Letter Urging FDA to Convene an Advisory Committee to Review Problems Related to the Use of Sildenafil (Viagra)
August 20, 1998
Michael Friedman, M.D.
Lead Deputy Commissioner
Food and Drug Administration
5600 Fishers Lane
Rockville, Md. 20857
Dear Dr. Friedman:
One purpose of this letter is to demand that the FDA immediately convene a meeting on Viagra of its cardiovascular advisory committee — a committee which was completely bypassed during the dangerously-rushed six months between the submission of the new drug application for Viagra to the FDA and its approval. Rarely, especially for a drug which is not for treatment of a life-threatening illness, does the FDA approve a drug which has not been reviewed by the appropriate FDA advisory committee.(1)
This is especially urgent because we have learned that an ongoing joint task force of the the American College of Cardiology and the American Heart Association (ACC/AHA), which will issue a longer report at the end of this year concerning new warnings for Viagra ("The Use of Sildenafil (Viagra) in Patients at Clinical Risk From Cardiovascular Effects"), has just issued an interim report which expresses concerns about the risks of the drug to new categories of patients with cardiovascular disease.(2) In a statement issued last week, the ACC/AHA said that:
The cardiovascular effects of Viagra may be potentially hazardous for patients with certain medical profiles, and clinicians need to exercise caution when advising the following patients who are considering taking Viagra:
- Patients with active coronary ischemia [decreased blood flow to the heart] who are not on nitrates;
- Patients with congestive heart failure and borderline low blood pressure and borderline low volume status;
- Patients on a complicated multi-drug, anti-hypertensive program; and
- Patients on drugs (erythromycin, cimetidine) or who have conditions (e.g. liver or renal disease) that can prolong the half-life of Viagra.
Summarizing these concerns, none of which (other than the erythromycin and cimetidine interactions) are reflected in the current labeling for Viagra, Dr Adolph M. Hutter, Jr. of Massachusetts General Hospital, co-chair of the expert committee that developed the statement, said:
It can be dangerous for some patients to take Viagra, even if they are not on nitrates. Their medical condition or their medications can alter the effect that Viagra might have on their bodies, which might lead to an excessive drop in blood pressure.
Although it is not the role of the ACC/AHA committee to recommend specific additions to the warnings on Viagra, the implications of their warning statement are clear enough and need to be immediately addressed by the FDA and its cardiovascular advisory committee and incorporated into the labeling for the drug.
On July 1st of this year we petitioned the FDA to strengthen the warning information on Viagra for patients and doctors. Patients with many different medical problems, considered to be at increased risk for using the drug, had been excluded during the pre-approval clinical trials. But once the drug was approved for marketing, people with these medical problems were not warned about their increased risk and cautioned against using the drug. Among these groups of patients were men with a recent heart attack or stroke, men with EKG evidence of inadequate blood flow to the heart (coronary ischemia) and other groups of patients including people with heart failure.
In addition to urgently requesting that the FDA convene its cardiovascular advisory committee to address the concerns that we and the ACC/AHA have expressed, we have found, from FDA documents, important information about other potential dangers of Viagra which are either not discussed or misrepresented in the FDA-approved labeling for Viagra. The other purpose of this letter, then, is to supplement our original (July 1st) petition to the FDA by requesting additional warnings to be added to the drug. Most of the information and data upon which this supplement to our petition is based is taken from the documents comprising the FDA's own reviews of sildenafil, conducted before the drug was cleared for marketing; additional information comes from the scientific and medical literature.
False and Inadequate Pregnancy Warnings
Since it is clear that Viagra is already being used off-label by women of child-bearing potential, and since experiments on women are about to begin, accurate information about pregnancy risks must be included in the label so that women and their physicians can be informed of potential risks and women of child-bearing age are not given the drug unless it is clear that they are not pregnant and that continued pregnancy tests are done if they use the drug.
