When can i take viagra after taking cialis

when can i take viagra after taking cialis

Cialis vs Viagra: Which is more effective?
Viagra is the most famous erectile dysfunction medication available but there are alternatives, like Cialis.
Viagra and Cialis work in a similar way but they do have differences. You may find one of them works better for you. But which one, Cialis or Viagra?
To help you decide which of these meds is right for you, we’ll explain how Viagra and Cialis are different. We’ll detail what they do, how they do it, any side effects, what dosage to take, and how you buy them.
What are Cialis and viagra?
Cialis and Viagra are medications used to treat erectile dysfunction (ED), which is when a man can’t get or keep an erection that’s hard enough for sex.
They’re both swallowed as a pill before you plan to have sex, and they both improve the flow of blood to your penis to make it easier for you to get an erection.
Neither medication will put you in the mood for sex or increase your sexual desire (libido), and they won’t give you an automatic erection. They help turn your desire into a lasting erection, and they’re amongst the most effective treatments for ED.
Viagra and Cialis also come in cheaper, equally as effective, generic versions too – sildenafil (Viagra) and tadalafil (Cialis).
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How do Cialis and viagra work?
Both medications belong to a class of drugs called phosphodiesterase type 5 (PDE5) inhibitors. They improve the flow of blood to your penis, making it easier for it to fill with blood, giving you an erection.
Viagra and Cialis work by increasing the amount of a substance in your body called cGMP (cyclic guanosine monophosphate). They do this by blocking the PDE5 enzymes that break down cGMP, causing the substance to build up in your blood. This is good, as cGMP relaxes the muscle tissue in your arteries and penis. This, in turn, causes them to relax and widen, improving the flow of blood to your penis. It will then fill with blood easier, which helps you to get an erection.
What’s the main difference between viagra and Cialis?
One of the main differences between Viagra and Cialis is that they are manufactured by different pharmaceutical companies. Viagra is made by Pfizer and Cialis is made by Eli Lilly.
Although both Viagra and Cialis work in the same way, there are some differences between how fast they work and how long they last for.
For most men, Viagra works a little quicker than Cialis. Viagra takes between 30 minutes and one hour to work, whereas Cialis takes a little longer, usually between one to two hours.
The biggest difference is how long they last for. Viagra lasts around four hours for most men, and you may be able to get more than one erection in this time. Cialis lasts for longer, however. It can be effective for up to 36 hours. This has led some people to call Cialis the “weekend pill”, as you can take it at the start of the weekend, and you may reap the benefits until Sunday.
How do you take viagra and Cialis?
Both drugs are usually taken as pills that are swallowed with water.
Rather than being taken on a regular basis, you take Viagra between 30 minutes and one hour before sex. You take Cialis between one to two hours before, although Cialis can be taken earlier as it works for much longer. You can also take a lower strength version of Cialis on a daily basis for certain conditions.
If you take Viagra when you’re eating, it can slow down how quickly it’s absorbed and how fast it works, particularly if you eat a large, high-fat meal. Food won’t affect how quickly Cialis works though.
What dosages do viagra and Cialis come in?
Viagra comes in three different dosages: 25 mg, 50 mg, and 100 mg. The usual starting dosage is 50 mg.
Cialis comes in two dosages: 10 mg and 20 mg. The usual starting dosage is 10 mg. Cialis also comes in 2.5 mg and 5 mg strengths pill that can be taken on a daily basis.
How do you buy viagra and Cialis?
In the US, both Viagra and Cialis are prescription drugs. You have to get a prescription from a licensed healthcare professional, usually a doctor. Some online retailers are also licensed to make prescriptions, like us at FROM MARS. You can have an online consultation with one of our doctors, and if approved, we’ll ship your medication to you for free. This is a fast, easy, and safe way to get the meds you need.
What side effects do Viagra and Cialis cause?
As Viagra and Cialis affect your body in broadly the same way, they can cause similar side effects, particularly the more common ones. These include headaches, nausea and stomach upsets, dizziness, facial flushing, and muscle pain. Viagra more often causes sight disturbances than Cialis though, like blurring and having color tints to your vision.
Side effects may be shorter-lasting with Viagra, as it doesn’t stay in your system for as long as Cialis does.
How much do Cialis and Viagra cost?
The cost of Viagra and Cialis will vary depending on where you buy them. Cialis tends to be slightly more expensive than Viagra, as it’s longer-lasting.
You can buy generic versions of these drugs too. Generic drugs are copies of branded medications, like Viagra and Cialis, made by different manufacturers. Generic drugs contain the same ingredients at the same strengths as the branded ones, so work just the same. They tend to be cheaper too.
Cialis vs viagra – frequently asked questions:
Can you mix viagra with Cialis?
No. Don’t take Viagra and Cialis together. As both drugs work in a similar way and contain similar ingredients, you risk increasing the likelihood of getting side effects, including the more serious ones.
Can you take viagra after Cialis?
Don’t take Viagra and Cialis together, as you risk making their side effects more likely. You should only take one after the other once the first drug is out of your system. Wait at least 24 hours after Viagra, and at least 36 hours after Cialis.
Can you take viagra or Cialis with alcohol?
Viagra and Cialis can be taken with moderate amounts of alcohol. Drinking excessive amounts of alcohol can make some side effects more likely. Alcohol can make it harder to get an erection, so it may counter the effects of Viagra or Cialis.
So which ED medication is right for me?
This depends on you. As Cialis works for longer, it can offer you a certain degree of spontaneity. You could feel its effects for up to 36 hours giving you more freedom over when you have sex and how many times.
But if these drugs do give you side effects, Viagra may be a better option, as it’s shorter lasting.
If you have ED and you want to try Cialis or Viagra, then you can always try both (although not at the same time). You can see which drug works best for you and make an informed decision of which is the right one for your needs.
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Sources.

Normal dose of cialis

normal dose of cialis

Normal dose of cialis.
CHICAGO — For men who don’t respond to on-demand tadalafil (Cialis), a low daily dose may do the trick, researchers said here. About 40% of men who took up to 5 mg of tadalafil every day were able to achieve normal erectile function even if they’d failed as-needed treatment, Edward Kim, MD, of the University of Tennessee Medical Center in Knoxville, and colleagues reported at the World Meeting on Sexual Medicine.
Action Points.
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal. Point out that this randomized study suggests that a significant proportion of men who did not achieve normal erectile function when using the maximum dose of a PRN phosphodiesterase type 5 inhibitor were able to achieve normal scores when treated with a once-daily dose.
Although on-demand treatment with phosphodiesterase 5 (PDE5) inhibitors is highly effective for most men, Kim said, some don’t achieve normal erectile function, even with maximum doses.
To assess whether men for whom on-demand treatment didn’t work would do any better on daily tadalafil, the researchers conducted two double-blind, randomized, controlled trials in 623 men who had a mean age of 58.
All of the men had no response to as-needed treatment over the course of a month. After an additional one-month washout period, they were randomized to one of three groups: tadalafil 2.5 mg titrated to 5 mg, 5 mg, or placebo every day for 12 weeks.
Erectile function, as measured on the International Index of Erectile Function (IIEF-EF) significantly improved over the study period for men who had taken either dose of tadalafil compared with placebo — a score of at least 26 was achieved by 39% of those on the 2.5 mg titrated to 5, 40% of those on 5 mg daily, and 12% of those on placebo ( P.
On average, men treated with either dose of daily tadalafil had an 8-point increase in IIEF-EF domain scores by the end of the trial compared with only a 2-point increase for men on placebo ( P.
They also had significantly greater improvements on the Sexual Encounter Profile (SEP-3) questionnaire with either dose of tadalafil compared with placebo (38% and 40% versus 12%, P.
Kim added that both daily doses of the drug were well tolerated, and that any adverse events were consistent with those seen in previous trials.
He cautioned, however, that the study was limited because it didn’t include an arm for a daily tadalafil dose of only 2.5 mg, and because it involved only a 4-week as-needed dosing period.
Still, he concluded that taking tadalafil once a day “may be a viable option for men with erectile dysfunction that could help restore normal erectile function.”
Kim reported relationships with Eli Lilly, Watson, Astellas, and Auxilium.
Source Reference: Kim ED, et al “Tadalafil once daily following PRN phosphodiesterase type 5 inhibitor treatment, an assessment of return to normal erectile function” WMSM 2012; Abstract 38.

Cialis daily

cialis daily

Cialis Daily vs Cialis: everything you need to know.
Erectile dysfunction (ED) is an incredibly common condition, it is thought to affect half of all men between the ages of 40 and 70. In some cases, it can be mild or only occur infrequently; in other cases, it can be an indication of an underlying health condition like high blood pressure, diabetes or an overactive thyroid.
For many men, ED becomes more of a problem as they age. The good news is that tablets known as PDE-5 inhibitors can be prescribed; these tablets contain medicine that temporarily increases blood flow to the penis, allowing you to attain and maintain an erection sufficient for sex.
There are several PDE-5 inhibitors available but one of the most popular is Cialis, which comes in two varieties: Cialis prescribed for one-off use and Cialis Daily taken every day.
If you’re suffering from erectile dysfunction and considering treatment, read on to learn more about the differences between Cialis, Cialis Daily and the other ED tablets on the market.
What are the side effects?
Cialis Daily comes in tablet sizes of 2.5mg and 5mg, and can cause nausea, vomiting, diarrhoea, an allergic rash, facial flushing, headache and back pain. These side effects are uncommon and usually resolve within a few days. More known side effects are an erection that does not go away and can cause damage to the penis. Additionally, a sudden decrease in vision and hearing may occur although these side effects are very uncommon. A full list of side effects can be found in the information leaflet.
Cialis is available in tablet sizes of 10mg and 20mg and is associated with the same side effects as Cialis Daily. However, because it is prescribed in higher dosages than Cialis Daily, these side effects can be stronger.
Looking for erectile dysfunction treatment?
What does it do?
Cialis Daily enables an erection in men who suffer from ED, and is designed to allow for spontaneous sex. When you take it every day, you should be able to get erections and have sex whenever you want to.
Cialis enables an erection in men with ED but it is designed for one-off use. To get an erection with regular Cialis you will have to take one tablet 30-60 minutes before you plan to have sex.
Who’s it for?
Cialis Daily is suited to men who have sex three or more times a week. It can be particularly helpful for men in long-term relationships who would like to have spontaneous sex with their partner.
Cialis is suited to men who have sex on a less regular basis, or whose ED comes and goes.
When do I take it?
Cialis Daily must be taken once every 24 hours, with or without food. It’s best to get into a routine and take it at the same time each day, as you should never take more than one tablet in a 24-hour period.
Cialis should be taken 30-60 minutes before you plan to have sex.
How quickly does it work, and how long does it last?
When taken correctly (see above), Cialis Daily should begin to work within 3-5 days. After this point, you should be able to achieve erections whenever you want them – bearing in mind that you will only get an erection if you are sexually aroused. Cialis Daily should continue to be effective for as long as you take it.
When taken correctly, Cialis should begin to work within 30-60 minutes. The effects of one Cialis tablet can last up to 36 hours; however during this period you will only achieve an erection if you become sexually aroused.
What’s the pack size, and how expensive is it?
Cialis Daily ordered from LloydsPharmacy Online Doctor comes in packs of 28. Per tablet, Cialis Daily is cheaper than Cialis, however you may end up using more tablets.
Cialis ordered from LloydsPharmacy Online Doctor comes in packs of 4, 8 or 16. Per tablet, Cialis is more expensive than Cialis Daily, however you may end up using fewer tablets.
Alternative ED tablets.
If you don’t think Cialis Daily or regular Cialis are right for you, there are some alternative ED tablets to consider. Just remember that Cialis Daily is currently the only ‘every day’ option for men with ED.
Viagra is the most famous ED tablet and works in the same way as Cialis. It lasts 4-6 hours and should be taken 30-60 minutes before sex.
Sildenafil contains the same active ingredient as Viagra and works in exactly the same way. Sildenafil is the most affordable ED tablet.
Spedra is the fastest-acting ED tablet, as it only has to be taken 15-30 minutes before sex.
Levitra is recommended for diabetics, and works in a very similar way to Viagra and Sildenafil.
For more information on ED treatments and comparisons visit the LloydsPharmacy Online Doctor ED page.

