A 69 y/o male patient presents to your clinic for a routine appointment. He mentions he's having some trouble 'in the bedroom' and ask for you help. He's seen the "blue pill" commercials on the television. His
medical history is significant for a CABG 14 months ago, mild CHF, and type II diabetes. His meds include simvastatin 20mg QD, lisinopril 10mg po QD, glyburide 3mg po QD, baby ASA po QD, SL nitroglycerin 0.4mg PRN. His vital signs and routine labs are within normal limits at this time. He states he's compliant with his medications and only uses the SL nitroglycerin 2-3 times a month.

Do you write the sildenafil [Viagra®] prescription or not? Why or why not?

 NO - do not write the prescription.

The package insert for Viagra® (sildenafil) lists nitroglycerin or any organic nitrates (isosorbide dinitrate, isosorbide mononitrate, etc) as a CONTRAindication. Whether scheduled dosing or PRN use, whether it's for angina or anything else, it's still a contraindication. The literature does not currently state when nitrates, if indicated, can be safely administered after a dose of sildenafil. Even in healthy male volunteers, there were large drops in blood pressure when given in combination. There have been deaths associated with this combination reported to the FDA and the manufacturer. The Pharmacy Data Transaction Service (PDTS) system lists this interaction as the on of the top 10 DUR edits, requiring consultation with the providers.

As explained more eloquently below, sildenafil prolongs and potentiates the HYPOtensive effects of organic nitrates. Blood pressure drops as great as 30-50 mm/Hg have been reported when these drugs were given in combination. As stated above, these drops were seen in normal healthy male volunteers. One could reasonably expect a similar blood pressure drop in this "Pearl" patient and the subsequent symptoms to this significant HYPOtension. And if this patient developed angina from the hypotension, what would he likely do? Probably use more of his SL nitroglycerin to relieve his chest pain! Bottom line - please don't use these drugs in combination.

FYI - there are a couple of other oral ED drugs soon to be marketed - tardenafil, vardenafil. To the best of my knowledge, they will carry the same CONTRAindication with organic nitrates when commercially available.

Another FYI - Sildenafil [Viagra®] is also NOT waiverable in aircrew members because of the blue-green vision it can cause in a small percentage of patients.

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From MICROmedex:

P. ORGANIC NITRATES

*    1. Summary: Sildenafil inhibits phosphodiesterase type 5 (PDE5) which is responsible for the metabolic degradation of cyclic guanosine monophosphate (cGMP). Organic nitrates exert their action by activation of guanylate cyclase, which increases cGMP. Because of the potential for excessive hypotensive effects as a result of increased cGMP, the concomitant use of sildenafil and organic nitrates is contraindicated. It is unknown when nitrates can again be safely administered following sildenafil
administration (Prod Info Viagra(R), 2000). A randomized, double-blind, placebo-controlled, 2-way crossover study of 12 healthy men demonstrated that sildenafil potentiates the hypotensive effects of organic nitrates (Webb et al, 1999).

*    2. Adverse Effect: potentiation of hypotensive effects

*    3. Clinical Management: The concomitant administration of sildenafil and organic nitrates in any form is contraindicated. It is unknown when nitrates can again be safely administered following sildenafil
administration.

*    4. Severity: major

*    5. Onset: rapid

*    6. Documentation: good

*    7. Probable Mechanism: increased levels of cyclic guanosine monophosphate (cGMP) from sildenafil and nitrates

*    8. Literature Reports:

         a. A randomized, double-blind, placebo-controlled, two-way crossover study of 12 healthy men demonstrated that sildenafil potentiates the hypotensive effects of organic nitrates. The men received either 25 mg sildenafil three times daily or placebo for four days, followed by a single morning dose on day 5. Nitroglycerin was given intravenously on day 4 as a stepwise infusion one hour after the sildenafil morning dose. On day 5, nitroglycerin 500 mcg was given sublingually one hour after the morning dose of sildenafil or placebo. In both cases, the nitroglycerin was discontinued when the subject's systolic blood pressure was decreased by more than 25 mm Hg. For the intravenous infusion, two of the 12 subjects in the placebo group completed the 25-minute infusion, while none completed the infusion in the sildenafil group. Similarly, with sublingual nitroglycerin, four of the 12 subjects in the placebo group removed the sublingual tablet after three to four minutes, versus 11 of 12 subjects who removed the tablet after two to seven minutes in the sildenafil group. The most frequently occurring adverse events reported by the 12 subjects were headache and dizziness (Webb et al, 1999).

          b. Two studies demonstrated the effects of a single oral dose of sildenafil citrate on blood pressure in men taking nitric oxide donor drugs, isosorbide mononitrate and glyceryl trinitrate, for stable angina. Two double-blind, placebo-controlled, randomized, two-way crossover trials were completed. Sixteen subjects received oral isosorbide mononitrate beginning five to seven days before receiving a single dose of sildenafil or placebo. Administration of isosorbide mononitrate with sildenafil resulted in substantially greater decreases in blood pressure from baseline (-52/-29 mm Hg) as compared with those subjects receiving isosorbide mononitrate plus placebo (-25/-15 mm Hg). The second study involved fifteen male subjects who were receiving sublingual nitroglycerin as needed for stable angina. A single dose of sildenafil or placebo followed by nitroglycerin sublingual one hour later was administered to patients. At least seven days later, subjects received the alternate study drug (sildenafil or placebo) and nitroglycerin sublingual one hour later. Sildenafil plus nitroglycerin resulted in an increase in mean reductions from baseline in systolic/diastolic blood pressure (-36/-21 mm Hg) compared with placebo plus nitroglycerin (-26/-12 mm Hg). Substantially greater decreases in blood pressure occur from baseline with administration of isosorbide mononitrate plus sildenafil compared to patients receiving isosorbide mononitrate plus placebo. A clinically significant reduction in blood pressure occurs with concomitant use of sildenafil and nitrates, such as isosorbide mononitrate and nitroglycerin (Webb et al, 2000). 

REFERENCES:

-Webb DJ, Freestone S, Allen MJ et al: Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Am J Cardiol 1999; 83(suppl a):21C-28C. 

- Product Information: Viagra(R), sildenafil citrate. Pfizer Labs, New York, NY, (PI revised 1/2000, reviewed 8/2000).

-    Webb D, Muirhead G, Wulff M et al: Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina. J Am Coll Cardiol 2000; 36(1):25-31.