Men's Health Express Report
Drug Currently Withdrawn From FDA Approval Process

First Centrally Acting Drug Therapy for ED is Recommended for Approval

This report was reviewed for medical and scientific accuracy by William H. Stuart, MD , Director,Multiple Sclerosis Center of the Shepherd Center, Founding Partner Peachtree Neurological Clinic, Medical Director for Rehabilitation Services, Piedmont Hospital, Atlanta,GA; Chairman, HealthMed Advisory Board, .

Erectile dysfunction is a condition that is only in recent years becoming fully understood. The Kinsey report published many years ago describing high sexual activity among older men, is almost certainly an error. Erectile dysfunction is a physiologic event that has many causes and begins to appear in approximately 50 percent of men by their late 50's. Its incidence increases with age. The dramatic use of Viagra® in older age groups has put to rest the notion that erectile dysfunction is a psychological event due to loss of libido. Now that erectile dysfunction has become a topic of study, loss of libido is rarely known to be the cause. Uprima® (apomorphine) has followed Viagra® into the field and will almost certainly provide another pharmacologic mechanism to further correct this problem. What its major side effects will be and how it will be used to treat erectile dysfunction will be determined in future studies.

On April 11, 2000, the US Food and Drug Administration's Urology Subcommittee of the Advisory Committee for Reproductive Health Drugs recommended approval for Uprima® (apomorphine HCI tablets) for the treatment of erectile dysfunction (ED). It also suggested that some cautionary labeling would be advisable and that educational materials be provided to patients.1 The FDA will consider the committee's favorable recommendation in the final review of the New Drug Application (NDA) for Uprima®.

Uprima® would be, if approved, a second generation drug therapy in the treatment of ED following the widely publicized Viagra® (sildenafil). Unlike Viagra®, which acts as a vasodilator and can have negative effects on patients with coronary or hypertension conditions, Uprima® acts on the central nervous system in a largely benign manner. It is administered in tablet form, like Viagra®, and acts in about 30 minutes. Side effects have been limited to mild nausea. Also, patients taking nitrates and Viagra® have been at risk for fatally-reduced blood pressure; patients taking the combination of Uprima® and nitrates have not been found to be at risk for the same problem.

It is interesting to reflect on the history of research, development, and product usage, which led to the development of this second generation and generally user-friendly drug therapy. Since 1992, when the National Institute of Health issued a "Consensus Development Conference Statement on Impotence," there has been a concentrated focus on addressing the problem of ED. Significantly, the NIH admitted that the scope of the problem had been vastly underestimated and no current surveys were available on the number of men suffering from erectile dysfunction. The NIH estimated that upwards of 30 million men in the US suffer from some degree of ED. Areas of concern that the conference addressed were "(1) the prevalence and clinical, psychological, and social impact of erectile dysfunction; (2) the risk factors for erectile dysfunction and how they might be used in preventing its development; (3) the need for appropriate diagnostic assessment and evaluation of patients with erectile dysfunction; (4) the results and risks of behavioral, pharmacological, surgical, and other treatments for erectile dysfunction; (5) strategies for improving public and professional awareness and knowledge of erectile dysfunction; and (6) future directions for research in prevention, diagnosis, and management of erectile dysfunction." After two days of presentations, a panel presented its consensus statement. The panel concluded among its findings that "(1) the term 'erectile dysfunction' should replace the term 'impotence'; (2) the likelihood of erectile dysfunction increases with age but is not an inevitable consequence of aging; (3) embarrassment of patients and reluctance of both patients and healthcare providers to discuss sexual matters candidly contribute to underdiagnosis of erectile dysfunction; (4) many cases of erectile dysfunction can be successfully managed with appropriately selected therapy; (5) the diagnosis and treatment of erectile dysfunction must be specific and responsive to the individual patient's needs, and that compliance, as well as the desires and expectations of both the patient and partner, be important considerations in selecting appropriate therapy; (6) education of healthcare providers and the public on aspects of human sexuality, sexual dysfunction, and the availability of successful treatments is essential; and (7) erectile dysfunction is an important public health problem deserving of increased support for basic science investigation and applied research."2

