Addressing Hypoactive Sexual Desire Disorder with Tadalafil

Eardley I, Carteledge J. Tadalafil (Cialis™) for men with erectile dysfunction.

• Tadalafil has been studied for use in women with diabetic sexual dysfunction.
• Some reports suggest improved functionality with daily use.
• It is being evaluated for postpartum sexual health issues.
• Female-specific studies include subjective sexual satisfaction assessments.
• Tadalafil's use in women remains an off-label option.
• Side effects in women tend to be mild but should be monitored.
• It may benefit women experiencing vaginal dryness due to blood flow issues.
• Weekly or as-needed dosing strategies are under investigation.
• Women interested should seek specialized medical advice.

de Tejada IS, Anglin G, Knight JR, Emmick JT.

Brand Name

Efficacy rates for the PDE-5 inhibitors vary widely throughout the literature with a range of 57% to 83%.5,11-13 Additionally, they have all shown efficacy in the treatment of ED in men with diabetes mellitus; however, no particular agent has yet to be recommended for patients with cardiovascular disease.2,8,10,12,14,15 Comparative trials are required to determine if a specific agent possesses better efficacy. There are drug-drug interactions with each of these medications, many of which involve the same drugs due to CYP 3A4 being the major enzymatic pathway for all of these agents. Due to the potential for severe hypotension, sildenafil and organic nitrates (e.g., nitroglycerin, isosorbide dinitrate [Isordil®, Sorbitrate®], and isosorbide mononitrate [Imdur, ISMO®, Monoket®]) are contraindicated (i.e., should not be taken together), and sildenafil doses > 25 mg should not be used within 4 hours of taking an alpha-blocker (e.g., prazosin [Minipress®], terazosin [Hytrin®], and doxazosin [Cardura®]). Sildenafil is a substrate of CYP 3A4 and 2C8/9 as well as an inhibitor of CYP 1A2, 2C8/9, 2C19, 2D6, 2E1, and 3A4; therefore, increased effects and possible toxicity of sildenafil occur when used concomitantly with drugs that inhibit these enzymes (e.g., cimetidine [Tagamet®], erythromycin, ketoconazole [Nizoral®], itraconazole [Sporanox®], amprenavir [Agenerase®], indinavir [Crixivan®], saquinavir [Fortovase®], and ritonavir [Norvir®]). Enzyme-inducing agents, such as St.

Female sexual arousal disorder

John's wort and rifampin, may have the opposite effect and cause decreased sildenafil levels. Drug-food interactions with sildenafil can also occur. The rate and extent of absorption of sildenafil is reduced when taken with a high-fat meal and grapefruit juice may cause increased serum concentrations of sildenafil, consequently, concurrent use should be avoided.8-10,16-18 Concomitant use of vardenafil is also contraindicated with alpha-blockers and organic nitrates due to the potential for severe hypotension. Vardenafil is a substrate of CYP 3A4, and to a minor extent the 2C isoforms, leading to interactions with drugs that induce or inhibit these enzymes. Other enzyme inhibitors that may increase vardenafil levels are amiodarone (Cordarone®), cimetidine (Tagamet®), clarithromycin (Biaxin®), delavirdine (Rescriptor®), diltiazem (e.g., Cardizem®, Cardizem® SR, Cardizem® CD, Cardizem® LA, Cartia XT, Dilacor® XR, Diltia XT, Taztia XT, and Tiazac®), fluoxetine (Prozac®), fluvoxamine (Luvox®), nefazodone (Serzone®), nevirapine (Viramune®), saquinavir (Fortovase®), verapamil (Calan®, Covera-HS, Isoptin®SR, Verelan®), and grapefruit juice, but there are no current recommendations for dosage adjustments with these agents.8-10,16-18 Tadalafil is also metabolized by CYP 3A4, resulting in the potential for an interaction with any drug that induces or inhibits this isoenzyme.

Study design

Ketoconazole (Nizoral®) and ritonavir (Norvir®) have both been shown to increase tadalafil levels; other CYP 450 inhibitors (e.g., erythromycin, itraconazole [Sporanox®], and grapefruit juice), however, have yet to be evaluated, but it is likely that they will also increase tadalafil levels. Patients taking potent inhibitors of CYP 3A4 (e.g., ketoconazole [Nizoral®] or ritonavir [Norvir®]) will require a dose adjustment of tadalafil. The dose should not exceed 10 mg and should not be administered more frequently than every 72 hours. Additionally, tadalafil is thought to increase the hypotensive effect of antihypertensive agents (e.g., calcium channel blockers, diuretics, angiotensin-receptor blockers, ACE-inhibitors, or adrenergic receptor-blocking agents) and therefore should be used with caution. Concomitant administration of tadalafil with the alpha-blockers, except tamsulosin (Flomax®) is contraindicated. Effects of tadalafil on erectile dysfunction in men with diabetes.

Jackson G, Betteridge J, Dean J, Eardley I, Hall R, Holdright D, et al.

Ethics declarations

Additional studies are necessary to establish clinical efficacy in a larger patient population and to define which female patients may receive benefit from treatment with sildenafil. Sildenafil, vardenafil, and tadalafil are all effective treatments for ED by inhibiting PDE-5. Some differences exist that may clinically differentiate these agents. Tadalafil has a longer time to maximum concentration and a longer half-life compared to sildenafil and vardenafil. This may allow greater spontaneity and less frequent dosing of tadalafil but may also prolong adverse effects.

