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Launching Pfizer's Viagra

The Sunday Times

Sex drugs & rock 'n' roll

Gay men are good Viagra customers, yet research for anti-Aids campaigns reveals that in sexual situations, whether at clubs or more privately, quite often health advice goes ignored. Maybe half are drunk. A good many are on grass. A few take harder drugs. If a little brown bottle containing poppers passes round, some will find it hard to say no.

There are also other Viagra users who appear to be running into trouble. Most conspicuous to date are heart condition patients who summon an ambulance. Medicinal nitrates are often carried in emergency vehicles to help relieve angina and other symptoms. So a man on Viagra who is administered this treatment may die as a consequence.

When a medicine is taken and a bad event follows, you can't assume cause-and-effect. But a string of fatal incidents has worried observers since Viagra went on American sale. At the end of July, the FDA announced that it knew of 77 deaths between March and June in which the drug may have played some role. Facts are thin for many of the reports, but 39 cases are solid enough to trigger a short review.

"Age was specified for 31 individuals, who had an average age of 66 years (median = 64, range = 48-87)," the agency says. "Of 18 with the dose reported, all but one had taken the 50mg dose. Six patients were administered nitro-glycerine or a nitrate medication that is contraindicated with the use of Viagra. Of reports that provided information on sexual activity, 14 men died or developed symptoms that led to death during or within 2 hours of sexual activity; 3 died or developed symptoms that led to death more than 2 hours after sexual activity."

These figures mean something, but nobody knows what, since there's no proper side-effects monitoring in America. Partly due to doctors' terror of being sued, fewer than 1% of suspected bad events are reckoned to be reported to watchdogs. But any drug's benefits are balanced against its risks, and Viagra's are no exception.

A possible pointer to the degree of risk is that of 3,700 men in pre-marketing trials such as Padma-Nathan's, two of them died of heart attacks for which no conclusive explanation was found. One was a 66-year-old taking just 10mg, but who was noted to have a history of smoking. The second was aged 53, on 100mg, and with no "pertinent" medical history.

For a drug with the benefits described for Viagra, a death rate of 1 in 3,700 would be considered to be alarmingly high. But Pfizer insists that the product is safe and that associated deaths may be due to older men resuming a strenuous sex life. Padma-Nathan agrees and points out that this age group has a high "background" death rate in any case. "If you took 330,000 men in the general population over the age of 49 and followed them over the course of a month," he says, "400 to 700 of them would die of natural causes."

But questions nag - not least because of the speed of Viagra's approval. Both the FDA and Europe's safety watchdogs have been slimmed and quickened during the 1990s, mainly in order to deregulate medicine and boost returns on research investment. Viagra's application, which totalled hundreds of thousands of documents, stormed through the FDA in just six months, compared with the two years which were common in the past.

More uncertainties lurk in the nature of the relatively small clinical trials. Tests such as those at the Male Clinic may show that the product seems to work, but its safety profile won't be clear until millions of people try it. "You just don't know all you need to know from the few thousand people who get a drug before marketing," explains Dr Robert Woosley, professor of pharmacology at Georgetown University, Washington. "I've called for educational programmes to let people know that, after they're on the market, drug side-effects are to be expected. And drug removals are to be expected."

A case of removal is a drug from Sanofi Winthrop called oral milrinone. It was taken off the market in 1992 despite getting the green light from watchdogs. This was a phosphodiesterase type 3 inhibitor, licensed for treating heart patients. But after special trials at 119 hospitals, independent researchers concluded that it "was associated with a 28% INCREASE in mortality".

As a phosphodiestarase type 5 inhibitor, Viagra is only roughly in the same class of medicine. But there have also been recent problems with other drugs with pharmaceutical similarities. In February, the antihistamine Seldane was withdrawn by its manufacturer, Hoechst Marion Roussel, after fatal heart-rhythm reports. In June, Roche withdrew the anti-angina/hypertension drug Posicor after a "three-year long-term study". And, also in June, following 38 death reports, Janssen Pharmaceutica alerted doctors about risks with Propulsid, for heartburn.

What these products have in common with sildenafil is the way in which they're metabolised, or processed, in the body. What concerns some specialists is that all four are taken up by a particular enzyme (cytochrome P450 3A4) which has a finite ability to process foreign chemicals, causing a potential toxic "back-up", or overload.

Related to this worry is that impotent men are often ill or taking medications. Yet pre-marketing tests for Viagra were designed to specifically exclude many of them. FDA documents that I read show that men were excluded from tests for as many as 17 different health reasons - and so the drug's effects on them after marketing are pretty much anyone's guess. These include people with a "history of alcohol or drug abuse", those with major liver or kidney disorders, uncontrolled diabetes, unstable angina, abnormal blood pressure, peptic ulcers, a history of retinitis, and what Pfizer's trial designers call "any clinically significant baseline laboratory abnormality."

In addition to not being tested on so many of its potential consumers, there's a well-itemised shopping list of acknowledged Viagra side-effects. Analyses of company data, which will soon be released in the European Union, shows that the commonest of these during placebo-controlled trials were:

  50gms 100gms
Headache 24% 29%
Vasodilation 20% 20%
Dyspepsia 8.1% 12%
Abnormal vision 2.3% 8.7%
Rhinitis 3.1% 5.2%

Most of these appear to be mild and brief. Users are often willing to accept them. "On my third time with Viagra my stomach got so upset there was no time for an 'afterglow' because I had to run to the bathroom," is how Gary, aged 37, recounts his experience with 50mg to an Internet discussion group. "This last time I was practically side-effects free. About 30 minutes after taking Viagra, I took two Tylenol and a Tums and started drinking water. After about 15 minutes I took another Tums and used a nasal spray for my stuffiness. The water seemed to help with the facial flushing. All I got was a great erection when the time came."