Individual researchers and the pharmaceutical industry responded to the call, and drug and other therapies soon came to the market. These "first generation" therapies were invasive and difficult to use. Mechanical vacuum pumps and other devices that increased blood flow to the penis became available, but were not widely accepted. In 1996, Pharmacia and Upjohn gained approval from the Food and Drug Administration for Caverject® Sterile Powder. It was the first prescribed medication for erectile dysfunction but was invasive, due to the need for self- administered needle injections. "Caverject® represents a significant development in the treatment of erectile dysfunction," asserted Upjohn about its commercially unsuccessful product.3 [A growing awareness existed among healthcare providers and the general public that a user-friendly therapy for ED was desirable, but no viable solution was on the horizon.] At the 1997 meeting of the American Urological Association, the first results of a new drug, sildenafil (Viagra®), were presented. Viagra® was discovered accidentally when it was tested and found to be ineffective as a blood pressure medicine. A side effect of penile erections was observed and the therapy developed from there. A success rate of 75-80 percent was found among men taking the new oral agent as needed one hour before anticipated sexual activity. Leonard Marks, MD, Director, Urological Sciences Research Foundation (USRF), reported that the FDA "fast track" reviewed Viagra® prior to final approval. According to Dr. Marks, "the drug was well-tolerated; side-effects were minor."4

On March 27, 1998, Viagra® was licensed by the US Food and Drug Administration and within a week was on most pharmacy shelves. It was the first "solution in a pill" therapy to come to the market for erectile dysfunction and quickly gained widespread acceptance by doctors and their patients. On April 21, 1998, the Washington Post reported that an estimated 15,000 to 40,000 new prescriptions were being written for Viagra® each day. Pfizer's campaign was soon to become one of the most successful product launches in pharmaceutical history.

More recently, a study conducted at Cedars-Sinai Medical Center in Los Angeles using adverse event reports made to the FDA, shows that there does appear to be a number of deaths and cardiovascular events associated with the use of Viagra®. Sanjay Kaul, MD and Babak Azarbal, MD presented these findings on March 14, 2000 at the American College of Cardiologists in Anaheim, CA. According to Dr. Kaul, in an analysis of 1,473 major adverse events, with 522 deaths, the majority of deaths were linked with the standard Viagra® dosages of 50 mg. Two-thirds of the deaths followed cardiovascular events that occurred within 4-5 hours of taking Viagra®. Most of the deaths (88 percent) occurred in patients less than 65 years of age who had no record of risk factors such as previous cardiovascular problems. This has led "investigators to speculate whether there are some susceptible individuals who don't need nitrates to unmask the harmful effects of Viagra®."5

Thus far, the FDA has had a measured reaction to these deaths and has taken into account the fact that millions of patients have taken Viagra® without complications. Sudden death during or after intercourse has been an observed medical phenomena for years, and it is possible that renewed sexual activity for men in the older age bracket has brought more people to risk. Whether the deaths are a direct effect of taking Viagra® or related to the very strenuous physical activity is still unclear.

The latest drug therapy, Uprima® (apomorphine), was introduced at the American Urological Association meeting in Dallas, on May 4, 1999. Three phase III studies were discussed, including a clinical trial in Europe in which over 3,500 men participated, including patients with coronary and hypertension conditions. Side effects of Uprima® (apomorphine) have been limited to occasional nausea, which seems to disappear following repeated dosages. No coronary problems or deaths have resulted from the use of Uprima®. 6

Like Viagra®, apomorphine was discovered by accident during research on spinal cord injuries and injuries in animals. Apomorphine causes an increase in the production of nitrous oxide in the cell bodies of the hypothalamus (in the central nervous system), which activates the autonomic nervous system and causes penile erection. 7

Uprima® is the product of a joint venture between TAP Holdings (Takeda Chemical Industries, Japan) and Abbott Laboratories (US). A representative of TAP stated that the date of final approval for Uprima® is unknown, but that approval generally takes about one year after the initial filing (July, 1999).


1. FDA Committee Recommends Uprima® (apomorphine) Sublingual Tablets for Erectile Dysfunction. Doctor's Guide Global Edition. April 11, 2000.

2. Impotence. NIH Consensus Statement Online. 1992 Dec 7-9; 10(4): 1-31.

3. Caverject® for Male Impotence Approved for Men. Doctor's Guide Global Edition. June 12, 1996.

4. Marks, L., MD. Impotency Update: Sildenafil (Viagra®). USRF News. Spring, 1998.

5. ACC: Viagra® (Sildenafil) Linked to Adverse Cardiovascular Effects. Doctor's Guide Global Edition. March 14, 2000.

6. Uprima®-A Future Rival for Viagra®? Drug Infoline. June 1999; Vol 1-2.

7. Melman, H., MD. Summary of Key Presentations on Erectile Dysfunction (ED) from the 94th American Urological Association Meeting, May 1-6, 1999. Medscape, June, 1999; 1-8.