Despite abundant evidence from animal studies of damage to the fetus by sildenafil (see below), the current label falsely states that sildenafil belongs in Pregnancy Category B because there was "No evidence of teratogenicity, embryotoxicity, or fetotoxicity observed in rats and rabbits..." (It is of interest that the findings detailed below were dismissed by the FDA, usually on the basis that Pfizer did not think that they were caused by Viagra.)
This FDA pregnancy category B is defined as follows:
Animal studies have not demonstrated a risk to the fetus but there are no adequate studies in pregnant women...or....Animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus during the first trimester of pregnancy and there is no evidence of risk in later trimesters.
Yet, in the rabbit teratogenicity study, there were ventricular septal [heart] defects in 5.3, 5.6, 11.8, and 12.5% of litters (no drug, low dose, medium dose, and high doses, respectively) with "remarkable anomalies reported for the high dose group only, consisting of atrophies of left or right ventricle and pulmonary artery, [and] enlarged aortic arches."(3)
In a rat teratogenicity study, there was decreased skull ossification in high dose vs. controls.(4)
In the rat pre- and postnatal development study, the no observed effect dose was considered by the reviewer to be 30 mg/kg/day given for 36 days.(5) Yet, in the high dose rats (60 mg/kg/day, with no noteworthy signs of toxicity in the dams)(6), there was a statistically significant decrease in viable pups at birth along with a 9% decrease in body weight. F1 (first generation) pups found dead or dying had dilatation of ureters and hydroureters; F2 (second generation) pups had dilatation or deformed ureters or distended bladder alone or in combination.
Fetal and neonatal pulmonary vascular resistance is modulated by cGMP, levels of which are controlled, in part, by the phosphodiesterase enzyme which is inhibited by sildenafil.(7) How this might affect fetuses and newborns needs to be delineated.
The designation of Viagra as Category B for pregnancy is a violation of FDA's own definition of Pregnancy Category B, which requires, if animal studies show risk, that "adequate studies in pregnant women have not demonstrated a risk to the fetus" (there are clearly no studies now nor will there ever be in which Viagra is given to pregnant women).
The correct pregnancy category for Viagra is Category C, defined by the FDA as "Animal studies have shown an adverse effect on the fetus but there are no adequate studies in humans ; the benefits from the drug in pregnant women may be acceptable despite its potential risks..."
The first definitive assay with human lymphocytes produced statistically significant increases in the number of cells with multiple chromosomal aberrations; a repeat study was negative.(8) It would appear from this that the overall results are equivocal, rather than negative as stated by the sponsor.
The label states that "No cases of priapism were reported" (persistent erection of the penis accompanied by pain and tenderness). However, there are now (as of June 30, 1998) at least six reports of priapism in the adverse events reports filed with the FDA, and these should be listed as adverse events in the label.
There is no information in the current label that addresses the findings of periarteritis (severe inflammation of blood vessels) that occurred in both rats and dogs, even though the Pharmacology Reviewer stated that this was the most important toxicological finding(9) (and appears closely related to the inhibition of the phosphodiesterase type 5 enzyme located in vascular smooth muscle). Furthermore, most toxicological findings noted in the pharmacology review lacked complete descriptions which makes analysis difficult (see below).
The FDA Pharmacology Review stated that "the major toxicological finding"(10) in the 1-year dog toxicity study was periarteritis, yet no clear and comprehensive description of this finding was provided in the FDA review other than the statement that it involved "the heart and other organs."
A similar lack of description occurred in the 6-month dog toxicity study where periarteritis was disseminated to "thymus, mediastinal lymph nodes, thyroid, epididymides, optic meninges, etc."(11) We are not informed as to what other organs were affected. What were the findings in affected organs? How serious and extensive were the findings?
A 1-month oral rat toxicity study showed mesenteric arteritis in mid- and high-dose males "considered by the sponsor to be drug-related."(12) Yet, there were no descriptions of this finding in the review nor any information as to how it might relate to periarteritis in dogs.
A 1-month i.v. rat toxicity study found "a chronic inflammation in the myocardium (left and right ventricles)"(13) but no information as to whether this also was related to the above findings.
