Doc 123 Cialis

Petition to Require a Black Box Warning for Erectile Dysfunction Drugs Sildenafil (Viagra), Tadalafil (Cialis) and Vardenafil (Levitra)

Public Citizen, representing more than 135,000 consumers nationwide, hereby petitions the Food and Drug Administration (FDA) pursuant to the Federal Food, Drug and Cosmetic Act 21 U.S.C. Section 355(e)(3), and 21 C.F.R. 10.30, to immediately add a black box warning regarding the risks of drug-induced blindness for the three phosphodiesterase 5 (PDE5) inhibitors that are prescribed for the treatment of erectile dysfunction [Viagra (sildenafil; Pfizer), Cialis (tadalafil; Lilly), and Levitra (vardenafil; Bayer)]. The label for Revatio, a version of sildenafil indicated for pulmonary arterial hypertension, should also be included in the changes recommended in this petition.

Public Citizen’s concern is based, in part, on our findings that 1) Viagra accounts for nineteen percent of the total cases of ischemic optic neuropathy (loss of vision) in the FDA’s adverse event database, more than 2-fold higher than that for the next most frequently-cited drug; and that 2) the number of cases of ischemic optic neuropathy per million prescriptions is 18-fold higher for patients taking Viagra compared with patients taking Lipitor, another drug used by people with similar risk factors.

Additional Requests

This petition also strongly urges the FDA to require that a “Dear Doctor” letter be sent to all physicians informing them about the signs and symptoms of non-arteritic ischemic optic neuropathy (NAION), an often irreversible loss of vision. Men who have had a previous attack of NAION in one eye should not take these drugs since these men are at increased risk of NAION in the other eye, especially if they have other risk factors such as diabetes and hypertension.

In order to inform patients, FDA should require the mandatory distribution by pharmacists of scientifically accurate information for consumers, written in non-technical language in the form of FDA-approved Medication Guides, with each new and refill prescription for these drugs. The current patient information leaflets (not FDA-approved) are given to patients when a prescription is filled and several patient information leaflets that we have collected do not adequately warn about this serious adverse reaction.

Finally, in order to try and define the causes and prevalence of NAION due to these drugs, FDA should require the manufacturers to establish a registry of all patients diagnosed with NAION and to immediately inform the FDA of new cases.

Background

NAION is a pathologic condition triggered by blockage of blood flow to the eye that is sudden but painless in onset and frequently leads to permanent blindness, usually in one eye. The exact causes are unknown, but it often appears upon first awakening and thus has been hypothesized to be precipitated by hypotension occurring during sleep, mainly in people over the age of 50.

NAION first came to public attention on May 27, 2005, when the FDA announced that it was in discussions with Pfizer to update its Viagra label to mention loss of vision. The FDA announcement was apparently triggered by an article published in the March 2005 issue of the Journal of Neuro-Ophthalmology that described seven new cases of NAION apparently linked to the use of Viagra.[1] Although this article produced the first major public focus on the relation of Viagra to this disease, there have been 19 cases in the medical literature implicating the PDE5 inhibitors beginning in 2000 (see ref. 15-24).

After media coverage of the FDA announcement, Senator Charles Grassley became concerned about the lack of any substantive action by FDA and began his own investigation.[2] Grassley’s staff interviewed the safety evaluator from the FDA Office of Drug Safety (ODS), who had produced the original analysis of NAION in Viagra users. By monitoring adverse event reports submitted to the FDA, the safety evaluator had concluded, as early as January 2004, that NAION was an important safety issue for Viagra users. Her review had been sufficient to convince the deputy director of the Division of Anti-inflammatory, Analgesic, and Ophthalmic Drug Products that the potential for NAION should be added to the Viagra label. The NAION report was finalized in April 2004 and sent to the Office of New Drugs (OND), the final arbiter of label changes. Nevertheless, it wasn’t until July 8, 2005, 13 months after the Office of New Drugs received documents from the safety evaluator, that the FDA finally published safety alerts for patients and healthcare professionals on its web site.[3]

There is now mention of NAION in the Precautions and Adverse Reactions sections of the professional labels for Viagra, Cialis, and Levitra (but no mention anywhere in the label for Revatio). However, the wording is ambiguous and the location of this information is buried: under Information for Patients in the Precautions section (information that usually is not given to patients), there is one untitled paragraph. In the Adverse Reactions section under Post-marketing Experience, one of several paragraphs discusses NAION. In the case of Viagra, NAION is discussed in one of two paragraphs under Adverse Reactions subheaded “Special Senses” which gives no indication as to what is discussed (the other two drugs have paragraphs that are at least titled “Ophthalmologic”).

