`(Viagra's) Dangers to the Drug Label
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`More information on sildenafil (Viagra)
`Petition to Require a Black Box Warning for Erectile
`Dysfunction Drugs Sildenafil (Viagra), Tadalafil (Cialis)
`and Vardenafil (Levitra) to Warn of the Potential for
`Irreversible Vision Loss, October 20, 2005
`Letter Urging the Therapeutic Products Program in Canada
`to Require Warnings on the Label of Sildenafil (Viagra),
`August 24, 1998
`Letter Urging FDA to Convene an Advisory Committee to
`Review Problems Related to the Use of Sildenafil (Viagra),
`August 20, 1998
`Letter Requesting Warnings on Sildenafil (Viagra), August
`27, 1998
`Petition to Add Information about Sildenafil's (Viagra's)
`Dangers to the Drug's Label, July 1, 1998
`
`July 1, 1998
`
`Michael A. Friedman, M.D.
`Lead Deputy Commissioner
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, Md. 20857
`
`Dear Dr. Friedman,
`
`The purposes of this letter are to petition FDA to change the labeling and other sources of information
`about Viagra to add important information about the drug's dangers currently missing from such
`sources and to warn doctors and patients that a substantial proportion of patients using the drug are
`unwittingly using it to treat impotence or other types of sexual dysfunction which are probably adverse
`reactions caused or worsened by other drugs known to impair sexual function.
`
`Most of the information and data upon which the first part of this petition is based, concerning Viagra's
`safety, is taken from the documents comprising the FDA's own review of sildenafil, conducted before
`the drug was cleared for marketing.
`
`There are several extremely troubling safety problems in the FDA's review of sildenafil. Most of these
`are not included in the FDAapproved labeling for Viagra, the unregulated patient information leaflets
`given to patients when they get their prescription filled, FDA's "Consumer Information about Viagra"
`(FDA web site, 4/30/98) or in the "Dear Doctor" letter sent by Pfizer to doctors in May, 1998.
`
`Men With Diseases Which Would Have Excluded Them from Pre
`Approval Experiments but Who are not Excluded from Viagra Use Now
`In all of the large multicenter clinical trials of Viagra, men with various medical conditions were
`excluded from the studies. Among those excluded were people with blood pressures of less than
`90/50 or more than 170/100; active peptic ulcer disease or bleeding disorder; any clinically significant
`baseline laboratory abnormality, need for anticoagulants, androgens, or trazodone (an
`antidepressant); need for aspirin or NSAIDS and a history of peptic ulcer disease; history of retinitis
`pigmentosa; uncontrolled diabetes or diabetic retinopathy; stroke or myocardial infarction within 6
`months, cardiac failure, unstable angina, ECG ischemia (a common finding in people with coronary
`artery disease); or lifethreatening arrhythmia within 6 months. For none of these conditions is there
`an exclusion in the FDAapproved labeling for sildenafil.
`
`Thus, people whom investigators correctly thought might be at higher risk for adverse effects of
`sildenafil were usually excluded from the preapproval experiments using the drug but people with
`such diseases are not excluded from using the drug now that it is on the market. The risks of this
`double standard are selfevident. It is especially irresponsible for Pfizer and others to ascribe deaths
`from cardiovascular events in people using Viagra to the fact that the patients were at increased risk
`of cardiovascular disease (such as the following exclusions listed above: blood pressures of less than
`90/50 or more than 170/100; uncontrolled diabetes or diabetic retinopathy; stroke or myocardial
`infarction within 6 months, cardiac failure, unstable angina, ECG ischemia (electrocardiographic
`evidence of inadequate blood supply to the heart); or lifethreatening arrhythmia within 6 months) and
`therefore that the deaths are not drugrelated when many men with these very increased risks were
`excluded from the preapproval trials.
`
`If these exclusions were applied to men currently using the drug, the number of people using the drug
`would be much lower and the overall dangers of the drug would be lessened. Because people with
`such medical problems were excluded from the controlled trials of Viagra based on the possibility that
`they would be at increased risk of adverse effects, only now, with the mass marketing to hundreds of
`thousands of men, many with these medical problems, is the "experiment" to find out about their
`increased risk being performed.