Buy tadalafil online

buy tadalafil online

Tadalafil Tablets (Generic Cialis)
Tadalafil tablets are the longest acting treatment for erectile dysfunction in men. The tablets are a generic version of the popular ED drug Cialis and work exactly the same. Onset of Action: 30min Duration of Action: 24-36hours.
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Frequently Asked Questions.
What are Tadalafil tablets?
Tadalafil tablets are used to treat erectile dysfunction, otherwise known as ED or male impotence in men. Tadalafil tablets (generic Cialis) work by stimulating the blood flow to the penis to get and maintain an erection when sexually stimulated. You can buy Tadalafil tablets online in 10mg and 20mg strength from e-Surgery.
You can buy Tadalafil in two versions, the branded version called Cialis and the non-branded generic version called Tadalafil tablets. The only difference is in price, as Tadalafil tablets are much cheaper, but works in the exact same way by allowing an erection. Tadalafil tablets are one of many Erectile Dysfunction medications that can help increase blood flow to the penis. Take a Tadalafil tablet at least 30 minutes before sexual intercourse, the medication will remain effective for up to 36 hours after taking it. Do not take more than 1 tablet a day, Tadalafil tablets are not intended for continuous daily use.
Erectile dysfunction can cause problems such as low self-esteem, stress and even depression, so it’s important to always consult your doctor/prescriber if you have any questions about Tadalafil tablets. Do not use Tadalafil tablets in combination with any other Erectile Dysfunction treatment.
You can buy Tadalafil tablets online or at your local pharmacy. Buying from e-Surgery will require a short 2-minute health questionnaire to verify you are receiving the correct medication. When buying Tadalafil tablets online, or any other medication, make sure to buy from reputable, registered pharmacies like e-Surgery.
How do you take Tadalafil tablets?
If you buy Tadalafil tablets you should always take them exactly as your doctor has prescribed. Check with your doctor or pharmacist if you are not sure.
Tadalafil generic tablets should be swallowed whole with some water and are able to be taken with or without food. Take 1 Tadalafil at least 30 minuets before sex, remember you will still need sexual stimulation to gain an erection. Tadalafil tablets will last for up to 36 hours and are not intended for daily use. Some men report that Tadalafil tablets are less effective after a large or heavy meal.
Side effects of Tadalafil tablets?
As with any form of medication, Tadalafil generic tablets have side effects. Below are a few of the common side effects of taking Tadalafil tablets:
For a full list of side effects, please read the Tadalafil Tablets Online Patient Information Leaflet. If you buy Tadalafil tablets and feel the effect is too strong or too weak, talk to your doctor or pharmacist. Tadalafil tablets are available in 10mg or 20mg.
Interactions of Tadalafil generic tablets with alcohol and food?
It is not recommended to consume alcohol when you take Tadalafil generic tablets, as it can worsen some of the side effects such as headaches, skin flushing, and dizziness.
Tadalafil tablets can contain lactose, consult your doctor or prescriber if you have been diagnosed with a sugar intolerance before using Tadalafil tablets.
Grapefruit products are best avoided when taking Tadalafil tablets as it can cause the side effects of the treatment to worsen.
You should not take Tadalafil tablets if you are on the following courses of treatment:
Is there any reason why I would not be able to take Tadalafil tablets?
You can NOT take Tadalafil generic tablets if you:
Are allergic to any of the ingredients Are taking organic nitrate or nitric oxide donors Have serious heart disease or recently had a heart attack within the last 90 days Have had a stroke within the last 6 months Have low blood pressure Had loss of vision from non-arteritic anterior ischemic optic neuropathy (NAION)
Why should I buy Tadalafil tablets?
Tadalafil tablets are used to treat erectile dysfunction in men. Tadalafil tablets have been shown to improve the ability of obtaining and keeping a hard-erect penis for sexual activity. Tadalafil tablets work by relaxing blood vessels in your penis. Studies show that by having a healthy sex life, you reduce your chances of more serious problems such as depression.
What is the difference between Tadalafil tablets and Cialis tablets?
Tadalafil generic is the active ingredient of the branded medication called Cialis. The two work exactly the same.
Cialis and Tadalafil tablets both have the same side effects, do not take more than one each day and do not take both at the same time. The main difference between Cialis and Tadalafil tablets is price, if you buy Tadalafil tablets they are much cheaper in comparison. This is only due to Cialis being branded, whereas Tadalafil tablets are a generic medication but works in the exact same way.
An example of this can be seen with over-the-counter pain killers such as paracetamol. The brands are much more expensive but generic tablets function in exactly the same way.
How do I store Tadalafil generic tablets?
Do not use Tadalafil tablets after the expiry date which is stated on the packaging. Store Tadalafil tablets in a cool, dry place as per instruction of the Tadalafil tablet patient information leaflet.
Can I buy Tadalafil tablets online?
Yes, you can buy Tadalafil tablets online from registered online Prescribers such as e-Surgery.
Whenever buying Tadalafil tablets online make sure the website you use displays the green GPhC logo. This lets you know the site is operating legally.
You can use the GPhC website to check if a pharmacy is registered. This will ensure that when you buy Tadalafil tablets online they are genuine.
Where can I get more information about Tadalafil generic tablets online?
You can learn more about this medication before you buy Tadalafil tablets in the Tadalafil tablet online Patient Information Leaflet, which contains more useful information.
You can also use our completely free Ask-a-Pharmacist service to get health advice from a trained professional. We’re here to help!
How much are Tadalafil tablets to buy online?
If you buy Tadalafil tablets online with e-Surgery the price starts at £9.50. This includes the cost of a private prescription.
How will my Tadalafil tablets be delivered?
e-Surgery uses Royal Mail delivery with choices starting from Royal Mail 48 tracked delivery, Royal Mail tracked 24 and Royal Mail 1pm special delivery (discover more about e-Surgery delivery). When you buy Tadalafil tablets online they will arrive in discreet, recyclable packaging at a delivery address of your choice. Find out how to recycle packaging from e-Surgery.
What does the Tadalafil tablet pack contain?
The Tadalafil tablet pack contains a patient information leaflet and a blister pack containing individual Tadalafil tablets in either 10mg or 20mg. You can buy Tadalafil tablets from e-Surgery in quantities of 4,8,12,16, 24, 32 and 64 tablets.
If I buy Tadalafil tablets online, how do I dispose of them?
When you buy Tadalafil tablets they will come in blister packs that are not currently recyclable, so once they have been used can be disposed of in a general waste bin. If the Tadalafil tablets are unfinished dispose of medication safely and drop them off at a local pharmacy. Cardboard packaging and paper patient information leaflets are recyclable.
For any more information you can use our free Ask-a-Pharmacist service.
What brand of Tadalafil tablets will I get when ordering online from e-Surgery?
Our Tadalafil generic brands can vary depending on our stock, but are always 100% UK branded. If you have a specific brand in mind (such as TEVA, Mylan or Accord), please let us know in the additional information box at checkout when buying your Tadalafil tablets online and we will do our best to get you the brand you prefer.
If you require more information before you buy Tadalafil tablets online please use our free Ask A Pharmacist service or read more about the medication on the NHS website.