Emphasis in the label is on the word “rarely”, downplaying the importance of NAION and is coupled with the caveat that, “It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors”. It is probably true that many factors are involved, but one factor clearly seems to be the drug (see below).

The current label has a paragraph titled “Effects of VIAGRA on Vision” which includes no reference to NAION. This needs to be amended.

Public Citizen’s Analysis

Public Citizen has been concerned about a number of safety issues with Viagra’s use since its approval in 1998 when we asked the FDA to include stronger warnings concerning adverse effects.[4] Public Citizen had, at that time, only looked at the FDA reviews since no postmarketing adverse event data were available. Our concerns relating to the eye were limited to color aberrations, increased sensitivity to light, and blurred vision. However, after the publicity in May 2005 about NAION, we began reading the literature reports and decided to undertake our own analysis using the FDA Adverse Event Reports (AERS) database.

We used the search term “ischemic optic neuropathy” (ION) as recommended by a neuro-ophthalmologist (the term NAION is not present in the AERS database). We searched the entire FDA database from 1/1/98 to 12/31/04 for all reports of ION that showed up for any drug (combining brand and generic names). We found 258 reports in which a drug was listed as the primary suspect for this adverse event.

The three drugs with the highest percentage of reports of ION in the FDA’s AERS database were Viagra, interferon, and amiodarone (Table 1). These three drugs (of thousands in the data set) accounted for 42% of all reported ION cases. Viagra had the highest percentage by a factor of more than 2-fold in spite of the fact that during this time period there was no mention of NAION in the label, whereas the labels for both interferon and amiodarone had prominent Warnings and amiodarone had a statement in the Precautions section as well.[5] The fact that Viagra’s large numbers of adverse reaction reports occurred without any warnings to the medical profession strongly suggests that Viagra is an important factor in causing ION (all of these cases accrued before the Viagra-NAION association first came to public attention in May 2005). All reports are for Viagra, since Revatio had not been approved during the time period we searched.

Docs ‘Astonished’: ED Drugs Tied to Prostate Cancer Return

Sometimes a scientific hypothesis is all wrong but scientific understanding moves forward anyway. That might be the case in a study of men with prostate cancer.

In the study, researchers found an association between the use of erectile dysfunction (ED) drugs after radical prostatectomy and biochemical recurrence.

They were surprised by the findings; they had hypothesized that the drugs would be protective because multiple lab studies and an observational clinical study suggested an anticancer effect in the prostate.

“We were astonished. We expected opposite results,” said lead researcher Uwe Michl, MD, from the Martini-Klinik Prostate Cancer Center in Hamburg, Germany, in an email to Medscape Medical News.

But, he added, the study should not change practice.

“We still advise our patients to use PDE5 [phosphodiesterase type 5] inhibitors on demand,” he explained. “PDE5 inhibitors are effective in treating ED following nerve-sparing radical prostatectomy, assuming that there are still some spontaneous but insufficient erections.”

“Our results need to be interpreted with caution,” Dr Michl and his colleagues write in their study, which was published in the February issue of the Journal of Urology.

The findings about cancer risk are not entirely novel.

Sildenafil was associated with an increased risk for melanoma in 25,000 men in the Health Professionals’ Follow-up Study (HPFS), as reported by Medscape Medical News.

Dr Michl reported that his team is hoping to work with the HPFS investigators to evaluate their data with respect to prostate cancer.

In their study, the German researchers reviewed data on 4752 consecutive men who had undergone radical prostatectomy from 2000 to 2010 at the Martini-Klinik, which is one of the world’s largest centers for prostate cancer.

After surgery, about a quarter of the men (23.4%) were treated with a PDE5 inhibitor for ED, which is a common complication of the procedure and a known problem in aging men. The drugs used included sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis).

The other 76.6% of the men did not receive a PDE5 inhibitor.

The two patient groups were comparable on most clinical parameters.

Five-year biochemical recurrence-free survival estimates were lower in the treated than in the untreated group (84.7% vs 89.2%; P = .0006).

In other words, ED treatment with a PDE5 inhibitor was associated with a significant reduction in the rate of being free of recurrence.

The median follow-up in the study was 60.3 months.

The researchers speculate about possible mechanisms behind the adverse outcome.

“The effects of sildenafil and other selective PDE5 inhibitors on the immune system, on autonomic nerve development as well as on angiogenesis, are conceivable causes of our findings,” they write.

The study is the first of its kind. No other research has looked at the use of these drugs after prostate cancer surgery and their impact on biochemical recurrence.

However, a previous observational study showed that the use of PDE5 inhibitors in men with ED (and no history of prostate cancer) was associated with a decreased incidence in the rate of prostate cancer (Asian J Androl. 2013;15:246-248). The investigators from Scott & White Healthcare in Temple, Texas, explain that men treated with PDE5 inhibitors might ejaculate more often than untreated men, which has been demonstrated to have a protective effect against prostate cancer (JAMA. 2004;291:1578-1586).