`
`Significant Lowering of Blood Pressure by Viagra Alone and with Drugs
`other Than Nitrates
`In laboratory studies involving animals, sildenafil caused a drop in blood pressure in 40 percent of the
`animals and increased the heart rate in 18 percent of the animals. Significant blood pressure lowering
`effects were also seen in human studies. As mentioned above, men with blood pressure less than
`90/50 were excluded from some of the studies and in people with these low blood pressures, now not
`excluded from using Viagra, the further blood pressure lowering effects of the drug might cause
`serious problems. In addition to human evidence of Viagra's blood pressure lowering effects on its
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`ATI 1015-0001
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`ATI v. ICOS
`IPR2018-01183
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`own, there was also a significant further lowering of blood pressure by Viagra in one study in people
`already stabilized on amlodipine (Norvasc), a calcium channel blocking drug used for the treatment of
`hypertension. Subjects on a stable dose of amlodipine were given a single oral 100 mg dose of
`sildenafil after an overnight fast. "By the sponsor's analyses, most of the treatment group differences
`were nominally highly statistically significant" [referring to additional decreases in systolic and
`diastolic pressure, both supine and standing.] Blood pressure effects occurred between an hour to
`several hours after the dose. "Although substantial, subjects were not symptomatic, at least under the
`controlled clinical conditions."
`
`The drug's effect on blood pressure has previously been addressed as a major safety concern, and
`men who are taking drugs like nitroglycerin (called nitrates) to control chest pain (angina) should not
`take sildenafil because the nitrates also affect blood pressure. Shortly after the drug was approved,
`six additional deaths were reported to the drug's maker, Pfizer Inc. of New York, and Pfizer sent out a
`"Dear Doctor" letter to remind physicians that sildenafil must not be used by men who are taking
`nitrates to control chest pain. (A list of nitrate drugs follows)
`
`Effects on Vision: Understated in Labeling and Other Information
`Vision abnormalities are another troubling adverse effect of sildenafil. The professional product
`labeling, or package insert, for the drug states that abnormal vision, usually a color tinge but also
`increased sensitivity to light or blurred vision, were seen in some studies in as many as 11 percent of
`men using the drug. Sildenafil works by inhibiting an enzyme, phosphodiesterase, a form of which is
`found in many parts of the body including the eye. Some scientists think changes in this enzyme can
`lead to some types of a serious disorder called retinitis pigmentosa, which in turn can cause retinal
`degeneration and loss of vision.
`
`In a single dose study (doses of 100800 mg), visual disturbances were seen in about half the
`subjects at doses >100 mg and included difficulty seeing in dim light, color aberration, and color
`tinges. The duration of these events increased with dose. "Effects attributable to inhibition of retinal
`phosphodiesterase appeared at doses >100 mg."
`
`Another study in healthy male volunteers found doserelated color discrimination errors beginning at
`100mg which lasted a few hours.
`
`A third study looked at visual function in 8 normal males and 8 subjects with diabetic retinopathy,
`given either 200 mg drug or placebo in a crossover design: the photopic electroretinogram (ERG)
`showed a 50% reduction in amplitude in the response to blue light at both 1.25 and 5 hours postdose
`(aberration in color vision was actually seen with most colors). There were delays in the ERG
`waveform in both the light and darkadapted states in normals; none of the diabetics underwent the
`ERG test.
`
`It should be noted that although the most serious and common visual abnormalities occurred at doses
`greater than the recommended maximum dose of 100 mg per day, the most common violation of the
`protocol in the studies on the drug was taking more than one dose a day. In addition, a 125 pound
`man taking 100 mg would be getting twice the dose per pound as a 250 pound man taking the same
`dose. In the unregulated patient information leaflets currently being dispensed with Viagra, it states
`"Take only as directed, usually once daily as needed." (emphasis supplied). Thus the directions for
`patients do not clearly warn against taking more than 100 mg a day, assuming this leaflet
`accompanies a prescription for the 100 mg dosage form.
`
`Drugs Which Can Cause Sexual Dysfunction Including Impotence
`Sexual dysfunction consists of a variety of complaints which include (either alone or in combination)
`loss of desire, inability to initiate or maintain an erection, ejaculatory failure, premature ejaculation, or
`inability to achieve orgasm. Impotence is simply defined as the failure to achieve erection, ejaculation,
`or both. A number of diseases can potentially cause sexual dysfunction, as can a large number of
`drugs. (A list of these medications is printed below.) There is a serious question as to whether
`patients, were they adequately informed, would choose to use sildenafil to treat the sexual adverse
`effects of another drug, especially if an alternative drug which did not cause sexual dysfunction or a
`lower dose of the same drug or would obviate the need for sildenafil.
