July 10, 2000 -- In the two years since it rocketed onto the market -- and became, almost overnight, a household word -- the impotence drug Viagra has helped men with erection problems enjoy satisfying sex. The little blue pill fired the male imagination with the notion of an enduring and youthful virility that could last into the golden years.
But truth is, Viagra is not the sexual cure-all that many men who have problems with erectile dysfunction believed it to be. As many as two in five men who try the drug don't get the desired results. And at least 39 Viagra users have died, mostly men who were also taking other drugs, or who had serious heart disease (see the November-December 1998 issue of Clinical Therapeutics).
No wonder that early reports of another, perhaps better, drug were so tantalizing -- both to the media and to men who got no satisfaction from Viagra. The very name of the new drug -- Uprima -- conjured up images of supremacy and conquest.
Then, last week, came the news that threw a splash of cold water on these oh-so-fond hopes: TAP Pharmaceuticals, the maker of Uprima, unexpectedly -- perhaps temporarily -- withdrew its application for approval by the Food and Drug Administration (FDA).
Why did the company pull a product that just weeks ago had been widely expected to gain FDA approval and give Viagra a run for its money in the billion-dollar impotence market? Experts speculate that the agency may, in fact, have been poised to reject the drug's application or to severely restrict its recommended use. The reason: serious questions about the drug's safety at higher doses and its efficacy at lower ones.
Before submitting its application to the drug agency, TAP Pharmaceuticals tested Uprima on more than 2,700 men in final clinical trials. The experience of two of those men, interviewed by WebMD, offers a glimpse at the drug's possibilities -- and drawbacks.
Tantalizing Possibilities, Alarming Problems
When John Doe (not his real name) noticed his sexual functioning was waning, he went straight to his doctor for help. Doe knew about Viagra (the brand name for sildenafil). His doctor, of course, knew about it too, and promptly gave him a sample of the drug to try at home. But when the 59-year-old engineer from Cincinnati took the pill, something unexpected happened.
It didn't work.
Invasive treatments like surgery, penile injections, or suppositories were out of the question, so Doe and his wife of 37 years were left to ponder the unpleasant prospect that they would never again enjoy sex the way they used to.
"I started telling myself that gardening was more fun than sex, as a way not to feel bad," he says.
But then Doe's doctor invited him to take part in a trial of Uprima. (Uprima's active ingredient, apomorphine, bears only a distant relationship to its precursor, morphine.) That was eight months ago, and it was the last time he and his wife worried about their sex life. He's been taking the experimental drug two times a week, he says, "and it's worked every time."
Doe liked Uprima so much that in April he testified in favor of the drug's approval before an FDA advisory committee; his expenses to come to Washington were paid for by drugmaker TAP.
Robert Carelli, a 69-year-old retired teacher from Thousand Oaks, Calif., also participated in a Uprima trial for the better part of a year. He, too, was pleased with how the drug helped him sexually -- at first.
"I was happy with it for a while," says Carelli, who also received an honorarium from TAP to speak on behalf of Uprima. "It worked; it certainly corrected the problem." But the drug also made him nauseated -- mildly so about 10% of the time and extremely so on a couple of occasions.
"That hardly made me feel amorous," Carelli says. Eventually, the nausea bothered him so much that he gave up on the drug and switched to Viagra.
Some men who took Uprima in clinical trials suffered more serious side effects. According to FDA medical reviewers, one in 30 men who took Uprima in its optimal 4 milligram dose either fainted or experienced dangerously low blood pressure. One 33-year-old man blacked out while driving about 30 minutes after taking a 4-milligram dose and crashed into a fence. Another man, 56, had his blood pressure plunge, lost consciousness for 15 minutes, then woke up and vomited before fainting again in the emergency room. Other patients fainted and struck their heads, suffering lacerations and fractures.
Most of the reported problems took place in doctors' offices where treatment was readily available.
Serious side effects were much more common with men who took 4 milligrams or more of the drug, as opposed to 2 milligrams. But the effectiveness of the lower dose was so limited, FDA medical reviewer Mark Hirsch, MD, told an agency advisory committee in April, that "few patients will actually remain on the dose of 2 milligrams when offered the opportunity to take higher doses."