There have also been multiple reports from labs that these drugs might thwart cancer prostate cancer growth and postpone metastasis.

In fact, lab evidence on ED drugs in prostate and other cancers has prompted some investigators to call for the “repurposing” of PDE5 inhibitors for adjuvant chemotherapy (Front Pharmacol. 2013;4:82).

On multivariate regression analysis, the use of PDE5 inhibitors was an independent risk factor for biochemical recurrence (hazard ratio [HR], 1.38; P = .0035), Dr Michl and his colleagues report.

Notably, the team found no significant association between biochemical recurrence and age, body mass index (BMI), or smoking in that analysis. These three variables are known risk factors for ED and have been associated with biochemical recurrence after prostatectomy.

On propensity score matched analysis (parameters included prostate-specific antigen, Gleason score, and tumor stage), biochemical recurrence-free survival was significantly worse in the treated than in the untreated group (P = .005).

“Correction for several confounders did not change these results,” Dr Michl said.

PDE5 inhibitors have “revolutionized” the treatment of ED, the researchers report. But right now, they say, it is not known whether that is a good or a bad thing for men who have undergone surgery for prostate cancer and use these drugs.

More study is needed, and men and their doctors await more data.

“Future results will be of special clinical significance as many patients use potency-enhancing drugs after radical prostatectomy,” they write.

The authors have disclosed no relevant financial relationships.

AMA Journal of Ethics ®

Ethical Implications of Drugs for Erectile Dysfunction

The Challenge of Male Sexual Dysfunction Prior to Viagra

Sex for many men before the appearance of erectile dysfunction drugs was a terrifying experience. They could not satisfy themselves or their partners. Aging leads to trouble: a high proportion of men age 60 and over cannot maintain an erection. Other men encounter problems due to stress, mental disorders, prostatectomies, drug and alcohol abuse, diabetes, multiple sclerosis, smoking, and even bicycling. Impairment in nerve function or blood circulation have long been known to be responsible for hindering blood flow to the penis, leading to difficulty in having or maintaining an erection [1].

About 30 million men in the United States and hundreds of millions worldwide suffer from some degree of sexual dysfunction due to the inability to maintain an erection. Fifty percent of US men over age 40 have some degree of dysfunction [1, 2].

Prior to the appearance in 1998 of the first FDA-approved drug treatment for erectile dysfunction, Viagra, treatments included injections into the penis or the insertion into the penis of a permanent implant. Neither treatment was cheap or viewed with much enthusiasm [2]. Indeed, for most of the twentieth century, male impotence was rarely mentioned by patients or identified as a potential problem by physicians.

Viagra, known generically as sildenafil, is a PDE5 inhibitor that relaxes smooth muscle present in the lining of blood vessels, which dilates the vessels and increases blood flow [3, 4]. That was the idea behind using the compound as an antihypertensive drug, which is the purpose for which Viagra was originally tested. The drug was not intended for men who could obtain erections.

Possible Ethical Challenges of an Erection-Related Drug

In 1998, I was hired by Pfizer as a consultant to provide them with ethical advice about moving Viagra forward in a responsible manner from clinical trials to FDA approval. There were a slew of ethical issues that surrounded a new drug for impotence. Pfizer was very aware of the potential for misuse of Viagra. They knew that men who did not need it might rush to buy it and that it might be used by adolescents or women suffering from sexual dysfunction thinking that they might benefit. They wanted to make sure the public understood that the drug was intended for the treatment of a specific problem—erectile dysfunction caused by inadequate blood flow—and that not all types of erectile dysfunction had this cause. Some causes are emotional, and some are due to the abuse of alcohol or tobacco.

There was also concern that some men might take huge doses—especially those for whom the drug initially did not work. In clinical trials, side effects, including impairment of vision, had been reported at high doses. Pfizer addressed the issue of overuse via education, packaging, and marketing. In addition to being accompanied by a typical informational insert, the drug was packaged in bubble-wrapped doses that made the recommended dose very clear. That information was also in all materials sent to doctors, and Pfizer salespeople were trained to make clear the appropriate dose and the ineffectiveness as well as the risk of using larger doses.

I raised other ethical questions that the company had not considered. Who should be prescribing Viagra—urologists or family doctors? What sort of work-up was appropriate for those seeking the drug? Would counseling always be a part of the prescription process, or would doctors simply write prescriptions on demand (something that later happened especially on the Internet with both real and fake Viagra)? What if someone raped or abused someone else while on the drug—what would the company say? What if an older sex offender were found in possession of the drug? Would elderly residents of nursing homes, both married and single, fully competent and not, be offered the chance to use the drug?