Cialis 5 mg

cialis 5 mg

Cialis 5 mg.
CIALIS ® 2.5 mg, 5 mg, 10 mg and 20 mg film-coated tablets.
Each 2.5 mg tablet contains 2.5 mg tadalafil.
Each coated tablet contains 87 mg of lactose (as monohydrate).
Each 5 mg tablet contains 5 mg tadalafil.
Each coated tablet contains 121 mg of lactose (as monohydrate).
Each 10 mg tablet contains 10 mg tadalafil.
Each coated tablet contains 170 mg of lactose (as monohydrate).
Each 20 mg tablet contains 20 mg tadalafil.
Each coated tablet contains 233 mg of lactose (as monohydrate).
For the full list of excipients, see section 6.1.
The 2.5 mg tablets are light orange-yellow and almond shaped tablets, marked ‘C 2 ½’ on one side.
The 5 mg tablets are light yellow and almond shaped tablets, marked ‘C 5’ on one side.
The 10 mg tablets are light yellow and almond shaped tablets, marked ‘C 10’ on one side.
The 20 mg tablets are yellow and almond shaped tablets, marked ‘C 20’ on one side.
Treatment of erectile dysfunction in adult males.
In order for tadalafil to be effective for the treatment of erectile dysfunction, sexual stimulation is required.
5 mg only: Treatment of the signs and symptoms of benign prostatic hyperplasia in adult males.
CIALIS is not indicated for use by women.
Erectile dysfunction in adult Men.
In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or without food.
In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried. It may be taken at least 30 minutes prior to sexual activity.
The maximum dose frequency is once per day.
Tadalafil 10 and 20 mg is intended for use prior to anticipated sexual activity and it is not recommended for continuous daily use.
In patients who anticipate a frequent use of CIALIS (i.e., at least twice weekly) a once daily regimen with the lowest doses of CIALIS might be considered suitable, based on patient choice and the physician’s judgement.
In these patients, the recommended dose is 5mg taken once a day at approximately the same time of day. The dose may be decreased to 2.5mg once a day based on individual tolerability.
The appropriateness of continued use of the daily regimen should be reassessed periodically.
Benign prostatic hyperplasia in adult men (tadalafil 5 mg only)
The recommended dose is 5 mg, taken at approximately the same time every day with or without food. For adult men being treated for both benign prostatic hyperplasia and erectile dysfunction the recommended dose is also 5 mg taken at approximately the same time every day. Patients who are unable to tolerate tadalafil 5 mg for the treatment of benign prostatic hyperplasia should consider an alternative therapy as the efficacy of tadalafil 2.5 mg for the treatment of benign prostatic hyperplasia has not been demonstrated.
Dose adjustments are not required in elderly patients.
Dose adjustments are not required in patients with mild to moderate renal impairment. For patients with severe renal impairment, 10 mg is the maximum recommended dose.
Once-a-day dosing of 2.5 or 5 mg tadalafil both for the treatment of erectile dysfunction or benign prostatic hyperplasia is not recommended in patients with severe renal impairment (see sections 4.4 and 5.2).
For the treatment of erectile dysfunction using on-demand CIALIS the recommended dose of CIALIS is 10 mg taken prior to anticipated sexual activity and with or without food. There is limited clinical data on the safety of CIALIS in patients with severe hepatic impairment (Child-Pugh class C); if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of doses higher than 10mg of tadalafil to patients with hepatic impairment.
Once-a-day dosing both for the treatment of erectile dysfunction and benign prostatic hyperplasia has not been evaluated in patients with hepatic impairment; therefore, if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician (see sections 4.4 and 5.2).
Dose adjustments are not required in diabetic patients.
There is no relevant use of CIALIS in the paediatric population with regard to the treatment of erectile dysfunction.
CIALIS is available as 2.5, 5, 10, and 20 mg film-coated tablets for oral use.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In clinical studies, tadalafil was shown to augment the hypotensive effects of nitrates. This is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, administration of CIALIS to patients who are using any form of organic nitrate is contraindicated (see section 4.5).
CIALIS must not be used in men with cardiac disease for whom sexual activity is inadvisable. Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease.
The following groups of patients with cardiovascular disease were not included in clinical trials and the use of tadalafil is therefore contraindicated:
– patients with myocardial infarction within the last 90 days,
– patients with unstable angina or angina occurring during sexual intercourse,
– patients with New York Heart Association Class 2 or greater heart failure in the last 6 months,
– patients with uncontrolled arrhythmias, hypotension (
– patients with a stroke within the last 6 months.
CIALIS is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure (see section 4.4).
The co-administration of PDE5 inhibitors, including tadalafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension (see section 4.5).
A medical history and physical examination should be undertaken to diagnose erectile dysfunction or benign prostatic hyperplasia and determine potential underlying causes, before pharmacological treatment is considered.
Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Tadalafil has vasodilator properties, resulting in mild and transient decreases in blood pressure (see section 5.1) and as such potentiates the hypotensive effect of nitrates (see section 4.3).
The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following an appropriate medical assessment. It is not known if CIALIS is effective in patients who have undergone pelvic surgery or radical non-nerve-sparing prostatectomy.
Tadalafil 5 mg – Prior to initiating treatment with tadalafil for benign prostatic hyperplasia patients should be examined to rule out the presence of carcinoma of the prostate and carefully assessed for cardiovascular conditions (see section 4.3).
Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular arrhythmia, stroke, transient ischaemic attacks, chest pain, palpitations and tachycardia, have been reported either post marketing and/or in clinical trials. Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors. However, it is not possible to definitively determine whether these events are related directly to these risk factors, to CIALIS, to sexual activity, or to a combination of these or other factors.
Tadalafil 2.5 mg and 5 mg – In patients receiving concomitant antihypertensive medicinal products, tadalafil may induce a blood pressure decrease. When initiating daily treatment with tadalafil, appropriate clinical considerations should be given to a possible dose adjustment of the antihypertensive therapy.
In patients who are taking alpha 1 blockers, concomitant administration of CIALIS may lead to symptomatic hypotension in some patients (see section 4.5). The combination of tadalafil and doxazosin is not recommended.
Visual defects and cases of NAION have been reported in connection with the intake of CIALIS and other PDE5 inhibitors. Analyses of observational data suggest an increased risk of acute NAION in men with erectile dysfunction following exposure to tadalafil or other PDE5 inhibitors. As this may be relevant for all patients exposed to tadalafil, the patient should be advised that in case of sudden visual defect, he should stop taking CIALIS and consult a physician immediately (see section 4.3).
Cases of sudden hearing loss have been reported after the use of tadalafil. Although other risk factors were present in some cases (such as age, diabetes, hypertension and previous hearing loss history) patients should be advised to stop taking tadalafil and seek prompt medical attention in the event of sudden decrease or loss of hearing.
Renal and hepatic impairment (tadalafil 2.5 mg and 5 mg)
Due to increased tadalafil exposure (AUC), limited clinical experience and the lack of ability to influence clearance by dialysis, once-a-day dosing of CIALIS is not recommended in patients with severe renal impairment.
There is limited clinical data on the safety of single-dose administration of CIALIS in patients with severe hepatic insufficiency (Child-Pugh Class C). Once-a-day administration has not been evaluated in patients with hepatic insufficiency. If CIALIS is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.
Hepatic impairment (tadalafil 10 mg and 20 mg)
There is limited clinical data on the safety of single-dose administration of CIALIS in patients with severe hepatic insufficiency (Child-Pugh Class C). If CIALIS is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.
Priapism and anatomical deformation of the penis.
Patients who experience erections lasting 4 hours or more should be instructed to seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.
CIALIS, should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia).
Caution should be exercised when prescribing CIALIS to patients using potent CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, and erythromycin), as increased tadalafil exposure (AUC) has been observed if the medicinal products are combined (see section 4.5).
CIALIS and other treatments for erectile dysfunction.
The safety and efficacy of combinations of CIALIS and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. The patients should be informed not to take CIALIS in such combinations.
CIALIS contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
Interaction studies were conducted with 10 mg and/or 20 mg tadalafil, as indicated below. With regard to those interaction studies where only the 10 mg tadalafil dose was used, clinically relevant interactions at higher doses cannot be completely ruled out.
Effects of Other Substances on Tadalafil.
Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (200 mg daily), increased tadalafil (10 mg) exposure (AUC) 2-fold and C max by 15%, relative to the AUC and C max values for tadalafil alone. Ketoconazole (400 mg daily) increased tadalafil (20 mg) exposure (AUC) 4-fold and C max by 22%. Ritonavir, a protease inhibitor (200 mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg) exposure (AUC) 2-fold with no change in C max . Although specific interactions have not been studied, other protease inhibitors, such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin, clarithromycin, itraconazole, and grapefruit juice, should be co-administered with caution, as they would be expected to increase plasma concentrations of tadalafil (see section 4.4). Consequently, the incidence of the adverse reactions listed in section 4.8 might be increased.
The role of transporters (for example, p-glycoprotein) in the disposition of tadalafil is not known. Therefore, there is the potential of drug interactions mediated by inhibition of transporters.
A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88%, relative to the AUC values for tadalafil alone (10 mg). This reduced exposure can be anticipated to decrease the efficacy of tadalafil; the magnitude of decreased efficacy is unknown. Other inducers of CYP3A4, such as phenobarbital, phenytoin, and carbamazepine, may also decrease plasma concentrations of tadalafil.
Effects of Tadalafil on Other Medicinal Products.
In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of nitrates. Therefore, administration of CIALIS to patients who are using any form of organic nitrate is contraindicated (see section 4.3). Based on the results of a clinical study in which 150 subjects receiving daily doses of tadalafil 20 mg for 7 days and 0.4 mg sublingual nitroglycerin at various times, this interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed after the last tadalafil dose. Thus, in a patient prescribed any dose of CIALIS (2.5 mg- 20 mg), where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should have elapsed after the last dose of CIALIS before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate haemodynamic monitoring.
Anti-hypertensives (including calcium channel blockers)
The co-administration of doxazosin (4 and 8 mg daily) and tadalafil (5 mg daily dose and 20 mg as a single dose) increases the blood pressure-lowering effect of this alpha-blocker in a significant manner. This effect lasts at least twelve hours and may be symptomatic, including syncope. Therefore, this combination is not recommended (see section 4.4).
In interaction studies performed in a limited number of healthy volunteers, these effects were not reported with alfuzosin or tamsulosin. However, caution should be exercised when using tadalafil in patients treated with any alpha-blockers, and notably in the elderly. Treatments should be initiated at minimal dosage and progressively adjusted.
In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects of antihypertensive medicinal products was examined. Major classes of antihypertensive medicinal products were studied, including calcium-channel blockers (amlodipine), angiotensin converting enzyme (ACE) inhibitors (enalapril), beta-adrenergic receptor blockers (metoprolol), thiazide diuretics (bendrofluazide), and angiotensin II receptor blockers (various types and doses, alone or in combination with thiazides, calcium-channel blockers, beta-blockers, and/or alpha-blockers). Tadalafil (10 mg, except for studies with angiotensin II receptor blockers and amlodipine in which a 20 mg dose was applied) had no clinically significant interaction with any of these classes. In another clinical pharmacology study, tadalafil (20 mg) was studied in combination with up to 4 classes of antihypertensives. In subjects taking multiple antihypertensives, the ambulatory-blood-pressure changes appeared to relate to the degree of blood pressure control. In this regard, study subjects whose blood pressure was well controlled, the reduction was minimal and similar to that seen in healthy subjects. In study subjects whose blood pressure was not controlled, the reduction was greater, although this reduction was not associated with hypotensive symptoms in the majority of subjects. In patients receiving concomitant antihypertensive medicinal products, tadalafil 20 mg may induce a blood pressure decrease, which (with the exception of alpha-blockers – see above) is, in general, minor and not likely to be clinically relevant. Analysis of Phase 3 clinical trial data showed no difference in adverse events in patients taking tadalafil with or without antihypertensive medicinal products. However, appropriate clinical advice should be given to patients regarding a possible decrease in blood pressure when they are treated with antihypertensive medicinal products.
Preclinical studies showed an additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment the hypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including tadalafil, is contraindicated (see section 4.3).
In a clinical trial that compared tadalafil 5 mg coadministered with finasteride 5 mg to placebo plus finasteride 5 mg in the relief of BPH symptoms, no new adverse reactions were identified. However, as a formal drug-drug interaction study evaluating the effects of tadalafil and 5-alpha reductase inhibitors (5-ARIs) has not been performed, caution should be exercised when tadalafil is co-administered with 5-ARIs.
When tadalafil 10 mg was administered with theophylline (a non-selective phosphodiesterase inhibitor) in a clinical pharmacology study, there was no pharmacokinetic interaction. The only pharmacodynamic effect was a small (3.5 bpm) increase in heart rate. Although this effect is minor and was of no clinical significance in this study, it should be considered when co-administering these medicinal products.
Tadalafil has been demonstrated to produce an increase in the oral bioavailability of ethinylestradiol; a similar increase may be expected with oral administration of terbutaline, although the clinical consequence of this is uncertain.
Alcohol concentrations (mean maximum blood concentration 0.08%) were not affected by co-administration with tadalafil (10 mg or 20 mg). In addition, no changes in tadalafil concentrations were seen 3 hours after co-administration with alcohol. Alcohol was administered in a manner to maximise the rate of alcohol absorption (overnight fast with no food until 2 hours after alcohol). Tadalafil (20 mg) did not augment the mean blood pressure decrease produced by alcohol (0.7 g/kg or approximately 180 ml of 40% alcohol [vodka] in an 80 kg male) but, in some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed and dizziness occurred with similar frequency to alcohol alone. The effect of alcohol on cognitive function was not augmented by tadalafil (10 mg).
Cytochrome P450 metabolised medicinal products.
Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of medicinal products metabolised by CYP450 isoforms. Studies have confirmed that tadalafil does not inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9 and CYP2C19.
Tadalafil (10 mg and 20 mg) had no clinically significant effect on exposure (AUC) to S-warfarin or R-warfarin (CYP2C9 substrate), nor did tadalafil affect changes in prothrombin time induced by warfarin.
Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid.
Specific interaction studies with antidiabetic medicinal products were not conducted.
CIALIS is not indicated for use by women.
There are limited data from the use of tadalafil in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy , embryonal/foetal development, parturition or postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid the use of CIALIS during pregnancy.
Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk. A risk to the suckling child cannot be excluded. CIALIS should not be used during breast feeding.
Effects were seen in dogs that might indicate impairment of fertility. Two subsequent clinical studies suggest that this effect is unlikely in humans, although a decrease in sperm concentration was seen in some men (see sections 5.1 and 5.3).
CIALIS has negligible influence on the ability to drive or use machines. Although the frequency of reports of dizziness in placebo and tadalafil arms in clinical trials was similar, patients should be aware of how they react to CIALIS before driving or using machines.
The most commonly reported adverse reactions in patients taking CIALIS for the treatment of erectile dysfunction or benign prostatic hyperplasia were headache, dyspepsia, back pain and myalgia, in which the incidences increase with increasing dose of CIALIS. The adverse reactions reported were transient, and generally mild or moderate. The majority of headaches reported with CIALIS once-a-day dosing are experienced within the first 10 to 30 days of starting treatment.
Tabulated summary of adverse reactions.
The table below lists the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 8022 patients on CIALIS and 4422 patients on placebo) for on-demand and once-a-day treatment of erectile dysfunction and the once-a-day treatment of benign prostatic hyperplasia.
Stroke 1 (including haemorrhagic events), Syncope, Transient ischaemic attacks 1 , Migraine 2 , Seizures 2 , Transient amnesia.
Blurred vision, Sensations described as eye pain.
Visual field defect, Swelling of eyelids, Conjunctival hyperaemia, Non-arteritic anterior ischaemic optic neuropathy (NAION) 2 , Retinal vascular occlusion 2.
Myocardial infarction, Unstable angina pectoris 2 , Ventricular arrhythmia 2.
Respiratory, thoracic and mediastinal disorders.
Abdominal pain, Vomiting, Nausea, Gastro-oesophageal reflux.
Skin and subcutaneous tissue disorders.
Urticaria, Stevens-Johnson syndrome 2 , Exfoliative dermatitis 2 , Hyperhydrosis (sweating)
Musculoskeletal, connective tissue and bone disorders.
Reproductive system and breast disorders.
Priapism, Penile haemorrhage, Haematospermia.
General disorders and administration site conditions.
Chest pain 1, Peripheral oedema, Fatigue.
Facial oedema 2 , Sudden cardiac death 1,2.
(1) Most of the patients had pre-existing cardiovascular risk factors (see section 4.4).
(2) Postmarketing surveillance reported adverse reactions not observed in placebo-controlled clinical trials.
(3) More commonly reported when tadalafil is given to patients who are already taking antihypertensive medicinal products.
Description of selected adverse reactions.
A slightly higher incidence of ECG abnormalities, primarily sinus bradycardia, has been reported in patients treated with tadalafil once a day as compared with placebo. Most of these ECG abnormalities were not associated with adverse reactions.
Data in patients over 65 years of age receiving tadalafil in clinical trials, either for the treatment of erectile dysfunction or the treatment of benign prostatic hyperplasia, are limited. In clinical trials with tadalafil taken on demand for the treatment of erectile dysfunction, diarrhoea was reported more frequently in patients over 65 years of age. In clinical trials with tadalafil 5 mg taken once a day for the treatment of benign prostatic hyperplasia, dizziness and diarrhoea were reported more frequently in patients over 75 years of age.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Single doses of up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients. Adverse events were similar to those seen at lower doses.
In cases of overdose, standard supportive measures should be adopted, as required. Haemodialysis contributes negligibly to tadalafil elimination.
Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction. ATC code: G04BE08.
Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Tadalafil has no effect in the treatment of erectile dysfunction in the absence of sexual stimulation.
Tadalafil 5 mg – The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum is also observed in the smooth muscle of the prostate, the bladder and their vascular supply. The resulting vascular relaxation increases blood perfusion which may be the mechanism by which symptoms of benign prostatic hyperplasia are reduced. These vascular effects may be complemented by inhibition of bladder afferent nerve activity and smooth muscle relaxation of the prostate and bladder.
Studies in vitro have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, and cerebellum. The effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. Tadalafil is > 10,000-fold more potent for PDE5 than for PDE1, PDE2, and PDE4 enzymes which are found in the heart, brain, blood vessels, liver, and other organs. Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility. Additionally, tadalafil is approximately 700-fold more potent for PDE5 than for PDE6, an enzyme which is found in the retina and is responsible for phototransduction. Tadalafil is also >10,000-fold more potent for PDE5 than for PDE7 through PDE10.
Tadalafil administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8mmHg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6mmHg, respectively), and no significant change in heart rate.
In a study to assess the effects of tadalafil on vision, no impairment of colour discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test. This finding is consistent with the low affinity of tadalafil for PDE6 compared to PDE5. Across all clinical studies, reports of changes in colour vision were rare (
Three studies were conducted in men to assess the potential effect on spermatogenesis of CIALIS 10mg (one 6-month study) and 20mg (one 6-month and one 9-month study) administered daily. In two of these studies decreases were observed in sperm count and concentration related to tadalafil treatment of unlikely clinical relevance. These effects were not associated with changes in other parameters, such as motility, morphology, and FSH.
For CIALIS on demand, three clinical studies were conducted in 1054 patients in an at-home setting to define the period of responsiveness. Tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well as patients’ ability to attain and maintain erections for successful intercourse compared to placebo as early as 16 minutes following dosing.
In a 12-week study performed in 186 patients (142 tadalafil, 44 placebo) with erectile dysfunction secondary to spinal cord injury, tadalafil significantly improved the erectile function leading to a mean per-subject proportion of successful attempts in patients treated with tadalafil 10 or 20 mg (flexible-dose, on demand) of 48% as compared to 17% with placebo.
Tadalafil at doses of 2 to 100mg has been evaluated in 16 clinical studies involving 3250 patients, including patients with erectile dysfunction of various severities (mild, moderate, severe), etiologies, ages (range 21-86 years), and ethnicities. Most patients reported erectile dysfunction of at least 1 year in duration. In the primary efficacy studies of general populations, 81% of patients reported that CIALIS improved their erections as compared to 35% with placebo. Also, patients with erectile dysfunction in all severity categories reported improved erections whilst taking CIALIS (86%, 83%, and 72% for mild, moderate, and severe, respectively, as compared to 45%, 42%, and 19% with placebo). In the primary efficacy studies, 75% of intercourse attempts were successful in CIALIS-treated patients as compared to 32% with placebo.
For once-a-day evaluation of tadalafil at doses of 2.5, 5, and 10 mg 3 clinical studies were initially conducted involving 853 patients of various ages (range 21-82 years) and ethnicities, with erectile dysfunction of various severities (mild, moderate, severe) and etiologies. In the two primary efficacy studies of general populations, the mean per-subject proportion of successful intercourse attempts were 57 and 67% on CIALIS 5mg, 50% on CIALIS 2.5mg as compared to 31 and 37% with placebo. In the study in patients with erectile dysfunction secondary to diabetes, the mean per-subject proportion of successful attempts were 41 and 46% on CIALIS 5mg and 2.5mg, respectively, as compared to 28% with placebo. Most patients in these three studies were responders to previous on-demand treatment with PDE5 inhibitors. In a subsequent study, 217 patients who were treatment-naive to PDE5 inhibitors were randomised to CIALIS 5mg once a day vs. placebo. The mean per-subject proportion of successful sexual intercourse attempts was 68% for CIALIS patients compared to 52% for patients on placebo.
CIALIS was studied in 4 clinical studies of 12 weeks duration enrolling over 1500 patients with signs and symptoms of benign prostatic hyperplasia. The improvement in the total international prostate symptom score with CIALIS 5mg in the four studies were -4.8, -5.6, -6.1 and -6.3 compared to -2.2, -3.6, -3.8 and -4.2 with placebo. The improvements in total international prostate symptom score occurred as early as 1 week. In one of the studies, which also included tamsulosin 0.4 mg as an active comparator, the improvement in total international prostate symptom score with CIALIS 5mg, tamsulosin and placebo were -6.3, -5.7 and -4.2 respectively.
One of these studies assessed improvements in erectile dysfunction and signs and symptoms of benign prostatic hyperplasia in patients with both conditions. The improvements in the erectile function domain of the international index of erectile function and the total international prostate symptom score in this study were 6.5 and -6.1 with CIALIS 5 mg compared to 1.8 and -3.8 with placebo, respectively. The mean per-subject proportion of successful sexual intercourse attempts was 71.9% with CIALIS 5 mg compared to 48.3% with placebo.
The maintenance of the effect was evaluated in an open-label extension to one of the studies, which showed that the improvement in total international prostate symptom score seen at 12 weeks was maintained for up to 1 additional year of treatment with CIALIS 5mg.
A single study has been performed in paediatric patients with Duchenne Muscular Dystrophy (DMD) in which no evidence of efficacy was seen. The randomised, double-blind, placebo-controlled, parallel, 3-arm study of tadalafil was conducted in 331 boys aged 7-14 years with DMD receiving concurrent corticosteroid therapy. The study included a 48-week double-blind period where patients were randomised to tadalafil 0.3 mg/kg, tadalafil 0.6 mg/kg, or placebo daily. Tadalafil did not show efficacy in slowing the decline in ambulation as measured by the primary 6 minute walk distance (6MWD) endpoint: least squares (LS) mean change in 6MWD at 48 weeks was -51.0 meters (m) in the placebo group, compared with -64.7 m in the tadalafil 0.3 mg/kg group (p = 0.307) and -59.1 m in the tadalafil 0.6 mg/kg group (p = 0.538). In addition, there was no evidence of efficacy from any of the secondary analyses performed in this study. The overall safety results from this study were generally consistent with the known safety profile of tadalafil and with adverse events (AEs) expected in a paediatric DMD population receiving corticosteroids.
The European Medicines Agency has waived the obligation to submit the results of studies in all subsets of the paediatric population in the treatment of the erectile dysfunction. See section 4.2 for information on paediatric use.
Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration (C max ) is achieved at a median time of 2 hours after dosing. Absolute bioavailability of tadalafil following oral dosing has not been determined.
The rate and extent of absorption of tadalafil are not influenced by food, thus CIALIS may be taken with or without food. The time of dosing (morning versus evening) had no clinically relevant effects on the rate and extent of absorption.
The mean volume of distribution is approximately 63 l, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Protein binding is not affected by impaired renal function.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Tadalafil is predominantly metabolised by the cytochrome P450 (CYP) 3A4 isoform. The major circulating metabolite is the methylcatechol glucuronide. This metabolite is at least 13,000-fold less potent than tadalafil for PDE5. Consequently, it is not expected to be clinically active at observed metabolite concentrations.
The mean oral clearance for tadalafil is 2.5 l/h and the mean half-life is 17.5 hours in healthy subjects.
Tadalafil is excreted predominantly as inactive metabolites, mainly in the faeces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range of 2.5 to 20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasma concentrations are attained within 5 days of once daily dosing.
Pharmacokinetics determined with a population approach in patients with erectile dysfunction are similar to pharmacokinetics in subjects without erectile dysfunction.
Healthy elderly subjects (65 years or over) had a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) relative to healthy subjects aged 19 to 45 years. This effect of age is not clinically significant and does not warrant a dose adjustment.
In clinical pharmacology studies using single dose tadalafil (5 to 20mg), tadalafil exposure (AUC) approximately doubled in subjects with mild (creatinine clearance 51 to 80 ml/min) or moderate (creatinine clearance 31 to 50 ml/min) renal impairment and in subjects with end-stage renal disease on dialysis. In haemodialysis patients, C max was 41% higher than that observed in healthy subjects. Haemodialysis contributes negligibly to tadalafil elimination.
Tadalafil exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh class A and B) is comparable to exposure in healthy subjects when a dose of 10 mg is administered. There is limited clinical data on the safety of CIALIS in patients with severe hepatic insufficiency (Child-Pugh class C). If CIALIS is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of once-a-day dosing of tadalafil to patients with hepatic impairment. If CIALIS is prescribed once-a-day, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of doses higher than 10 mg of tadalafil to patients with hepatic impairment.
Tadalafil exposure (AUC) in patients with diabetes was approximately 19% lower than the AUC value for healthy subjects. This difference in exposure does not warrant a dose adjustment.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.
There was no evidence of teratogenicity, embryotoxicity, or foetotoxicity in rats or mice that received up to 1000 mg/kg/day tadalafil. In a rat prenatal and postnatal development study, the no observed effect dose was 30 mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was approximately 18-times the human AUC at a 20 mg dose.
There was no impairment of fertility in male and female rats. In dogs given tadalafil daily for 6 to 12 months at doses of 25 mg/kg/day (resulting in at least a 3-fold greater exposure [range 3.7-18.6] than seen in humans given a single 20 mg dose) and above, there was regression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs. See also section 5.1.

