Tougher Warnings About Quit-Smoking Drug

Drug regulators in the United Kingdom have asked the makers of Zyban (bupropion) — the world’s most widely-used anti-smoking medication — to step up warnings that physicians should be very careful when they prescribe it. Their concern includes reports of side effects and an unknown number of deaths.

A British Airways stewardess who had been taking Zyban died in January of an epileptic seizure. She had also been taking an antimalarial drug and sleeping pills, and had a history of seizures about which she had not told her doctor. Her death, however, touched off a media flap, and as a result, the British Committee on the Safety of Medicines (CSM) took steps this week to control the use of the medicine more tightly.

Zyban is also sold as the antidepressant Wellbutrin. It was approved for use in smoking cessation in the U.S. in May of 1997, and in the UK in June of 2000. Used by itself or along with nicotine replacement therapy, it has helped a high percentage of its millions of users to quit smoking successfully.

A BBC news report said the drug had been prescribed for 419,000 people in the first 10 months of its use in the UK, and since then 5,352 adverse reactions, including 38 deaths, had been reported. However, the chairman of the CSM, Alasdair Breckenridge, noted that this was a relatively small percentage. About 2 percent of adverse reports for all medicines involve a fatal outcome, he said, while for Zyban the proportion reported was only 1 percent.

Doubt has been cast on the 38 deaths figure. A spokesman for the UK Action on Smoking and Health said he believed many of the reports in British media were exaggerated and inaccurate. Two of those deaths were suicides, he said, and a number of the others may have been caused by serious medical conditions the users already had, or by taking Zyban along with other drugs.

A U.S. spokesperson for the drug’s manufacturer, Glaxo Wellcome, Inc., said the company knows of few adverse reactions having been reported to the Food and Drug Administration, and no deaths.

Holly Russell said the company “is committed to seeing that prescribers receive clear information on the use of Zyban.” She said it has played a major role in reducing diseases and deaths associated with smoking, and for most people its benefits far outweigh the risks.

For a small percentage of smokers, however, it apparently can be dangerous. In the product information packaged with the drug, doctors are warned that Zyban should not be prescribed for patients taking the depressant Wellbutrin, which is the same drug, or for people with conditions that increase their risk of seizures, including epilepsy, head injuries, a CNS (brain) tumor, severe cirrhosis of the liver, or diabetes which is being treated with oral hypoglycemics or insulin.

The insert also warns that Zyban should not be given to patients who are taking the class of antidepression prescription drugs called MAO inhibitors, and that it increases the risk of seizures in those taking other antidepressants, or several other types of drugs, including antipsychotics and systemic steroids.

Russell said future inserts packaged with the product for Europe will contain a change in the recommended dosages. The recommendation has been that patients take 150 milligrams for three days, and then double the dosage to 300. The European insert will make that six days instead of three, which is what the British CSM suggested. The inserts in the U.S. will not be changed.

Unlike other anti-smoking medicines, Zyban does not contain nicotine. It works by changing the chemistry of smokers’ brains. Exactly why and how it does that is not fully understood, but it seems to involve the “pleasure chemicals” associated with addiction — beta-endorphins, acetylcholine, dopamine and norephinephrin.

It is also used differently from nicotine-containing patches, inhalers and chewing gum. Smokers go on smoking for a time after they start taking Zyban, and then are supposed to quit after a week or two.

Studies of Zyban’s effectiveness have found that after 10 weeks, 46 percent of smokers given it are still tobacco-free, compared with 32 percent who received nicotine replacement medications. Zyban can also be combined with nicotine replacement, increasing the success rate to 51 percent after 10 weeks.

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