicotine to give up smoking. Wellbutrin SR acts in the brain but is not the same as nicotine replacement therapy.

It is not fully understood how Wellbutrin SR works to help people give up smoking, but it is known that bupropion affects neurotransmitters in the brain. Neurotransmitters are chemicals that are stored in nerve cells and are involved in transmitting messages between the nerve cells.

Neurotransmitters are released from nerve cells as a message is transmitted. Once the message has been transmitted, the nerve cells then reabsorb the neurotransmitter.

Wellbutrin SR prevents two of these neurotransmitters, noradrenaline and dopamine, from being reabsorbed back into the nerve cells. Noradrenaline and dopamine are responsible for moderating mood and various other processes in the brain. It is thought that bupropion helps people to quit smoking by increasing the amount of noradrenaline and dopamine free to act in the brain.

Wellbutrin SR is used in combination with motivational support techniques. You should seek help and support as much as possible while giving up smoking, even while taking Wellbutrin SR, as this will increase your chance of success.

You should start taking Wellbutrin SR while you are still smoking and set a 'target stop date' for within the first two weeks of treatment, preferably in the first week. This is because Wellbutrin SR needs time to start working.

4. WELLBUTRIN SR EFFECTIVENESS
When is Wellbutrin SR best taken?

Absorption: Following oral administration of Wellbutrin SR Tablets to healthy volunteers, peak plasma concentrations of bupropion are achieved within 3 hours. Food increased C max and AUC of bupropion by 11% and 17%, respectively, indicating that there is no clinically significant food effect.

Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for Wellbutrin SR, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion.

Metabolism : Wellbutrin SR is extensively metabolized in humans. Three metabolites have been shown to be active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to Wellbutrin SR have not been fully characterized. However, it has been demonstrated in an antidepressant-screening test in mice that hydroxybupropion is one half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high or higher than those of bupropion.

Because Wellbutrin SR is extensively metabolized, there is the potential for drug-drug interactions, particularly with those agents that are metabolized by the cytochrome P450IIB6 (CYP2B6) isoenzyme. Although Wellbutrin SR is not metabolized by cytochrome P450IID6 (CYP2D6), there is the potential for drug-drug interactions when Wellbutrin SR is co-administered with drugs metabolized by this isoenzyme.

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

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

Elimination : Following oral administration of 150 mg of Wellbutrin SR in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of Wellbutrin SR excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of Wellbutrin SR.

5. WELLBUTRIN SR EFFECTS ON SPECIAL POPULATION
How do different people react to Wellbutrin SR?

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

Pediatric Use : The safety and effectiveness of Wellbutrin SR Tablets in pediatric patients below 18 years old have not been established. The immediate-release formulation of Wellbutrin SR was studied in 104 pediatric patients (age range, 6 to 16) in clinical trials of the drug for other indications. Although generally well tolerated, the limited exposure is insufficient to assess the safety of Wellbutrin SR in pediatric patients.

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

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

Wellbutrin SR is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of toxic reaction to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

6. WELLBUTRIN SR EFFECTS ON MEDICAL CONDITIONS
How does Wellbutrin SR affect your existing condition/ailment?

Agitation and Insomnia : Patients in placebo-controlled trials with Wellbutrin SR Tablets experienced agitation, anxiety, and insomnia as shown in the table below.

Incidence of Agitation, Anxiety, and Insomnia in Placebo-Controlled Trials
Adverse Event Term	WELLBUTRIN SR 300 mg/day (n = 376)	WELLBUTRIN SR 400 mg/day (n = 114)	Placebo (n = 385)
Agitation	3%	9%	2%
Anxiety	5%	6%	3%
Insomnia	11%	16%	6%

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

Symptoms were sufficiently severe to require discontinuation of treatment in 1% and 2.6% of patients treated with 300 and 400 mg/day, respectively, of Wellbutrin SR Tablets and 0.8% of patients treated with placebo.

Psychosis, Confusion, and Other Neuropsychiatric Phenomena : Depressed patients treated with an immediate-release formulation of Wellbutrin SR Tablets have been reported to show a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment.

Activation of Psychosis and/or Mania : Antidepressants can precipitate manic episodes in bipolar disorder patients during the depressed phase of their illness and may activate latent psychosis in other susceptible patients. Wellbutrin SR is expected to pose similar risks.

Altered Appetite and Weight : In placebo-controlled studies, patients experienced weight gain or weight loss as shown in the table below.

Incidence of Weight Gain and Weight Loss in Placebo-Controlled Trials
Weight Change	WELLBUTRIN SR 300 mg/day (n = 339)	WELLBUTRIN SR 400 mg/day (n = 112)	Placebo (n = 347)
Gained  >5 lbs	3%	2%	4%
Lost >5 lbs	14%	19%	6%

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

Suicide: The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Accordingly, prescriptions for WELLBUTRIN SR Tablets should be written for the smallest number of tablets consistent with good patient management.

Allergic Reactions : Anaphylactoid/anaphylactic reactions characterized by symptoms such as pruritus, urticaria, angioedema, and dyspneas requiring medical treatment have been reported in clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. A patient should stop taking Wellbutrin SR and consult a doctor if experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment.