Is cialis safe?

cialis, alcohol

Is It Safe to Take Cialis and Drink Alcohol?
Cialis is used to treat erectile dysfunction, or difficulty getting or maintaining an erection. Generally, Cialis is a safe drug. However, you need to consider the other substances you take with it and the effects the combination can cause.
For example, alcohol and Cialis may interact. Excessive drinking may lead to some very serious side effects. In moderation, though, drinking alcohol likely won’t cause problems. Here’s what to know to help you stay safe while taking Cialis.
Having just a glass of wine or other drink is unlikely to affect Cialis or cause any health risks. But if you take Cialis and drink excessively, you may be setting yourself up for some problems.
In particular, drinking too much alcohol while you take Cialis can lead to orthostatic hypotension. This can cause a headache, dizziness, and fainting, which can cause fractures or other injuries. Hypotension may also make your heart beat at a faster rate. In some cases, this can lead to severe heart problems.
This effect can occur because Cialis and alcohol both act as vasodilators. Vasodilators are substances that lower your blood pressure by relaxing the walls of your blood vessels, which allow the blood vessels to open wider.
Orthostatic hypotension can be even more likely with Cialis than with some other erectile dysfunction drugs. This may be because Cialis stays in your system longer than many other ED drugs.
What’s more, if you drink too much alcohol while you’re taking Cialis, stopping your drinking can lead to a sudden increase in your blood pressure level.
Moderate drinking is fewer than three alcoholic drinks per day. The amount in an alcoholic drink varies according to the type of alcohol. For example, one alcoholic drink could be:
Consuming five or more drinks at a time while taking Cialis has been linked with orthostatic hypotension. That amount is a bit more than what is considered “moderate” drinking.
If you notice symptoms such as dizziness or headaches, stop drinking and tell your doctor.
If you regularly have three or more drinks per day or feel that you need to have a drink every day, talk with your doctor or a mental health counselor. Long-term excessive alcohol use is not only dangerous while you take Cialis, it also increases your risk of many health problems, including heart disease, obesity, and early dementia.
Cialis is a prescription medication, so before you start taking it, make sure your doctor knows your medical history and your current health status. That includes a list of all the medications you take. You should also be honest with your doctor about how much alcohol you drink on a regular basis.
Overall, moderate alcohol consumption while you take Cialis is usually safe. If you want to avoid potentially dangerous side effects, limit yourself to one or two drinks per day.
Last medically reviewed on October 12, 2016.