`
`Many commonly used drugs can interfere with sexual function in both men and women, causing loss
`of libido, or can interfere with erection or ejaculation in men, or can delay or prevent orgasm in
`women. Drugrelated effects on sexual function may be difficult to distinguish from the effects of
`depression or disease, but most are reversible when drug use is stopped and sometimes when
`dosage is decreased.
`
`This list of drugs was originally prepared by the editors of The Medical Letter on Drugs and
`Therapeutics, a highly respected independent source of drug information, written for doctors and
`pharmacists. We have added new drugs to the list if there was evidence from published studies that
`they can cause sexual dysfunction.
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`ATI 1015-0002
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`In the first 174 adverse reaction reports received by FDA since Viagra was marketed and up to
`June 30, 1998, 75 listed one or more drugs being taken by the patient in addition to Viagra. Of
`these 75 reports, the other drugs were fully listed in 69 of the reports. Of these 69 adverse
`reaction reports, 32 (46.4%) included one or more drugs known to cause sexual dysfunction.
`
`Of the 75 reports in which patients were using one or more drugs in addition to Viagra, in 27 or
`36%, one or more drugs for the treatment of cardiovascular diseases were used, many of which
`were probably the diseases for which people were excluded in the preapproval clinical trials.
`Some of the cardiovascular disease (including diabetes) for which people are taking these drugs, in
`addition to Viagra, are themselves associated with an increased amount of sexual dysfunction. But to
`worsen preexisting sexual dysfunction and then treat this with Viagra, instead of attempting to
`substitute another drug less likely to cause sexual dysfunction or to lower the dose of the offending
`drug seems to be an unwise medical decision, if indeed it is being made with full knowledge.
`
`List of Drugs Which Can Cause Sexual Dysfunction
`(Patients should not stop using or modify the dose of any of these drugs without consulting their
`physicians)
`
`Heart and Blood Vessel Drugs
`Antianginal Drugs:
`digoxin (Lanoxin); nifedipine (Adalat, Adalat CC, Procardia, Procardia XL); verapamil (Calan, Covera
`HS, Isoptin, Verelan)
`
`Antiarrhythmics:
`amiodarone (Cordarone); disopyramide (Norpace); mexiletine (Mexitil)
`
`Blood Vessel Dilators:
`papaverine (Cerespan)
`
`Cholesterollowering Drugs:
`clofibrate (AtromidS); gemfibrozil (Lopid)
`
`High Blood Pressure Drugs, (Betablockers):
`atenolol (Tenormin); betaxolol (Kerlone); bisoprolol (ZeBeta); carteolol (Cartrol); carvedilol (Coreg);
`labetalol (Normodyne, Trandate); metoprolol (Lopressor); penbutolol (Levatol); propranolol (Inderal);
`timolol (Blocadren)
`
`High Blood Pressure Drugs, (Diuretics):
`amiloride (Madamor); chlorthalidone (Hygroton); hydrochlorothiazide (HydroDiuril); indapamide
`(Lozol)
`
`High Blood Pressure Drugs, (Other):
`ALDACTONE; ALDOMET; APRESOLINE; CATAPRES; clonidine (Catapres); guanabenz (Wytensin);
`guanadrel (Hylorel); guanethidine (Ismelin); guanfacine (Tenex); hydralazine (Apresoline);
`mecamylamine (Inversene); methyldopa (Aldomet); metyrosine (Demser); prazosin (Minipress);
`reserpine (Serpasil); spironolactone (Aldactone)
`
`Antibiotics and Other AntiInfective Agents
`ketoconazole (Nizoral)
`
`Anticholinergic Drugs
`anisotropine (Valpin); clidinium (Quarzan); dicyclomine (Bentyl); glycopyrrolate (Robinul);
`homatropine (Isopto Homatropine); isopropamide (Darbid); mepenzolate (Cantil); methanetheline
`(Banthine); methscopolamine (Pamine); oxybutynin (Ditropan); propantheline (ProBanthine);
`scopolamine (Transderm Scop); tridihexethyl (Pathilon)
`
`Cancer Drugs
`interferon alfa (Intron A); leuprolide (Lupron); methotrexate (Rheumatrex); tamoxifen (Nolvadex)
`
`Eye Drugs
`acetazolamide (Diamox)
