Archived - Important Drug Warning - ZYBAN® - GlaxoSmithKline

Important drug safety information

GlaxoSmithKline
7333 Mississauga Road
North Mississauga, Ontario
Canada
L5N 6L4

Tel. 905 819 3000
Fax. 905 819 3099
www.gsk.com

July 3, 2001

Dear Health Professional(s),

This letter is being sent out following agreement with Health Canada. GlaxoSmithKline would like to inform you of important safety information regarding bupropion (ZYBAN® and WELLBUTRIN® SR). ZYBAN® is indicated for smoking cessation treatment in conjunction with behavioural modification. WELLBUTRIN® SR is indicated for the symptomatic relief of depressive illness. GlaxoSmithKline is also aware that, WELLBUTRIN® SR is being prescribed in some patients for the non-indicated use of smoking cessation treatment.

As of April 30, 2001, there have been an estimated 1,245,000 patients prescribed ZYBAN® since it became available in Canada in August 1998 and an estimated 699,000 patients prescribed WELLBUTRIN® SR since it was approved for market in May 1998. The Canadian Adverse Reaction Monitoring Programme (CADRMP) has received a total of 1127 reports of suspected adverse reactions associated with the use of bupropion, as of May 28, 2001. Where the report did not specify the brand name, it is listed as "bupropion". Of these reports, 682 (ZYBAN®: 573, WELLBUTRIN® SR: 88, bupropion: 21) were considered 'serious', and 19 (ZYBAN®: 12, WELLBUTRIN® SR: 5, bupropion: 2) had a fatal outcome, 172 (ZYBAN®: 120, WELLBUTRIN® SR: 46, bupropion: 6) involved seizures/convulsions, and 37 (ZYBAN®: 36, WELLBUTRIN® SR: 1) were reports of serum sickness/serum sickness-like reactions. Of the cases of fatal outcome, there was 1 case of liver failure (WELLBUTRIN® SR), 1 case of myocarditis (ZYBAN®) and 3 cases of suicide (2 ZYBAN®, 1 bupropion). Cause and effect relationships have not been established or speculated in the vast majority of reports submitted. Not all suspected reactions are reported to the CADRMP and consequently this information should not be used to estimate the incidence of adverse reactions.

Most of the information summarized below is currently in our approved Product Monographs for ZYBAN® and WELLBUTRIN® SR. However, to ensure physicians are prescribing bupropion optimally, please note the following important safety information:

To reduce the risk of seizures, bupropion is contraindicated in patients

• with a current seizure disorder
• with a current or prior diagnosis of bulimia or anorexia nervosa
• using another medication containing bupropion (e.g. ZYBAN, an anti-smoking aid; WELLBUTRIN SR, an antidepressant)
• undergoing abrupt withdrawal from alcohol or benzodiazepines or other sedatives
• with known hypersensitivity to bupropion

To reduce risks due to drug interactions, the concomitant use of bupropion is contraindicated in patients currently taking

• monoamine oxidase inhibitors (MAOIs)
• the antipsychotic thioridazine, since bupropion may inhibit thioridazine metabolism, thus causing an increase in thioridazine levels and a potential increased risk of thioridazine-related serious ventricular arrhythmias and sudden death

In all cases, at least 14 days should elapse between discontinuation of one drug and the start of the other.

Related to the risk of seizures

Bupropion is associated with a dose related risk of seizures. Therefore, the recommended maximum dose of bupropion (300 mg/day) must not be exceeded, and no single dose should exceed 150 mg.

The seizure rate associated with doses of sustained-release bupropion up to 300 mg/day is approximately 1 in 1000.

Patients should be warned to see a clinician immediately if a seizure occurs, and to stop taking bupropion. Treatment with bupropion should not be restarted.

There is also an increased risk of seizures occurring in the presence of factors which lower the seizure threshold. Bupropion should be used with extreme caution, when treating patients with such risk factors, which include:

• history of head trauma or prior seizure
• central nervous system tumor
• concomitant medications known to lower seizure threshold, including but not limited to: antidepressants, antipsychotics, theophylline, systemic steroids, quinolone antibiotics, and antimalarials
• excessive use of alcohol
• diabetes treated with hypoglycemics or insulin
• use of over the counter stimulants or anorectics
• addiction to opiates, cocaine, or stimulants

The above list of risk factors, including medications, should not be considered exhaustive; for each patient, all potential predisposing factors must be carefully considered.

Related to risks for patients with hepatic impairment

Bupropion is not recommended for use in patients with severe hepatic impairment. Should clinical judgement deem use of bupropion necessary in these patients, the drug should be used with a reduced dose and extreme caution.

Related to risks of serious allergic reactions

Anaphylactoid/anaphylactic reactions characterized by symptoms such as pruritus, urticaria, angioedema, and dyspnea have been reported at a rate of one to three per thousand in clinical trials. 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 bupropion and consult a doctor if experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritis, hives, chest pain, edema, and shortness of breath) during treatment.

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

Bupropion should be discontinued immediately if any hypersensitivity reactions are experienced. Symptoms of hypersensitivity reactions should be treated in accordance with established medical practice.

Drug Interactions

As many patients who are prescribed bupropion may be using other medications, the attached table provides a summary of potential drug interactions with bupropion and their management.

GlaxoSmithKline routinely assesses safety information as it becomes available and updates Product Monographs accordingly. Changes will be made to the Product Monographs to reflect the above information. Revised prescribing information and patient information will be distributed to you once approved by Health Canada.

The identification, characterization, and management of drug-related adverse events are dependent on the active participation of health care professionals in adverse drug reaction reporting programmes. Health care professionals are asked to report any suspected adverse reactions in patients receiving bupropion (ZYBAN® and WELLBUTRIN® SR) directly to GlaxoSmithKline or to the Bureau of Licensed Product Assessment:

GlaxoSmithKline Inc.
7333 Mississauga Road N
Mississauga, Ontario
L5N 6L4
Tel: 1-800-387-7374

Your professional commitment in this regard has an important role in protecting the well-being of your patients by contributing to early signal detection and informed drug use.

Any questions from health care professionals may be directed to our Medical Information department via GlaxoSmithKline Customer Service at 1-800-387-7374.

Sincerely,

original signed by

Ravinder Kumar, Ph.D.
Vice-President, Regulatory Affairs & Pharmaceutical Development
GlaxoSmithKline Inc.

Any suspected adverse drug reactions can also be reported to:

Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
Bureau of Licensed Product Assessment
Therapeutic Products Directorate
Health Canada
Address Locator: 0201C2
Ottawa, Ontario, K1A 1B9
Tel: (613) 957-0337 or Fax: (613) 957-0335
cadrmp@hc-sc.gc.ca

The ADR Reporting Form can be found in The Canadian Compendium of Pharmaceuticals and Specialties, or on the TPD website, along with the ADR Guidelines.