How long does cialis

how long does cialis

How Long Does Cialis Stay In Your System?
We make it easy for you to participate in a clinical trial for Erectile dysfunction, and get access to the latest treatments not yet widely available – and be a part of finding a cure.
What is Cialis?
Cialis¹ (tadalafil) is an erectile dysfunction (ED) treatment that works by increasing blood flow to the penis. Compared to other ED treatments, Cialis works much longer, with a one-and-a-half-day enhancement window. Other ED medications, like Viagra, typically only last for hours, not days.
What is Cialis prescribed for?
Cialis is intended for patients with erectile dysfunction or benign prostatic hyperplasia (an enlarged prostate).
How does Cialis treat ED?
An erection generally results from mental or physical stimulation. It occurs when arousal causes the muscles of your penis to relax, allowing blood to flow into the spongy tissue in your penis, called the corpora cavernosa.
When this happens, the blood in your penis causes it to become firm, resulting in an erection.
Additionally, a sheath surrounding the corpora cavernosa helps to stop the blood from leaving your penis, helping you stay hard. In most cases, ED results from a lack of blood flow to the penis or an inability to trap the blood during an erection. The former leads to an inability to get an erection, while the latter makes it difficult to sustain one.
Cialis² works by inhibiting an enzyme called phosphodiesterase-5³ (PDE5), which blocks a messenger molecule called cyclic guanosine monophosphate⁴ (cGMP). cGMP plays a key role in expanding blood vessels to promote blood flow, so by inhibiting PDE5 and boosting cGMP, Cialis improves blood flow to the penis and enhances erectile functioning.
Is Cialis safe to take for ED?
Cialis is FDA approved for the treatment of ED (and BPD). Therefore, in general, Cialis is considered safe when used as prescribed. However, some people with heart or liver issues shouldn’t take Cialis.
Beyond that, there are known interactions between Cialis and some foods (most notably, grapefruit) and drugs (alpha-blockers, antifungals, high blood pressure medications, and more).
Grapefruit and Cialis affect the same enzymes in the body. Combining the two can relax your blood vessels, resulting in hypotension (low blood pressure).
Additionally, excessive drinking results in low blood pressure and dizziness when taken with this medication.
Medications known to interact with Cialis include:
Nitrates,⁵ which may be prescribed for angina, heart failure, or hypertension, and can lead to low blood pressure when taken with Cialis Alpha-blockers,⁶ drugs commonly prescribed for high blood pressure and prostate enlargement that can cause low blood pressure if taken alongside Cialis High blood pressure medications,⁷ which, combined with Cialis, can lower blood pressure too much Fungal infection drugs (CYP3A4 inhibitors), can increase the amount of Cialis in the body per dose Certain antibiotics (CYP3A4 inducers), can reduce the effectiveness of Cialis.
When you visit your doctor to discuss treatment options for ED, bring along a list of the supplements, vitamins, and medications you’re taking, and mention any health conditions you have.
Benefits of Cialis.
Cialis is well-known for its duration of effectiveness, that is, how long the drug works before you need to take another dose. Another top ED drug, Viagra, also works by inhibiting PDE5. However, Viagra only lasts 30 minutes to four hours, compared to Cialis’ 36 hours.
Cialis also works faster. While Viagra users need to plan at least an hour in advance, Cialis is effective in as little as 30 minutes.
How should you take Cialis?
When your pharmacist dispenses Cialis, they’ll provide a leaflet with instructions on how to take the medication. In addition, there’s a pharmacy phone number on the bottle in case you’re unsure about something and need advice when you get home. You’ll take Cialis as needed or once daily, but never more than once within a 24-hour period.
If you’re taking Cialis in anticipation of sexual activity, take it at least 30 minutes in advance. If you’re taking it daily, take it at about the same time each day. You can discuss the pros and cons of each method with your doctor.
How long does it take Cialis to work?
When taken correctly, Cialis should start to work in an hour or less (and as little as 30 minutes for some men) and should be taken at least 30 minutes prior to sexual activity. One of the main benefits of Cialis is that its effects can last for up to 36 hours.
It is important to note that you must be sexually aroused during this period for Cialis to work as intended. Cialis will not trigger an erection unless you’re aroused.
How long does Cialis stay in your system?
One dose of Cialis can stay in your system for more than two days. Certain health conditions involving the kidneys and liver and some medications can extend the window. Because Cialis stays in the system for a while, it’s essential you don’t exceed one dose per 24-hour period.
Side effects of Cialis.
Almost all medications have some risk of side effects, ranging from mild to moderate, serious, and even life-threatening. The common and rare side effects of Cialis are listed below.
Common side effects.
Headache Upset stomach Back or limb pain Muscle pain Stuffy nose Flushing (redness in the face) Indigestion.
Less common and potentially serious side effects.
Sudden vision changes Sudden decrease or loss of hearing Dizziness Painful or prolonged erection lasting four or more hours Allergic reactions, including a rash, itching, swelling, dizziness, or trouble breathing Seizures.
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Yao Guang and Yu Sanniang looked at each other, and they both saw panic in each other is eyes. Jianjian and Kangkang were pretending to be asleep in various ways, but when they heard that they were going skiing today, they jumped out of bed excitedly.
Did not you ask him the old man Xiao Yuduo chuckled and said, The condition is also very simple, that is, brother Zhao is order should grow from fifty horses to eighty to one hundred horses. Aunt Dong is eyes lit up, Oh, I just happened to be hungry.
Since entering this home, Liu Yingnan has realized what warmth is, and being treated like this by her family, she feels that this rebirth is really worth it. Up. He Lianjue did not respond to her words, turned around and walked towards the vine passage. Officer, my wife is too impulsive, she is just impulsive, do not worry about it.
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Su Nian was very worried about her elder brother, even if his elder brother had the best aptitude but had not grown up yet, what if he was not their opponent If elder brother is not their opponent, will they and even the people in this village be in danger Thinking of these things, Su Nian felt restless, and she could not relax without seeing her brother.
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She closed her eyes slowly, opened them again after a while, and said with a sneer, I do not care what she says about me. The culprit is not me, so I am not afraid. The Void Butterfly Flame exploded. No way Both are married, why kill the child Some young girls are like sisters, while others are different from each other.
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Xu Ran. When Peak Master Miyue and his group left, Elder Gongxi said, I do not know whether it is for leaving this small space or for the treasure. Yes, I will go back and tell grandma. When talking about the big cadre, she was full of anger, obviously referring to Su Junqiang from Haicheng.
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The quarrel between Guan Qingbai and Fang Ling came to an abrupt end. The underground ark, also known as the last human remains in the last era, was buried under the former city by a thick crust and steel, isolating the poisonous fog pollution on the ground and the monsters corroded in the fog.
She will record every change of the child, from the child is first laugh, first vaccination, first teething, first Feeding complementary food, turning over for the first time, sitting for the first time. On the way here, he did not dare to guess what happened.
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Block the alley in front of the door tightly, and from a distance you can see those who came to celebrate the birthday from the back of the alley, kneeling on the ground, and no one dared to look up. But the other party never spoke. Gong Jiaxin never thought that Hua Miaozhu could teach her how to paint. She never thought that semenax in store she would take the initiative to speak now.
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Everyone understands this number, the bigger the better, but what is the basis for judging the number The person who raised the question first was the handsome Moxiu, his eyes were fixed on the number above Luo Yuexi is head, Various thoughts swirled in my heart.
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Working Groups.
Name Affiliation Country WG1. Lifestyles Chairperson Juan A. Rivera National Institute of Public Health Mexico Support Tania Cony Aburto National Institute of Public Health Mexico Mariana Stern USC Norris Comprehensive Cancer Center USA Pedro Rodrigues Curi Hallal Universidade Federal de Pelotas Brazil Joaquin Barnoya Integra Cancer Institute Guatemala Luz Myriam Reynales National Institute of Public Health Mexico Simón Barquera National Institute of Public Health Mexico Isabelle Romieu National Institute of Public Health Mexico Camila Corvalán Institute of Nutrition and Food Technology (INTA), University of Chile Chile Tânia Cavalcante Instituto Nacional de Câncer José Alencar Gomes da Silva Brazil WG2. Environmental and occupational risks Chairperson Catterina Ferreccio Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile Chile Support Estela Blanco Universidad Mayor Chile Eduardo Algranti FUNDACENTRO Brazil Julietta Rodriguez-Guzmán Pan American Health Organization (USA)/Universidad El Bosque Colombia Ana Maria Mora Center for Environmental Research and Community Health, University of California, Berkeley USA Lizbeth Teresita Lopez Carrillo National Institute of Public Health Mexico Lene H.S. Veiga National Cancer Institute USA Luis Abdón Cifuentes Pontificia Universidad Católica de Chile Chile Laura Andrea Rodríguez Villamizar Industrial University of Santander Colombia WG3. Infections Chairperson Rolando Herrero Costa Rican Agency for Biomedical Research – INCIENSA Foundation Costa Rica Loretto Carvajal National Cancer Institute USA Carolina Porras Costa Rican Agency for Biomedical Research – INCIENSA Foundation Costa Rica Arnoldo Javier Riquelme Pérez Pontifical Catholic University of Chile Chile Maria Constanza Camargo National Cancer Institute USA Eduardo Lazcano-Ponce National Institute of Public Health Mexico Ana Patricia Ortiz University of Puerto Rico Comprehensive Cancer Center Puerto Rico Vanessa Van de Wyngard Pontifical Catholic University of Chile Chile Luis Fernando Aranha Camargo Hospital Israelita Albert Einstein Brazil Valeria Fink Fundación Huésped Argentina WG4. Medical interventions Chairperson Maribel Almonte International Agency for Research on Cancer France Support Armando Baena International Agency for Research on Cancer France Melisa Paolino Center for the Study of State and Society Argentina Mauricio Maza Pan American Health Organization USA Gabriela Torres-Mejía National Institute of Public Health Mexico Jóse Jerónimo National Cancer Institute USA Lucía Delgado Honorary Commission for the Fight against Cancer Uruguay Cynthia Villarreal-Garza Zambrano Hellion Hospital, Tecnológico de Monterrey Mexico Leonardo Javier Arcuri Hospital Israelita Albert Einstein Brazil Rossana Ruiz National Institute for Neoplastic Diseases Peru WG5. Communication Chairperson Carolyn Finck Universidad de los Andes Colombia Support Maríantonia Lemos EAFIT University Mexico Fernanda de Albuquerque Melo Nogueira Instituto Nacional do Câncer José Alencar Gomes da Silva Brazil Claudia Jurberg Brazilian National Academy of Medicine & Foundation Carlos Chagas Filho Research Support Brazil Isabel Cristina Garcés Palacio University of Antioquia Colombia Anabelle Bonvecchio Arenas National Institute of Public Health Mexico Orlando Martínez Granera Movimiento Contra el Cáncer Foundation Nicaragua Elmer E. Huerta George Washington University Cancer Center USA Karina Pesce Hospital Italiano de Buenos Aires Argentina Arlette Bahena Botello National Institute of Public Health Mexico.
Scientific Committee.
Name Affiliation Country Liz Maria de Almeida Instituto Nacional de Câncer Brazil Silvina Arrossi Center for the Study of State and Society/National Council for Scientific and Technical Research Argentina National Council for Scientific and Technical Research Argentina Patricia J. García Funegra Universidad Peruana Cayetano Heredía Peru María Luisa Garmendia Institute of Nutrition and Food Technology Chile Alejandro Mohar National Institute of Cancerology/Institute of Biomedical Research Mexico Raúl Murillo San Ignacio University Hospital Colombia Julio Santamaría Centro Hemato Oncológico Panamá Panama.
Advocacy Group.
Name Affiliation Country Eduardo Cazap Latin American and Caribbean Society of Medical Oncology (SLACOM)/Network of National Cancer Institutes and Institutions (RINC/SLACOM) Argentina Gabriel O. Owen Healthy Caribbean Coalition/Owen King EU Hospital Santa Lucía Diego Paonessa Asociación Latina e Ibérica Contra el Cáncer Argentina Walter Zoss Network of National Cancer Institutes and Institutions (RINC/SLACOM) Brazil.
IARC/PAHO Secretariat.
Name Affiliation Country IARC/PAHO Secretariat Principal Investigator Carolina Espina International Agency for Research on Cancer France Researcher Ariadna Feliu International Agency for Research on Cancer France Senior Advisor Joachim Schüz International Agency for Research on Cancer France Senior Advisor Andre Carvalho International Agency for Research on Cancer France PAHO Advisor Mauricio Maza Pan American Health Organization USA.