The Challenges of Advertising a Sex-Related Drug

But the main ethical issue as I saw it then was whether Pfizer could hold the line on making sure that Viagra was sold as a drug to treat erectile dysfunction and not as an aphrodisiac or a performance-enhancing drug. Could the company resist the temptation to make promises about the drug—that it might help women, that many younger men might benefit [5]—that did not square with the actual pharmacological action of the drug? Would ads suggest that men can solve all their sexual problems via a pill—and that this pill would turn any man into a sexual superman [6]?

The company wanted to use direct-to-consumer marketing since they had data to confirm that few men talked about sexual dysfunction with their doctors or anyone else. Nor did doctors typically ask about the sex lives of their patients. Ultimately, the initial advertising and marketing focused on older men in heterosexual relationships—this being the largest group of probable users and the least controversial for a company looking to avoid a conservative backlash. The early commercial ads for Viagra, which were the first of the massive direct-to-consumer ads for drugs and devices, showed an older couple dancing. The man’s wedding ring was clearly visible. The implicit message was this is a drug for older (married) men who might be having erectile problems, not a performance-enhancing drug or an aphrodisiac [1]. Viagra opened the door to large-scale, direct-to-consumer ads—a strategy that may have made sense for this drug, given the stigma associated with impotence, but one that remains ethically dubious today.

The Social Worth of Viagra

Many Americans are not comfortable talking about sex. There are restrictions on using federal funds to support studies of sexual behavior in adolescents. For decades the entire subject of sex was off-limits in academia. It was and is unfair that many other treatments related to sex, including infertility treatment, psychological counseling, and contraception information, are often not covered by insurance. And, prior to the appearance of a pharmacologic intervention, few men were willing to discuss the problem of sexual dysfunction with anyone—including their doctors. Before Viagra, men were left not only without a key aspect of their emotional life but often also with frustrated partners. Given the bleak standing of sexuality in American medicine [1], I felt comfortable supporting efforts to bring forward a drug that would help many men suffering from a problem of great importance to them.

Ultimately, Viagra took the taboo out of impotence. Former presidential candidate and Kansas Senator Bob Dole admitted in national advertisements that he suffered from erectile dysfunction. Once he and his wife appeared in these commercials, it became easier for many men and indeed for American culture to acknowledge male sexual dysfunction. Having an easy-to-use treatment transformed the embarrassment and silence that surrounded impotence into far more open, frank, and even sometimes funny discussions of the malady [1].

Viagra may also have a use in nursing homes, even by older men with mild dementia or mild Alzheimer’s disease. Do they not have a right to sexuality? My view is that older people do have a right to be sexual as long as they are competent enough to be responsible for their sexual activity. But most nursing homes in the US are not set up to allow older persons to have much privacy. And to this day I am not sure how many nursing homes include such drugs in their pharmacies, offer it to residents, or routinely discuss its possible use with the families of residents.

Conclusion

Studies show that sexuality remains important to older people and that it is a key aspect of emotional satisfaction [7]. Despite efforts to introduce discussions of sex into the routine care of patients, promoting maintenance of sexual function and satisfaction remains a challenge for medicine. Although the marketing and sale of erectile dysfunction drugs have evolved in some ways toward “disease mongering” [8], the fact remains that the treatment of actual sexual dysfunction should be a key part of patient care.

Read More

References

Loe M. The Rise of Viagra: How the Little Blue Pill Changed Sex in America. New York, NY: New York University Press; 2004.

Schiavocampo M, Jesko J, Effron L. Fight over “little pink pill” raises sexism questions. ABC News. May 21, 2014. http://abcnews.go.com/Health/fight-pink-pill-boosting-womens-sex-drive-raises/story?id=23813586. Accessed September 15, 2014.

Potts A, Grace V, Gavey N, Vares T. “Viagra stories”: challenging ‘erectile dysfunction.’ Soc Sci Med. 2004;59(3):489-499.

Gott M, Hinchliff S. How important is sex in later life? Soc Sci Med. 2003;56(8):1617-1628.

Lexchin J. Bigger and better: how Pfizer redefined erectile dysfunction. PLoS Med. 2006;3(4):e132.

Citation

The viewpoints expressed in this article are those of the author(s) and do not necessarily reflect the views and policies of the AMA.

Author Information

Arthur Caplan, PhD is the director of the Division of Medical Ethics in the Department of Population Health at the New York University Langone Medical Center in New York City. He is the author or editor of more than 30 books and 600 articles in peer-reviewed journals. His most recent book is Contemporary Debates in Bioethics (Wiley-Blackwell, 2013).