Table 4.

Additionally, tadalafil and vardenafil have greater selectivity for PDE-5 than sildenafil; this may produce a lower incidence of ocular adverse effects. These differences will need to be substantiated in post-marketing surveillance to provide evidence of their clinical significance. When selecting the most suitable PDE-5 inhibitor for a patient, sildenafil has the greatest amount of data supporting its efficacy and safety long-term and will most likely remain the drug of choice until more long-term data are available for the other agents. Sildenafil, vardenafil, and tadalafil are currently not on the Cleveland Clinic Foundation Formulary of Accepted Drugs. Erectile dysfunction in the elderly: epidemiology, etiology, and approaches to treatment. A systematic approach to erectile dysfunction in the cardiovascular patient: a consensus statement-update 2002. Efficacy and safety of tadalafil for the treatment of erectile dysfunction:results of integrated analyses. Porst H, Padma-Nathan H, Giuliano F, Anglin G, Varanese L, Rosen R.

• Tadalafil's mechanism targets blood vessels to promote dilation.
• It may help women with blood flow-related sexual problems.
• The drug's research status means limited official approvals.
• Female studies explore impacts on sexual satisfaction and arousal.
• Its off-label use is increasing with ongoing research.
• Tadalafil could improve genital flushing and sensitivity.
• Women with cardiac risk factors should avoid tadalafil.
• Clinical trials are testing daily versus as-needed dosing.
• User reports vary, and more evidence is necessary.

Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial.

Briggs GG, Freeman RK, Yaffe SJ, editors. A reference guide to fetal and neonatal risk: drugs in pregnancy and lactation 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2002. p.

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Further information

Tadalafail was evaluated in combination with doxazosin (Cardura®) and resulted in a significant increase in the blood pressure-lowering effect of doxazosin. Similarly to the other agents, tadalafil is also contraindicated with the use of organic nitrates. This combination can cause severe, possibly fatal, hypotensive episodes.2,10,18 All three agents may potentially cause a prolonged erection greater than 4 hours and priapism, a painful erection greater than 6 hours in duration. Medical assistance should be sought if an erection lasts longer than 4 hours. Additionally, if priapism is not immediately treated, penile tissue damage and permanent loss of potency may result.8-10 There do not appear to be any major differences in contraindications among sildenafil, vardenafil, and tadalafil.

Introduction and Hypothesis

Sildenafil is contraindicated with known hypersensitivity to the drug or concurrent use of organic nitrates.8-10,16-18 Both vardenafil and tadalafil have the same contraindication and, additionally, both are contraindicated with concomitant use of alpha-blockers (with the exception of tamsulosin with tadalafil).8-10,16-18 Due to the presence of PDE-5 in all vascular smooth muscle and inhibition of other PDE isoenzymes, all of these medications may produce adverse effects.7 The most common adverse effects with sildenafil, vardenafil, and tadalafil are listed in Table 1. The major adverse effect that may differ between these agents is ocular effects. It is believed that vardenafil and tadalafil may produce less abnormal vision than sildenafil due to their greater selectivity for PDE-5 compared to PDE-6, the isoenzyme responsible for ocular effects. Any clinically significant difference in effect will need to be clarified by post-marketing surveillance of vardenafil and tadalafil.2,12 While sildenafil and vardenafil have similar recommended dosing, the dosing schedule for tadalafil may differ due to its greater time to maximum concentration and longer half-life. Dosing guidelines are listed in Table 2.2,13 The PDE-5 inhibitors are not FDA-approved for use in women or children.

Professional resources

All of these agents are classified as pregnancy-risk category B.8-10 Pregnancy category B is defined as either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters).21 The price of sildenafil 25- or 50-mg tablets is $90.99 for ten tablets or $259.97 for 30 tablets, while the 100 mg strength of sildenafil is $93.99 for ten tablets or $267.97 for 30 tablets. Finally, the price of tadalafil 5-, 10-, or 20-mg tablets is $89.99 for ten tablets or $259.97 for 30 tablets.22-24 Recently, sildenafil has been investigated for the treatment of pulmonary hypertension.25 It has been shown to decrease pulmonary artery pressure and pulmonary vascular resistance, decrease symptoms, and improve New York Heart Association functional class in patients with pulmonary hypertension. No trials 10 mg tadalafil assessing the ability of vardenafil or tadalafil to treat pulmonary hypertension have been reported. The place of sildenafil and the other PDE-5 inhibitors in treating pulmonary hypertension remains to be elucidated. Researchers have also studied sildenafil for the treatment of sexual dysfunction in women.26,27 While sil-denafil is currently not FDA-approved for this indication, clinical trials have shown improvement of sexual function for some women. Sildenafil for iatrogenic serotonergic antidepressant medication-induced sexual dysfunction in 4 patients.

Study Design

Tadalafil: an oral selective phosphodiesterase 5 inhibitor for treatment of erectile dysfunction. National Institutes of Health consensus development panel on impotence. In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. West Haven, CT: Bayer Pharmaceuticals Corporation; 2003 August. Indianapolis, IN: Eli Lilly and Corporation; 2003 November.