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If you want to take a bath, you should also boil water to take a bath during these two time periods. I said, can we catch it another day In such a hot weather, I will suffer from heat stroke. Wu Song could not bear to ask her for an explanation, and seeing her mysterious and hidden appearance, he actually found it quite amusing and was amused by it. Tingfang said Not yet.
The first person I was looking What Is The Best Cream For Erectile Dysfunction can you sleep with viagra for was Zimo, but Zimo could not evade and refused to go with the domineering prince, so he and Xiao Qinyu ran away with the injured Mu Yunfei, and hid in Prince Wu is mansion to be punished. A few days later, the prince did not give up after thinking about it, but for some reason turned his target to Xiao Qinyu, and even provoked the third prince Feng Zixian.
It is just that the current society is sometimes so helpless. Qi Jingnian paused for a moment, At that time, let him go to Xiao Er is side to help first during the winter and summer vacations, and then let him go to Uncle Will is side to stay for a while after graduation.
What is the situation should not it be said can you sleep with viagra no, saying that the daughter in law only needs to be in charge of being beautiful and beautiful, and he is in charge of making money. Everyone has always equated officers and soldiers with cowards, but now they finally reversed their impressions, and called Han Shizhong a big brother, not to mention being affectionate.
Third brother, I still have something to tell you yesterday, but when I talked about the discipline mother, I forgot about that, it is the second prince, Can ED Be Cured what do sex pills do do not deal with him, leave this matter to me Let is do it. Brother Huang, do not you refuse so quickly, okay The little royal uncle has not spoken yet.
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Instead, he rested his hands on his knees, propped his chin, and looked at Ruyi with a pair of smiling eyes. Gong Ruiwen is so thick skinned, she can see what Gong Ruini can do, What Is The Best Cream For Erectile Dysfunction can you sleep with viagra this should be the task assigned by her mother, that is, no matter how noisy she is, she can only accept it.
They are not a couple, Uncle Zhao Shangshu might have no face to mention Duke Ding Jiang Yuxin is personality is a bit like her parents in her previous life, they worked hard to make money, and they were reluctant to eat and wear, but they were willing to spend a lot of money to enroll her can tadalafil cause anxiety in can you sleep with viagra various remedial classes.
However, she was very unwilling to be screened out like this. She believed that the chorus competition should be singing skills, and should not be better looking than other chorus members, so she has been trying to find a way to enter the chorus team to show her strength.
Jiang Yutong seemed to have no strength at all, and his whole body slid on the ground, so he quickly hugged her. You see, except for the younger brother of the third uncle is family, they went to see a few times, and none of the uncle is family came forward.
Now that this sound spirit is out of control, the best way is to give up everything you have now. Maybe this is Buddhist practice. Everyone knew that this was not normal. Many people said that it was because of years of wars and too many casualties, which caused the wrath of the heavens and condemned the whole world.
The waiter in charge of serving the dishes finished serving Taotao is why do i have no libido male table, and then told Dong Mingchun, Comrade, our chef said that there is no white porridge, so you can change it to something with the same price Your Highness, you will definitely lose.
Whether the man is rich or not, no matter whether this man can give her a more prosperous life in the future, she still loves this man. Li Jingying is still thinking about the last trace of old love, not for Xu Weibing, but for her youngest son who has loved her for Mens Viagra Pills can you sleep with viagra many years.
I am afraid he will not have can you sleep with viagra much time to talk to Murong Qing about these two days. They are orphans and can you sleep with viagra widows, how could they beat the mighty Princess Wu If she kills their mother and daughter, not only will no one dare to speak out, but she will also help clean up, and then lie that they died of illness.
Ting Fang swept can you sleep with viagra over quickly, and sure enough, her brows were furrowed. Never thought Master Liu Chen said Xue Ting failed to enter my Heavenly Star Gate back then, so you can be regarded as half a disciple of my Heavenly Star Gate. Calmly passed Wang Ruyi, mainly to ask Yu Xingzhi. After all, the little girl in the wedding gown in front of her did not look like a living person.
I am going to kill her. The handsome young man with a gloomy expression had a gloomy tone, his eyes flashed with madness, he loaded his hand and aimed at it when he raised his hand, and his pair of protruding animal pupils turned to stare at Yuan Youshan below.
After listening to her words, as long as she catches the opportunity, will you subconsciously want to talk to her and become a bosom friend if you can you sleep with viagra have suspicions in your heart Simply not too delicious As soon as he entered the mansion, he met Mei Shuiyan waiting there.
Xiao Yuduo hurriedly lowered her head and pretended to roll up her trouser legs to avoid the swimming hormones ashwashila for erectile dysfunction in the water. The dense rat tide under the three people strung together candied haws was still jumping, but as Yuan Youshan lifted his right arm up a little bit, Xue Youcai and Bao Changsheng is bodies were raised, avoiding the jumping people below.
It will not be like this in the future, right My grandson said what is this, what is the end of the world I believe in your shoes The members of the alliance saw their boss admitting that they had been thinking about whether to release Princess Xiao Anran, but now, it seems that the release of Xiao Anran is imperative.
According to speculation, there may be restrictions on age or cultivation. We may not be able to enter it, so it depends on you. The lying girl suddenly opened her eyes and smiled faintly at the man in front of her. Because of the can you sleep with viagra poisoning, her face was blushing as if she was about to bleed, and her big soft eyes were slightly raised, as if she could suck people in.
Tang Xiaonan pouted, I am going to play with Brother Huo, I agreed yesterday. Before that, of can you smoke weed and take viagra course, they also contacted the UK side to confirm that it is a real joint school, teachers will be sent from the UK, and after the academic qualifications are shared, some people have already booked places.
With the can you sleep with viagra martial arts of the emperor they saw just now, these people are not enough for him to torture, but he can not let these people die under the sword of the emperor, otherwise when the emperor wakes up and knows that he killed himself The soldier will definitely be hurt and angry.
He was a majestic emperor, but he could not subdue the guy next to him Thinking about Ting Fang is dog legged appearance, it turns out that this is the real master He is mad at him When he was the prince, he gave Yan Chunwen his sincerity, but Yan Chunwen slapped him on the face.
The silly sister had to look guilty again. This is fatal Come in. She dare not. The three people looked desperate and terrified, and they screamed, as if they were asking for help. Is not he the richest man in the country Money is the best thing to earn. Zhuge Liuyun said again I have prepared some small presents for my mother. When you recover, we will go back and visit her together. This time she is exhausted.
Huo Jinzhi was a little disappointed, and spared no effort to coax, even took out a villa as a bait, but Tang Xiaonan was unmoved, Why do you have to accompany me when you go to school abroad, you are not a three year old child anymore, I do not want to go out.
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It will can you sleep after viagra affect the collective production and labor, and it will also damage the reputation of the production team. Everyone sat down, and the maids quickly served hot tea. The one for Shui Linglong was a cup of chrysanthemum tea. Shui Linglong leaned on the back of the chair with Sixi soft pillows, and took a few sips slowly.
Did not you find that I can pick the lock is not this self defense secret good enough Also, who told you that if you come from a rich family, you will know the secrets of self defense The ladies of the rich family are all indifferent to the outside world, and video of erectile dysfunction exam they do not work hard We need to raise chickens Chickens are delicious.
Bother you for something. And those snakes do not know what they eat to grow up, they can eat a hole in the stone with a spray of saliva, and they are so flexible that she almost wrapped herself into a mummy just in case. In fact, there is no choice to start this factory. It is not a job suitable for our female educated youths.
Luo Yuexi jumped onto a tall tree without a sound. She found a branch with a wide view and sat down. On the tree trunk, the sitting posture is quite heroic. She greeted everyone, stood up and walked to the lawn. She never thought that when these officials sent them up, the things she did not care much about were not ordinary. It is really suitable for him. Wan Yihui is choice made Zhao Xuran very happy. He thought Jowan ED drug injection would rebel.
Grandpa, if we call it that way, would not my great grandmother be called the ancestor And that, the eldest wife and the others in the house, what should I call my elder brother more appropriate After Yi Xuan made the sound last time, she finally made another small sound can you sleep with viagra after yesterday is treatment.
The corner of Yi Zhuo is mouth twitched. Xiao Qingrong is mind was filled with three questions in succession male enhancement surgery before and after pictures before he could outline everything that happened in this body. Seeing that it was almost noon, Xiao Qingrong went to the cafeteria to eat with his roommates after class. Because of his appearance and recent events, along the way, many people secretly looked at him.
The pain comes and goes, this feeling is really ecstasy. He hurriedly but briskly came to the side of Prince Yong who was resting with his eyes closed, and reported in a low voice Master, those people are already on the move, and the test paper of Mr.
The main words of Qixing Peak, who wanted Su Yao and Su Nian to come back immediately, were pre empted, and it was not good to say it at this time, but just said Have a rest, come back as soon as possible, nowhere is as comfortable as Tianxingmen, is not it Han Lijuan was standing in front of a meat stall picking meat.
He is not afraid of his children being bullied, but he is afraid that his children will bully others. As for the kids having their old friends to reunite too But Su Yao took advantage of Su Nian, and Ban Xia was worried that Su Nian is distribution of the pills to Su Yao would not be enough for him, so he specially prepared some more.
Mei Shuiyan smiled, You will understand everything when you die by the way, are not can you sleep with viagra you worried that I will expose and kill you Now let me tell you, do not worry at all, because I will create a strongman to come Think about it, if a strongman comes to attack you again, your kung fu is not as good as Fang, and it is normal to be killed by chaotic swords.
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When the water surface widened again, Sister Zhen let out a wow, which made her jump for the fourth time. Ruan Xiaoqi was very proud, pointing and said Look Both An An and Mr. Sun are good at cooking. Gu Weiqiang cooks the last difficult dish himself.
Taking advantage of the opportunity of coming to worship, Cai is mother, Tu Chunni, took Cai Meina is hand and cried in a sad way, Your brother and sister in law is job is not good, so just go out and work for so little money, the boss is cruel. Early the next morning after that, before Jian Tong got up from the bed, Xia Jinye woke him up Hurry up, I will take you to the old Chinese doctor for a check up, can you sleep with viagra and ask him to can you sleep with viagra Erectile Dysfunction Meaning feel your pulse.
Suddenly someone shouted in the yard, interrupting Ruan Xiuzhi is words. On the melon seedlings in the front and back of i have erectile dysfunction what should i do Xiaosuo is garden, it is fine that there are still melons, and those without melons are also pulled out, and green vegetables are planted.
Look at the thin layer of black tube boots, but looking inside, there is a thick layer of white wool mattress around the inside of the boots, which is warm. With his spiritual power blocked and cut off, Cen Qingyou ended up no different from an ordinary person.
The national economy has developed rapidly, and material resources are no longer as scarce as in previous years. In the past two years At that time, there were already five or six bicycles in the village. Whether to cooperate or not is my choice. And, even if there is no cooperation, I will be the winner in the end.
After the end, Jiang Yutong discussed with the leaders of the school to invite graduate students or doctors in the school can you sleep with viagra Erectile Dysfunction Meaning to join the laboratory team. What did my brother do The emperor frowned, sighed softly, and said in a soft voice I still have a few important memorials waiting to be dealt with.
What is going on Why did it suddenly stop Bai Zhenzhu, did not you say so But now, the one being treated sincerely by the little princess is a child from the countryside, even though Qiu Wanwan is one year older than this child. Master Xu did not know about it.
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Your Majesty, this is the sign you turned over tonight. The eunuch is legs trembled. Gu Weiqiang hugged Dongdong and turned back. It was the old can you sleep with viagra lady. Xiao Qinxin confessed, and took the lead in chasing her out. As for what that person looks like. Nonsence She is just messing with me. Ye Mao walked in Miss, a letter from the Yao Mansion.
In rural areas, pigs are fed with rice bran water and pig grass. This is also cost saving. No one is willing to spend money to feed pigs. Xiao Tianzi, hurry up and ask someone to move things and load them into the car. Be careful. If you bump into something, you will never be forgiven. Ruan Wen did not intend to obey either. Even if it was not for Concubine Jing this time, she would still go to the Land of Water.
Maybe it was because he was neatly dressed and a bit majestic, but the two of them did not dare to fight all of a sudden and looked at him. Although Gong Ruini was wearing the clothes that Cai Ming and the others brought back from Yangcheng, she knew a thing or two about where the clothes in Beijing were cheap.
He was going to throw his things off the roof, but he still could not bear it, so he went down after eating, and gave the guard a hard look I do not have a bed today, so strange side effects of erectile dysfunction drugs you can go to bed with me. The latrine Almost at the same time, bursts of cheers came from the technical department of Star Game Company.
How can I teach others A lot of people squeezed into the live broadcast room, and seeing the luxurious reception scene, bullet screens appeared one after another. Forgive me, I have been eating noodles every day for the past two can you sleep with viagra days, and my stomach is almost overwhelmed.
The emperor is here, and the pressure is really too great. The kang on Yi Zhuo is side is different, it burns very hot all night. Zhao Xuran was drawing circles in various ways, while Gong Ruini was anxious to run up. King Yi enjoyed it very much, closed his eyes, and said slowly This opportunity can only be through a banquet or something.
