While sildenafil, vardenafil, and tadalafil are all hepatically metabolized, there are variances in their pharmacokinetic profiles.

Key Takeaways

Sildenafil is approximately 75% metabolized, predominantly by cytochrome P450 (CYP) 3A4 with contribution from CYP 2C9.7,8 Vardenafil is primarily metabolized by CYP 3A4 and secondarily by CYP 3A5 and 2C isoforms.7,9 Tadalafil is also metabolized by CYP 3A4.2,10 With CYP 3A4 being the major enzyme responsible for the metabolism of all three agents, they will potentially have many of the same drug interactions with some possible contributions from the minor enzymatic pathways. Other pharmacokinetic differences include time to maximum concentration and half-life. The slightly faster time to maximum concentration of vardenafil (0.7 hours) compared to sildenafil (0.8 hours) is likely clinically irrelevant, while tadalafil has the slowest onset and may require 2 hours to reach maximum concentration. Tadalafil, however, has the longest half-life (17.5 hours), followed by vardenafil (4 hours) and sildenafil (3.7 hours).7-10 These differences will account for variation in dosage timing and duration of effect. The considerably longer duration of effect for tadalafil will likely allow less frequent dosing and greater impulsiveness between partners, but also could potentially prolong adverse effects.

Product	Dosage	Quantity + Bonus	Price
Cialis Generic	10mg	30 + 4 Pills	63.32€ 60.30€
Cialis Generic	20mg	180 + 10 Pills	254.09€ 241.99€
Cialis Generic	20mg	360 + 10 Pills	427.34€ 406.99€
Tadalista Super Active	20mg	120 + 16 Pills	382.15€ 363.95€
Cialis Generic	10mg	270 + 10 Pills	308.71€ 294.01€
Cialis Generic	40mg	30 + 4 Pills	74.97€ 71.40€
Cialis Generic	40mg	10 Pills	37.79€ 35.99€
Cialis Generic	40mg	90 + 6 Pills	171.35€ 163.19€
Cialis Generic	5mg	10 Pills	29.39€ 27.99€
Cialis Generic	5mg	120 + 6 Pills	132.92€ 126.59€

There are no comparative trials evaluating sildenafil, vardenafil, and tadalafil; therefore, it is difficult to compare the individual trials available due to differences in study design and methodology. However, all three agents have been proven effective in treating ED in clinical trials based on the Erectile Function domain score of the International Index of Erectile Function, a sexual function questionnaire commonly used throughout the studies.

Eligibility Criteria

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.

Side Effect	Frequency	Severity	Management Tips
Headaches	20%	Mild	Hydration, analgesics
Flushing	15%	Mild	Cooling measures
Nasal Congestion	10%	Mild	Decongestants
Dyspepsia	8%	Mild	Dietary adjustments

Tadalafil generally takes about 30-60 minutes to work in women.
Its effects can last up to 36 hours, providing flexibility.
It is not a standard treatment but a research tool in women.
The drug is often compared to sildenafil in studies.
Women should avoid heavy meals before taking tadalafil.
Proper hydration may improve its effectiveness.
Women with hypertension should consult a doctor before use.
Tadalafil may cause visual disturbances in rare cases.
Its safety profile in women continues to be studied.

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 sublingual tadalafil 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. 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.

Contraindication	Explanation	Alternatives
Use of Nitrates	Risk of severe hypotension	Consult doctor for other options
Severe Liver Impairment	Metabolism issues	Adjusted doses or avoid use
Heart Conditions	Possible cardiovascular risk	Medical supervision required
Hypotension	Blood pressure may drop excessively	Monitor BP regularly

Concomitant administration of tadalafil with the alpha-blockers, except tamsulosin (Flomax®) is contraindicated. Tadalafail was evaluated in combination with doxazosin (Cardura®) and resulted in a significant increase in the blood pressure-lowering effect of doxazosin.

Aspect	Feedback from Users	Common Concerns
Efficacy	Some report improved sexual satisfaction	Mixed results, placebo effect possible
Side effects	Mild headaches, flushing reported	Worry about adverse effects
Accessibility	Often limited to trials or off-label use	Cost and regulation issues
Desire for more research	Strong demand for more data	Lack of official approval

Similarly to the other agents, tadalafil is also contraindicated with the use of organic nitrates.

Ethics declarations

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 tadalafil for premature ejaculation 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. 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.

Ethical Approval

No trials 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. 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.

Who may be considered for tadalafil?

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. 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. 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.

What happens if I miss a dose?

Comparison with other treatments

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. 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.

Tadalafil's role in female sexual health is promising but unconfirmed.
It may be used alongside counseling for better outcomes.
The medication helps enhance blood flow to the clitoris and labia.
Not recommended as a first-line treatment for women.
Tadalafil research involves small sample sizes so far.
Its use in women is increasingly accepted in clinical trials.
Women should discuss potential risks with healthcare providers.
It is available in some countries specifically for research use.
Further evidence needed to recommend widespread use.

Tadalafil is sometimes studied for female sexual arousal disorder.
It may increase blood flow to genital areas in women.
Tadalafil can help improve sexual satisfaction in women.
Used off-label, as it’s not officially approved for women.
Potential side effects include headache and flushing in women.
Research on tadalafil’s effects on female libido is ongoing.
Tadalafil might benefit women with sexual arousal issues.
Dosage for women is not standardized; typically lower doses.
Used in clinical trials to assess its safety for women.

Any tadalafil for premature ejaculation 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. 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 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.

What special precautions should I follow?

While sildenafil, vardenafil, and tadalafil are all hepatically metabolized, there are variances in their pharmacokinetic profiles. Sildenafil is approximately 75% metabolized, predominantly by cytochrome P450 (CYP) 3A4 with contribution from CYP 2C9.7,8 Vardenafil is primarily metabolized by CYP 3A4 and secondarily by CYP 3A5 and 2C isoforms.7,9 Tadalafil is also metabolized by CYP 3A4.2,10 With CYP 3A4 being the major enzyme responsible for the metabolism of all three agents, they will potentially have many of the same drug interactions with some possible contributions from the minor enzymatic pathways. Other pharmacokinetic differences include time to maximum concentration and half-life. The slightly faster time to maximum concentration of vardenafil (0.7 hours) compared to sildenafil (0.8 hours) is likely clinically irrelevant, while tadalafil has the slowest onset and may require 2 hours to reach maximum concentration. Tadalafil, however, has the longest half-life (17.5 hours), followed by vardenafil (4 hours) and sildenafil (3.7 hours).7-10 These differences will account for variation in dosage timing and duration of effect.

Conflicts of interest

The considerably longer duration of effect for tadalafil will likely allow less frequent dosing and greater impulsiveness between partners, but also could potentially prolong adverse effects. There are no comparative trials evaluating sildenafil, vardenafil, and tadalafil; therefore, it is difficult to compare the individual trials available due to differences in study design and methodology. However, all three agents have been proven effective in treating ED in clinical trials based on the Erectile Function domain score of the International Index of Erectile Function, a sexual function questionnaire commonly used throughout the studies. 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.

Female sexual arousal disorder

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. John's wort and rifampin, may have the opposite effect and cause decreased sildenafil levels. Drug-food interactions with sildenafil can also occur. 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. 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. 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.

Why Choose Tadalafil & Oxytocin Therapy?

Adverse Effects

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. 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.

Authors and Affiliations

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. 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.