Despite the questions raised about Uprima, the advisory committee voted 9 to 3 to recommend that the agency approve the drug. Now, with TAP withdrawing its application, the FDA will not be considering the drug's fate until the manufacturer resubmits its request, something the company vows to do after completing two ongoing clinical trials.
"We are still very confident," TAP spokesperson Kim Modroy told WebMD. "We hope by taking this extra time we will have a much stronger product."
Same Ends, Different Means
If Uprima does get approved, it will face comparison with its world-famous predecessor. Viagra and Uprima both facilitate erections, but in different ways. Viagra effects a more direct response in the vascular system, temporarily widening arteries and allowing more blood flow to the penis. Uprima works by inhibiting a part of the brain that controls the body's smooth muscle contractions. Curbing those contractions allows more blood to flow, ideally with the same happy results.
The way the two drugs get into the body differs, too. Viagra, a pill, is swallowed, while Uprima is a lozenge meant to be dissolved under the tongue. Uprima bypasses the stomach to enter the blood stream directly, so it works faster than Viagra. That would score a point for Uprima on spontaneity, since it could be taken right after a meal. Viagra is less effective, sometimes even useless, if taken on a full stomach -- a big disadvantage when an evening turns romantic after dessert.
Neither drug is an aphrodisiac: They can make it easier for a man to get an erection, but they can't improve his libido. And they won't make him desire a partner any more than he would on his own.
So which drug appears to work better? "There is no answer yet," says Ira Sharlip, MD, an assistant clinical professor of urology at the University of California at San Francisco who has conducted clinical trials of both drugs. More research needs to be done, he says.
Clinical trials show that both Uprima and Viagra are between 50% and 60% effective, depending on the dosage and on what counts as success (May 14, 1998, New England Journal of Medicine and presentations at the May 2000 meeting of the American Urological Association). The best kind of comparison -- a head-to-head clinical trial pitting Viagra against Uprima -- has not been done.
Some patients would appreciate that Uprima reaches maximum effectiveness after only about 15 minutes, compared with an hour or more for Viagra. But again, Uprima's potency comes with a price. Like Robert Carelli, about 15% of men who took the drug in the clinical trial wound up feeling nauseated afterward -- or worse.
If Uprima does end up receiving FDA approval, many patients and their doctors may still continue to choose Viagra simply because it's more familiar to them, says Robert P. Nelson, MD, a professor of urology at the Medical University of South Carolina in Charleston. Having no competition, Pfizer, Viagra's manufacturer, has been able to put together a marketing and sales force that will be hard for Uprima to challenge.
A careful history and physical examination are necessary in order to determine if any drugs are needed to treat a case of erectile dysfunction. For starters, Viagra cannot be taken by anyone who is taking nitrate medications for heart disease because mixing these drugs can cause dangerous drops in blood pressure.
Uprima could be taken by patients on nitrates, but experts say more research would need to be done to convince them that the combination would be safe. In any case, patients with heart disease should check with their doctor about engaging in any strenuous physical activity, including sex.
The underlying cause of erectile dysfunction may also play a part in choosing a drug. Because Viagra acts at the level of the tissues, it may be more effective in the 50% of patients whose problem is caused by a vascular disease (such as diabetes), says John Morley, MD, a professor of medicine at the St. Louis University School of Medicine. Uprima, on the other hand, works in the pathways of the brain that control anxiety, so it could be more helpful for the 10% to 15% of patients whose erection problems stem from performance anxiety, says Morley.
If Uprima does get the FDA's nod, many experts think the best treatment choice may be to combine Uprima and Viagra for a synergistic effect. This "erection cocktail" has been tested so far only in animals, with some success, but will not be used in humans until further studies are performed.
As for John Doe, he says Uprima "saved" him from "having to just accept the fact that my [sex] life was going to have to slow down." Will other guys find the same happy ending? That remains to be seen.
Todd Zwillich is a freelance journalist living in Washington, D.C. He has covered health care politics and medicine for International Medical News Group and Science magazine.