Mother, dear mother, you lend me Mama Gao. I like her, she is kind, and she can cook delicious food can you sleep with viagra However, Xiaoqiu did not think so. There is a separate kitchen and bathroom at home. There must be a balcony to dry. It is getting late, I am going back. Glancing at the food on the dinner table, there was really no desire to make people do Mens Viagra Pills can you sleep with viagra it. Ahem, I mean, it is not suitable. The conditions of the place I stay in are poor, and this person can you sleep with viagra must not be used to it.
Could it be the little girl in front of her who is less than 1. 6 Meters tall Qiao Wan was still unmoved Why do you think I want to go back to Kunshan I will help you brother, first, to solve the pursuit, and second, if this happens, revenge Zhou Yan and Mu Xiaoxiao.
Impossible Twenty years have passed, Miss Huang, do you still let the hidden guards keep an eye on Yong an Xi This is basically the practice of all dynasties. Even if the Empress Dowager wanted to fool Fourth Master, can you sleep with viagra what would she do She could not do it either, because fourth master would not believe her at all.
The victory of this battle completely consolidated Xiao Qingrong is identity as Crown Prince Xiao Qingrong, and after Xiao Qingrong led the army back to the empire, the Imperial Academy of Sciences finally released the psychoactive naturally huge male enlargement pills drug jointly developed by Xiao Qingrong and Xiao Anran, although it can only suppress Three hours what do sex pills do is enough to save lives.
He was beaten so hard that he bled almost as soon as he punched him. Little Song Yan curled up tightly. He is very experienced in being beaten, as long as he gets through it will be fine. No one knew exactly how long it had passed, but it was a long, long time like suffering, before a weak cry of a baby was heard again in the delivery room.
What are you running Gong Tao was lying under the blanket, feeling really uncomfortable, By the way, before Gong Zhuang said that he had the opportunity to come back, I declined, so do not be angry. So now Luo Yuexi, who was a little impatient with being roasted by this stove, opened her eyes with great difficulty, to see which idiot actually put the stove beside her.
Seeing Sister He Mens Viagra Pills can you sleep with viagra Li is firm and happy appearance, Han Mingxiu smiled and said sincerely Well, since you have confidence, sister, I wish you well It is better to suffer now than to suffer later, especially this time, Gong Ruini reckoned that many related households wanted to withdraw.
He hesitated can you sleep with viagra for a moment, but still asked Shiyan, if according to their plan, you really died can you sleep with viagra Erectile Dysfunction Meaning in the northwest under such circumstances, would the situation with Fourth Master be difficult He thought for a while, and then said There is one more thing, it is said that the female Tianji left two kits for the Tianji clan before her betrayal, and it was one of the kits that saved the Tianji clan during the big incident that year.
Once you are successful in cultivation, you can refine the Great Yuan Golden Elixir and reshape your body. At that time, our family can be together again. When Chunsi heard the words, she glanced at the empress for an instant, and then hurriedly avoided. Mother Hu stepped forward and pinched Tingfang is face I love can you sleep with viagra your generous temper the most.
After Mr. Sun switched seats, Xia Lele was sitting in Jian Tong is seat. Yuan penile enlargement injections near me Jinxun turned over at the same time, wanting to put pressure on Lin Yiyi, it is a rule to pay bills, otherwise Lin Yiyi would cry a river. Hearing this, Guan Tianyou blushed, and he hurriedly filled the aluminum lunch box with noodle soup.
How can a busy person like Ruan Wen be idle when his career is on the rise. Simple, right When you receive the invitation, you can go to the first book. Here, it is this one. Take a look like this Oh, I remember last year can you sleep with viagra is ceremony. That is great. Mr. Qi is looking forward to it every day. Now he is very happy.
Are you happy Han Lijuan saw that Han Mingcui refused, and immediately enlightened her, Xiao Cui er, no The old lady said you, with your current conditions, what else do you want to find It is cheaper to find Jianguo from our family. Jianguo from our family has never been married and has never had a date.
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As a result, no one can shake her back position. I think this one is good, let is go in and have a look. Sister Yingnan, do not think of me as a child, I am an adult, I can do many things. I let it marry a wife, but it is not happy anymore. Go to the photo studio to take pictures. The photo studio will prepare family portraits with clothes. I think what do sex pills do Pills To Make Your Penis Bigger we can wear cheongsam directly. Jian Tong wanted to wear cheongsam a long time ago, but she never had the chance.
Are you sending gifts back home as usual Fang Lihong felt that she was right to take care of Xia Yunyou from childhood to adulthood, but she has a son, her own, so she only hoped that after Xia Yunyou got married, the young couple could live happily and happily.
Keiko Tajima thought in a trance that she was the child picked up by her grandfather, and that Ronglin was the descendant of the Tajima family. The daughter in law is eyes widened in an instant What Is The Best Cream For Erectile Dysfunction can you sleep with viagra Zhan Banxia was actually hesitant, after all, he brought everyone here to find Zhao Xuran.
As soon as Qiao Wan touched the protrusion inside the Buddha statue, she fell headfirst to the other side and hit the inner wall of the Buddha statue. Before she could cry out in pain, Qiao Wan clenched her teeth, like an octopus, using her hands and feet together, Trying to hang myself in the Buddha statue.
If it were not for the fact that the remaining 200 million yuan would not be easy to throw away at can you sleep with viagra Mens Viagra Pills can you sleep with viagra once, he and Uncle Guan Shi had the same idea, it would be better to throw it away as much as possible. As for the girl who does not know her well, it is easy to handle, is not he back From today onwards, he has been going around his daughter every day, trying to make her happy.
His face sank slightly, and he said, It is not the first time I have lost everything, why are you complaining so much this time Since this Tang Xiaonan has a net worth of several billion, of course a hundred million is not too much, and she will definitely be able to collect the ransom.
Mr. Zhou also said helplessly There is nothing you can do about it. The rules in the imperial court are very strict. You should cancel the vacation or you have to sell it The moment Lou Qi fell down, she saw Shu Chongzhou give her a wink. In the twinkling of an eye, it has been almost three months since she came to this world. For her, this period of time is like a rare vacation. She stretched out her hand and shook it back. Zhou Zimo is attitude was extremely respectful.
When his wife and children got into the car, he motioned for Jiang Yutong to get in the car too, I will wait for you. Mr. In fact, Pei Tian was as good as he was, and just as he had speculated, Mozun did not intend to kill him at all. When Mrs. In her perception, Father Sharp is not such an irresponsible person. Outside the car, Yuan Gui asked these people with a smile on his face. It is not your turn to be our master. What a good name.
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Even if Su Wanrou came back, she would not be able to live a good life. In this kind of environment, it is most likely to be separated, and with a little ingenious artificiality, it is only natural that the rampant brigade just now will be torn apart.
Han Mingxiu stopped in his tracks, turned his head and smiled brightly, and said, That is right, do not treat everyone as a bad person Seventy big characters An An was a little curious, not to mention how eager she was in her small eyes, she felt that she was jealous, it was too discriminatory for Lu Yan to tell the two children and not tell her.
Leaving aside this point, what about Nalan Huaxin is kindness to the savior back then And this time, Nalan Huaxin went to the inner circle of the Valley of Gods and Demons to find medicine for him without fear of danger. does keto affect sex drive Although Lou Qi got the Sanhanqiujiao in the end, Nalan Huaxin is friendship cannot be erased just because of this.
Yi Zhuo did not give Shiyan a chance to moan, and asked casually, By the way, Shiyan, the goat is wool I asked you to find before, did you send someone to look for it Under everyone is noses, Yu Guizhen hid the money, and happily got into the carriage, and went to town with her son and Han Mingxiu.
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Finally, it was mentioned that the person in charge should bear 30 of the responsibility. Since all the members of the Witch Village are her most loyal believers, it was like opening any door when she went home, and she arrived directly with a swish.
Han Mingxiu picked up the piece of oil that the eldest sister is family gave her, and put it in his mouth to chew. As soon as this news came out, many people in the industry said that if this momentum continues to develop, a listed company will soon be born under Jiang Yutong is name.
Princess Cheng cautiously persuaded, Yuanyuan, do not talk nonsense like that. The twelve princes are also doing it for your own good. Your previous behavior was wrong. How could you do that to your child Xiaoshanhu is executioners were interested and asked the assistant coach next to him for the team is two month training records.
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Watching Zheng Yunqing leave at the gate of the barracks, Su Tianhan and Xiao Yuduo walked into the barracks, while saying Duo er, if we succeed, we will open the throat of the capital, and Liu Xu will be even more frightened. Over the years, Gong Ruini has been used to listening to Zhao Xuran, since he said there is no problem, Gong Ruini will follow his wishes.
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Shen Yuzhu completely denied the old man is kindness as a professor, even the teacher is kindness. No matter what the purpose was, But this woman is not as beautiful as the author described Jiang Yutong knew that he had misunderstood, so he did not explain it.
He lifted the chin of a lesbian because of the need of his work when he pulled out the tooth of a lesbian. In the end, he was sued by the woman across the road, and was sent here. With this belief that death would be their home, the three of them left Xiangyun Hall together. Lou Qi glanced at him, decided to kidnap and sell the elderly, ah no, ask for help.
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After dinner, he casually found a friendly soldier and asked, Where is your former army staff officer I want to see you. She said, Then, why do not we just strike while the iron is hot and burn bricks directly It just so happens that we have time this winter, so we will burn bricks and build a school in spring.
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Working Groups.
Name Affiliation Country WG1. Lifestyles Chairperson Juan A. Rivera National Institute of Public Health Mexico Support Tania Cony Aburto National Institute of Public Health Mexico Mariana Stern USC Norris Comprehensive Cancer Center USA Pedro Rodrigues Curi Hallal Universidade Federal de Pelotas Brazil Joaquin Barnoya Integra Cancer Institute Guatemala Luz Myriam Reynales National Institute of Public Health Mexico Simón Barquera National Institute of Public Health Mexico Isabelle Romieu National Institute of Public Health Mexico Camila Corvalán Institute of Nutrition and Food Technology (INTA), University of Chile Chile Tânia Cavalcante Instituto Nacional de Câncer José Alencar Gomes da Silva Brazil WG2. Environmental and occupational risks Chairperson Catterina Ferreccio Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile Chile Support Estela Blanco Universidad Mayor Chile Eduardo Algranti FUNDACENTRO Brazil Julietta Rodriguez-Guzmán Pan American Health Organization (USA)/Universidad El Bosque Colombia Ana Maria Mora Center for Environmental Research and Community Health, University of California, Berkeley USA Lizbeth Teresita Lopez Carrillo National Institute of Public Health Mexico Lene H.S. Veiga National Cancer Institute USA Luis Abdón Cifuentes Pontificia Universidad Católica de Chile Chile Laura Andrea Rodríguez Villamizar Industrial University of Santander Colombia WG3. Infections Chairperson Rolando Herrero Costa Rican Agency for Biomedical Research – INCIENSA Foundation Costa Rica Loretto Carvajal National Cancer Institute USA Carolina Porras Costa Rican Agency for Biomedical Research – INCIENSA Foundation Costa Rica Arnoldo Javier Riquelme Pérez Pontifical Catholic University of Chile Chile Maria Constanza Camargo National Cancer Institute USA Eduardo Lazcano-Ponce National Institute of Public Health Mexico Ana Patricia Ortiz University of Puerto Rico Comprehensive Cancer Center Puerto Rico Vanessa Van de Wyngard Pontifical Catholic University of Chile Chile Luis Fernando Aranha Camargo Hospital Israelita Albert Einstein Brazil Valeria Fink Fundación Huésped Argentina WG4. Medical interventions Chairperson Maribel Almonte International Agency for Research on Cancer France Support Armando Baena International Agency for Research on Cancer France Melisa Paolino Center for the Study of State and Society Argentina Mauricio Maza Pan American Health Organization USA Gabriela Torres-Mejía National Institute of Public Health Mexico Jóse Jerónimo National Cancer Institute USA Lucía Delgado Honorary Commission for the Fight against Cancer Uruguay Cynthia Villarreal-Garza Zambrano Hellion Hospital, Tecnológico de Monterrey Mexico Leonardo Javier Arcuri Hospital Israelita Albert Einstein Brazil Rossana Ruiz National Institute for Neoplastic Diseases Peru WG5. Communication Chairperson Carolyn Finck Universidad de los Andes Colombia Support Maríantonia Lemos EAFIT University Mexico Fernanda de Albuquerque Melo Nogueira Instituto Nacional do Câncer José Alencar Gomes da Silva Brazil Claudia Jurberg Brazilian National Academy of Medicine & Foundation Carlos Chagas Filho Research Support Brazil Isabel Cristina Garcés Palacio University of Antioquia Colombia Anabelle Bonvecchio Arenas National Institute of Public Health Mexico Orlando Martínez Granera Movimiento Contra el Cáncer Foundation Nicaragua Elmer E. Huerta George Washington University Cancer Center USA Karina Pesce Hospital Italiano de Buenos Aires Argentina Arlette Bahena Botello National Institute of Public Health Mexico.
Scientific Committee.
Name Affiliation Country Liz Maria de Almeida Instituto Nacional de Câncer Brazil Silvina Arrossi Center for the Study of State and Society/National Council for Scientific and Technical Research Argentina National Council for Scientific and Technical Research Argentina Patricia J. García Funegra Universidad Peruana Cayetano Heredía Peru María Luisa Garmendia Institute of Nutrition and Food Technology Chile Alejandro Mohar National Institute of Cancerology/Institute of Biomedical Research Mexico Raúl Murillo San Ignacio University Hospital Colombia Julio Santamaría Centro Hemato Oncológico Panamá Panama.
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Name Affiliation Country IARC/PAHO Secretariat Principal Investigator Carolina Espina International Agency for Research on Cancer France Researcher Ariadna Feliu International Agency for Research on Cancer France Senior Advisor Joachim Schüz International Agency for Research on Cancer France Senior Advisor Andre Carvalho International Agency for Research on Cancer France PAHO Advisor Mauricio Maza Pan American Health Organization USA.