Since the findings of arteritis occurred in two species and are serious, a fuller description of findings based on the toxicity studies appears justified, and if, as it now appears, they are of sufficient extent and severity, a section in the label on animal toxicity should be added, especially since this drug is given to people with diseases of the heart and circulatory systems.
Effects of Phosphodiesterase (PDE) Inhibition on Vision
Phosphodiesterase controls the level of cyclic GMP (cGMP) in the retina by breaking down cGMP as it is formed. This function is extremely important as high levels of cGMP can damage the retina leading to the degeneration of the photoreceptors and eventual blindness. "Inactive PDE led to accumulation of cGMP and subsequent rapid retinal degeneration. In humans, mutations in both the PDE and PDE genes have been linked to autosomal recessive retinitis pigmentosa (arRP) in some families."(14) Viagra, by inhibiting the PDE in the retina, has the potential of producing high and damaging levels of cGMP in some individuals. The current labeling does caution about using the drug in patients with retinitis pigmentosa but fails to explain that visual problems more severe than just "blue" vision may be possible.
Viagra is a potent inhibitor of PDE VI (located in the retina) as well as PDE V (located in platelets and vascular smooth muscle). Viagra has a longer half-life in retina than any other tissue and the highest concentration 24 hours postdose (observed in rat, the only animal tested). Repeated dosing would be expected to further increase retinal levels of Viagra, leading to increased inhibition of PDE and resultant rise in cGMP.
This leaves important unanswered questions: Will cGMP rise to toxic levels in some individuals when Viagra is taken repeatedly (with the potential for retinal degeneration)? How will vision be monitored in people using the drug? Will those with pre-existing retinal diseases be at increased risk of further retinal damage?
In summary, it is urgent that the FDA immediately convene an advisory committee to review the various serious problems related to the use of Viagra, particularly focusing on the risks of patients who, according to the present labeling would not appear to be at risk, with the intention of adding new warnings to the labeling for doctors and patients. We look forward to a prompt reply to this petition and the original one of July 1.
Sidney M. Wolfe, M.D.
Public Citizen's Health Research Group
Larry Sasich, Pharm. D., M.P.H.
Public Citizen's Health Research Group
Elizabeth Barbehenn, Ph.D.
Public Citizen's Health Research Group
1. The most recent time a drug was approved without first being reviewed by an outside advisory committee was with the painkiller, Duract (bromfenac) which was taken off the market this summer after many cases of life-threatening or fatal liver toxicity.
2. Summary Statement of the American College of Cardiology and the American Heart Association on the Use of Sildenafil (Viagra) in Patients at Clinical Risk From Cardiovascular Effects. August 10, 1998.
3. FDA Pharmacology Review; p. 96.
4. FDA Pharmacology Review; p. 93.
5. FDA Pharmacology Review; p. 101.
6. FDA Pharmacology Review; p. 99.
7. Sanchez LS, de la Monte SM, Filippov G, Jones RC, Zapol WM, Bloch KD. Cyclic-GMP-binding, cyclic-GMP-specific phosphodiesterase (PDE5) gene expression is regulated during rat pulmonary development. Pediatric Research 1998; 43:63-8.
Ziegler JW, Ivy DD, Fox JJ, Kinsella JP, Clarke WR, Abman SH. Dipyridamole potentiates pulmonary vasodilation induced by acetylcholine and nitric oxide in the ovine fetus. American Journal of Respiratory Critical Care Medicine 1998; 57:1104-10.
8. FDA Pharmacology Review; p. 108.
9. FDA Pharmacology Review; p. 45.
10. FDA Pharmacology Review; p. 45.
11. FDA Pharmacology Review; p. 42.
12. FDA Pharmacology Review; p. 31.
13. FDA Pharmacology Review; p. 36.
14. Li N, Florio SK, Pettenati MJ, Rao PN, Beavo JA, Baehr W. Characterization of human and mouse rod cGMP phosphodiesterase delta subunit (PDE6D) and chromosomal localization of the human gene. Genomics 1998; 49:76-82.