*****

With the FDA's approval in the bag last March, Pfizer now looks to Canary Wharf in London and the offices of the second most powerful licensing body: the European Medicines Evaluation Agency. Under gentle pressure from the company's management and from the ferocious media frenzy, officials are finishing the paperwork on Viagra, faxing and phoning back and forth with Brussels, which must give the go-ahead for marketing. An advisory committee has already said "Yes", although stronger safety warnings have been ordered.

Pfizer bosses declare that the decision is imminent, yet Brussels has been dragging its feet as the problems in America are closely analysed. When Viagra was first released in the US, fewer than 550 people had taken it for more than 12 months, leaving big holes in regulators' knowledge about what may happen during long-term use.

One concern which has prompted strengthened warnings is the drug's possibly damaging effect on the eyes. As well as inhibiting the phosphodiesterase type 5 enzyme, it also inhibits the closely-related type 6, which is found in the retina. Among users this sometimes leads to blue vision and light sensitivity.

"Blue vision and light sensitivity are somewhat unusual and mildly worrisome symptoms," explains Michael Marmor, professor of ophthalmology at Stanford University, California, who believes that Europe still has time to ask Pfizer for more safety data. "I don't tell people not to use it. I just think the public should be informed that it does affect the eye directly, that we don't have all of the information that we might have about potential damage, and that this might be a greater risk to people who have underlying eye disease."

But if problems such as retinal damage arise, there's a good chance they won't become public knowledge until after Europeans take the drug. Compared with America's hopeless side-effects monitoring, several European countries have reasonably clever and well-tried systems for tracking deaths and other adverse reactions. In that sense, the Germans, the French and the British will be Viagra's guinea pigs.

Britain's arrangements have been in place since 1964. Using so-called "yellow cards", which are given out to doctors, those patients who complain of adverse reactions can be notified to the Department of Health. In France, meanwhile, Europe's best-regarded system, called Pharmacovigilance, involves 31 regional centres which collect reports and also give advice. Both schemes have flaws, but they pick up problems. Only New Zealand's is thought to be better.

But even such schemes can't tackle another difficulty that doctors told me about: the extent to which Viagra may cause medical problems to be overlooked. A drop-off in erectile function can be a warning about serious underlying conditions. Atherosclerosis, heart disease and diabetes are three examples. Avoidable matters can also cause it: such as smoking, bad nutrition and stress.

Nor can safety watchdogs pick up risks which aren't classified as adverse reactions. There can, for instance, be risks of psychological dependence, or of losing pre-existing physical function. Pharmacology's history is littered with medicines which in time stop working or even worsen the condition for which they are prescribed. And while sildenafil isn't suspected of failing over time, I notice one mildly interesting fact. In Padma-Nathan's second New England Journal of Medicine trial, where men started on 50mg but could vary their dose, only 2% halved it to 25mg, while 74% upped it to 100mg - or twice the standard prescription.

Pfizer is confident, doesn't expect problems and hopes for a long life for its product. The company's exclusive patent rights extend to 2011, during which, some predict, Viagra sales will top $1bn a year. But its window of opportunity may not be quite as wide as such optimistic forecasts suggest. Sildenafil will soon have rivals from other products. And Pfizer's frantic foot soldiers, the Drs Viagra, will shortly roll on, with mass media in tow, to impotence remedies new.

If you recall the Chino slide-show where Padma-Nathan and I began, he had 17 frames full of facts about Viagra, but he also flashed a pair on alternatives. From the Zonagen Corporation comes oral phentolamine, a fast-absorbed version of an old medication which acts at a different stage in the erection process by blocking neurotransmitter action. Next, from TAP Holdings, is sublingual apomorphine, which works on a spot in the centre of the brain thought to be involved with arousal. Both are now with the FDA. The first license is imminent.

The doctor also had a slide with a passing reference to the potential for gene therapies. In New York I heard of one, for which a patent has been sought, entailing local, but infrequent, injections. And then there was a mention for a prostaglandin ointment, which developers hope can be massaged into the penis (without making your hands get bigger, boom, boom).

One of Padma-Nathan's next contracts is to look at a phosphodiesterase inhibitor which is less likely to affect the eyes. It's being developed by the Washington State-based ICOS Corporation, in which Microsoft's chairman Bill Gates is said to be the largest individual investor. "It works for 24 hours instead of Viagra's 3-5 hours, so there would be less need to time the administration," Padma-Nathan tells me, when I call him on the phone from London. "You could even take it once a day."

But before that happens, if happen it will, he has something else on his plate. Padma-Nathan is about to move to a new Santa Monica office which, at 6,000 square feet, is triple the space he has now. And he plans to dump the label "Male Clinic" from the business and take female patients as well. He believes in the need to test Viagra in women and that he is just the man to do it. He is drawn to the name Sexual Medicine Research Institute. He says: "We need to broaden it out, obviously."

Pick up the sex drug story by five years later in Sexual Interest Disorder

Launching Pfizer's Viagra
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This report is copyright, Brian Deer. No portion of this article on the launch of Pfizer's erectile dysfunction drug Viagra in 1998 may be copied, retransmitted, reposted, duplicated or otherwise used without the express permission of the author. Responses, information and other feedback are appreciated