`
`Gastrointestinal Drugs
`cimetidine (Tagamet, Tagamet HB); famotidine (Pepcid); metoclopramide (Reglan); nizatidine (Axid);
`omeprazole (Prilosec); ranitidine (Zantac); sulfasalazine (Azulfidine EN)
`
`MindAffecting Drugs
`Antidepressants:
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`ATI 1015-0003
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`amitriptyline (Elavil); amoxapine (Asendin); desipramine (Norpramin); doxepin (Sinequan); fluoxetine
`(Prozac); fluvoxamine (Luvox); imipramine (Tofranil); isocarboxazid (Marplan); lithium (Lithobid);
`maprotiline (Ludiomil); nefazodone (Serzone); nortriptyline (Norpramine); paroxetine (Zoloft); PAXIL;
`PERTOFRANE; phenelzine (Nardil); protiptyline (Vivactil); trancylpromine (Parnate); trazodone
`(Desyrel); venlafaxine (Effexor)
`
`Antipsychotics:
`chlorpromazine (Thorazine); chlorprothixene (Taractan); clozapine (Clozaril); fluphenazine (Prolixin);
`haloperidol (Haldol); mesoridazine (Serentil); molidone (Moban); olanzapine (Zyprexa);
`perphenazine (Trilafon); pimozide (Orap); risperidone (Resperdal); thioridazine (Mellaril); thiothixene
`(Navane); trifluoperazine (Stelazine)
`
`Barbiturates:
`pentobarbital (Nembutal)
`
`Tranquilizers:
`alprazolam (Xanax); buspirone Buspar); diazepam (Valium)
`
`Neurological Drugs
`Anticonvulsants:
`carbamazepine (Tegretol) ; ethosuximide (Zarontin); phenytoin (Dilantin)
`
`Antiparkinsonians:
`bromocriptine (Parlodel); levodopa (Dopar); pergolide (Permax)
`
`Painkillers/Narcotics
`indomethacin (Indocin); methadone (Dolophine); naltrexone (Trexan); naproxen (Naproxyn)
`
`Other Drugs
`alcohol; baclofen (Lioresal); cocaine; danazol (Danocrine); diethylpropion (Tenuate); disulfuram
`(Antabuse); etretinate (Tegison); fat emulsion (Intralipid); finasteride (Proscar); mazindol (Sanorex);
`nafarelin (Synarel); phenmetrazine (Plegine); phentermine (Ionamin); propofol (Diprivan);
`testosterone (DepoTestosterone)
`
`Drugs Containing Nitrates: Do Not Use With Viagra
`Nitroglycerin Containing Drugs:
`Deponit; Minitran; Nitrek; NitroBid; Nitrocine; NitroDerm; Nitro Disc; NitroDur; Nitrogard;
`Nitroglycerin; Nitroglycerin T/R; Nitroglyn; Nitrol Ointment; Nitrolan; Nitrolingual Spray; Nitrong;
`Nitropar; Nitropress; Nitroprex; Nitro S.A.; Nitrospan; Nitrostat; NitroTrans System; Nitro Transdermal;
`NitroTime; TransdermNitro; Tridil.
`
`Isosorbide Mononitrate Containing Drugs:
`Imdur; ISMO; Isosorbide Mononitrate; Monoket; Isosorbide Nitrate; DilatrateSR; Isobid; Isordil; Isordil
`Tembids; Isosorbide Dinitrate; Isosorbide Dinitrate LA; Sorbitrate; Sorbitrate SA.
`
`Pentaerythritol Tetranitrate Containing Drugs:
`Peritrate; Peritrate SA.
`
`Erythrityl Tetranitrate Containing Drugs:
`Cardilate.
`
`Isosorbide Dinitrate/Phenobarbital Containing Drugs:
`Isordil w/PB.
`
`Illicit Substances Containing Nitrates:
`Amyl nitrate or nitrite that goes by various names, including "poppers" and butyl nitrate.
`
`Summary
`We urge you to act immediately to protect American patients by changing the labeling for Viagra to
`include more information about adverse effects on vision, dangers of use with certain drugs for
`treating hypertension and to contraindicate the drug in people with the diseases or conditions which
`served as a basis for exclusion during the clinical trials. In addition, doctors and patients need to be
`informed about the long list of drugs which can cause impotence or other forms of sexual dysfunction
`in order to decrease the likelihood that Viagra is being used as a treatment for druginduced sexual
`dysfunction.
`
`Sincerely,
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`ATI 1015-0004
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`
`
`Sidney M. Wolfe, M.D.
`Director
`
`Larry Sasich, Pharm. D., M.P.H.
`
`Elizabeth Barbehenn, Ph.D.
`Staff Pharmacologist
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`ATI 1015-0005
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