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

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

Hepatic Impairment: Wellbutrin SR should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients, a reduced frequency and/or dose is required. Wellbutrin SR should be used with caution in patients with hepatic impairment (including mild to moderate hepatic cirrhosis) and reduced frequency and/or dose should be considered in patients with mild to moderate hepatic cirrhosis.

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

Renal Impairment : No studies have been conducted in patients with renal impairment. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. Wellbutrin SR should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered as bupropion and its metabolites may accumulate in such patients to a greater extent than usual. The patient should be closely monitored for possible adverse effects that could indicate high drug or metabolite levels.

7. OTHER/ALTERNATE USES OF WELLBUTRIN SR
What else does Wellbutrin SR treat?

Wellbutrin SR is used for the treatment of depression and as an aid for quitting smoking.

8. ADVERSE/SIDE EFFECTS of WELLBUTRIN SR
What are the side effects of Wellbutrin SR?

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

Adverse events were sufficiently troublesome to cause discontinuation of treatment with Wellbutrin SR in approximately ten percent of the 2400 patients and volunteers who participated in clinical trials during the product's initial development. The more common events causing discontinuation include neuropsychiatric disturbances (3.0%), primarily agitation and abnormalities in mental status; gastrointestinal disturbances (2.1%), primarily nausea and vomiting; neurological disturbances (1.7%), primarily seizures, headaches, and sleep disturbances; and dermatologic problems (1.4%), primarily rashes. It is important to note, however, that many of these events occurred at doses that exceed the recommended daily dose.

Accurate estimates of the incidence of adverse events associated with the use of any drug are difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician judgments, etc. Consequently, the table below is presented solely to indicate the relative frequency of adverse events reported in representative controlled clinical studies conducted to evaluate the safety and efficacy of Wellbutrin SR under relatively similar conditions of daily dosage (300 to 600 mg), setting, and duration (3 to 4 weeks). The figures cited cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors must differ from those, which prevailed in the clinical trials. These incidence figures also cannot be compared with those obtained from other clinical studies involving related drug products as each group of drug trials is conducted under a different set of conditions.

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

TREATMENT EMERGENT ADVERSE EXPERIENCE INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS (Percent of Patients Reporting)
Adverse Experience	Wellbutrin SR (n=323)	Placebo Patients (n=185)
CARDIOVASCULAR
Cardiac Arrhythmias	5.3	4.3
Dizziness	22.3	16.2
Hypertension	4.3	1.6
Hypotension	2.5	2.2
Palpitations	3.7	2.2
Syncope	1.2	0.5
Tachycardia	10.8	8.6
DERMATOLOGIC
Pruritus	2.2	0.0
Rash	8.0	6.5
GASTROINTESTINAL
Anorexia	18.3	18.4
Appetite increase	3.7	2.2
Constipation	26.0	17.3
Diarrhea	6.8	8.6
Dyspepsia	3.1	2.2
Nausea/Vomiting	22.9	18.9
Weight Gain	13.6	22.7
Weight Loss	23.2	23.2
GENITOURINARY
Impotence	3.4	3.1
Menstrual Complaints	4.7	1.1
Urinary Frequency	2.5	2.2
Urinary Retention	1.9	2.2
MUSCULOSKELETAL
Arthritis	3.1	2.7
NEUROLOGICAL
Akathisia	1.5	1.1
Akinesia/Bradykinesia	8.0	8.6
Cutaneous Temperature Disturbance	1.9	1.6
Dry Mouth	27.6	18.4
Excessive Sweating	22.3	14.6
Headache/Migraine	25.7	22.2
Impaired Sleep Quality	4.0	1.6
Increased Salivary Flow	3.4	3.8
Insomnia	18.6	15.7
Muscle Spasms	1.9	3.2
Pseudoparkinsonism	1.5	1.6
Sedation	19.8	19.5
Sensory Disturbance	4.0	3.2
Tremor	21.1	7.6
NEUROPSYCHIATRIC
Agitation	31.9	22.2
Anxiety	3.1	1.1
Confusion	8.4	4.9
Decreased Libido	3.1	1.6
Delusions	1.2	1.1
Disturbed concentration	3.1	3.8
Euphoria	1.2	0.5
Hostility	5.6	3.8
NONSPECIFIC
Fatigue	5.0	8.6
Fever/Chills	1.2	0.5
RESPIRATORY
Upper Respiratory Complaints	5.0	11.4
SPECIAL SENSES
Auditory Disturbance	5.3	3.2
Blurred Vision	14.6	10.3
Gustatory Disturbance	3.1	1.1

Other Events Observed During the Development of Bupropion:

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

The following definitions of frequency are used: Frequent adverse events are defined as those occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1000 patients, while rare events are those occurring in less than 1/1000 patients.

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

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

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

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

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

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

Musculoskeletal : Rare was musculoskeletal chest pain.

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

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

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

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

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

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

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

Cardiovascular : orthostatic hypotension, third degree heart block

Endocrine : syndrome of inappropriate antidiuretic hormone secretion

Gastrointestinal : esophagitis, hepatitis

Hemic and Lymphatic : ecchymosis, leukocytosis, leukopenia

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

Nervous : coma, delirium, dream abnormalities, paresthesia, unmasking of tardive dyskinesia

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

Special Senses : tinnitus