Tadalafil for erectile dysfunction

tadalafil for erectile dysfunction

Effects of Tadalafil on Erectile Dysfunction in Men With Diabetes.
Iñigo Sáenz de Tejada , Greg Anglin , James R. Knight , Jeffrey T. Emmick; Effects of Tadalafil on Erectile Dysfunction in Men With Diabetes. Diabetes Care 1 December 2002; 25 (12): 2159–2164. https://doi.org/10.2337/diacare.25.12.2159.
OBJECTIVE —To evaluate the efficacy and safety of tadalafil taken as needed before sexual activity by men with diabetes and erectile dysfunction (ED).
RESEARCH DESIGN AND METHODS —Men with type 1 or type 2 diabetes and a minimum 3-month history of ED were randomly allocated to one of three groups: placebo ( n = 71), tadalafil 10 mg ( n = 73), or tadalafil 20 mg ( n = 72) taken up to once daily for 12 weeks. Changes from baseline in mean scores on the erectile function domain of the International Index of Erectile Function (IIEF) and changes from baseline in the proportion of “yes” responses to question 2, “Were you able to penetrate?,” and 3, “Were you able to complete intercourse?,” of the Sexual Encounter Profile were coprimary outcome measures.
RESULTS —A total of 191 (88%) of 216 patients completed the study. Treatment with tadalafil significantly improved all primary efficacy variables, regardless of baseline HbA 1c level. Therapy with tadalafil also significantly improved a number of secondary outcome measures, including changes in other IIEF domains, individual IIEF questions, and percentage of positive responses to a global assessment question measuring erection improvement. Treatment with tadalafil did not alter mean HbA 1c levels. Tadalafil was well tolerated, with headache and dyspepsia being the most frequent adverse events with active treatment.
CONCLUSIONS —Tadalafil therapy significantly enhanced erectile function and was well tolerated by men with diabetes and ED.
Erectile dysfunction (ED) is a common comorbidity in patients with diabetes. As many as 75% of diabetic men will be confronted at some time in their lives with a consistent or recurrent inability to achieve and maintain an erection adequate for sexual performance (1), typically at an earlier age than their counterparts with normal glycemic control (2).
Whereas the incidence of ED increases as a function of age in the general population (3), the gradient is particularly steep in men with diabetes. In one cohort study (4), ED affected >47% of men with type 1 diabetes aged ≥43 years, compared with 1.1% of those aged 21–30 years ( P 50% of men will develop ED within 10 years of diabetes onset.
Not only does diabetes increase the risk of ED nearly twofold, but ED may also be the first symptom of diabetes and was significantly predictive of neuropathic symptoms and poor glycemic control in a 5-year prospective study (6). ED and diabetes each affect >150 million people worldwide, and this value is projected to double by the year 2025 (7–9).
Recent trials (10,11) demonstrated that the oral phosphodiesterase type 5 (PDE5) inhibitor sildenafil citrate was effective and well tolerated in men with concomitant ED and diabetes. The mechanism of action for PDE5 inhibitors is well established. In response to sexual stimulation in potent men, nitric oxide (NO) is released by nonadrenergic noncholinergic nerve terminals (12). NO induces relaxation of smooth muscle within the arterioles perfusing the lacunar tissues, sinusoidal endothelium, and trabecular erectile tissues of the corpus cavernosum (13,14). Lacunar expansion against the tunica albuginea surrounding the corpora compresses subtunical venules, resulting in venous congestion, engorgement of the corporal bodies, and thus physiological erection. The smooth muscle-relaxing properties of NO are mediated by cyclic 3′,5′-guanosine monophosphate (cGMP), a second messenger that is synthesized by guanylyl cyclase under the influence of NO. Blockade of PDE5, which hydrolyzes cGMP, thus potentiates the physiological NO-mediated erectile response.
Tadalafil is a potent, reversible, and selective inhibitor of PDE5 in development as an oral therapy for mild-to-severe ED of psychogenic, organic, or mixed etiology (15). The objective of this study was to assess the efficacy and safety of tadalafil in men with diabetes and mild-to-severe ED.
RESEARCH DESIGN AND METHODS.
This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial was conducted at 18 sites in Spain from December 1999 through August 2000. A total of 216 men aged ≥18 years with a clinical diagnosis of type 1 or type 2 diabetes (mean duration 11.7 years), a minimum 3-month history of mild-to-severe ED, and a stable monogamous relationship with a female partner were eligible. Men with a history of hypertension ( n = 80; 37%) and hypercholesterolemia ( n = 38; 18%) were included.
A clinical diagnosis of diabetes was predicated on either current therapy with insulin, metformin, or sulfonylureas or a history within the previous year of two occasions of diagnostic-level hyperglycemia, including 1 ) fasting plasma, serum, or blood glucose >7 mmol/l (126 mg/dl); 2 ) randomly obtained plasma, serum, or blood glucose ≥11.1 mmol/l (200 mg/dl) associated with symptoms of polyuria, polydipsia, or unexplained weight loss; or 3 ) plasma, serum, or blood glucose ≥11.1 mmol/l (200 mg/dl) 2 h after administration of 75 g oral glucose. Any patient with an onset of diabetes before the age of 30 years who had received continuous insulin treatment since diagnosis was considered to have type 1 diabetes.
The vast majority of patients (>72%) had moderate-to-severe ED, an ED history of >1 year (93%), and a diagnosis of type 2 diabetes (>90%) at study onset (Table 1). Patients were eligible for study inclusion irrespective of previous responses to ED treatments, including sildenafil.
Patients with HbA 1c >13.0% at the screening visit (visit 1, week –4), a recent history of diabetic ketoacidosis (≥2 episodes), or ≥3 episodes of hypoglycemia requiring assistance as specified by the Diabetes Control and Complications Trial (16) were excluded. However, men with microvascular complications, including retinopathy, were eligible ( n = 48; 22%); most patients (>80%) had fair-to-poor glycemic control (HbA 1c >7.0%). Ophthalmologic histories were obtained and analyses of urinary albumin were conducted at the screening visit to determine the presence of diabetic complications at baseline.
After the screening visit, eligible candidates qualified for randomization by making at least four attempts at sexual intercourse during a 4-week treatment-free run-in phase to determine baseline erectile function. Participants were randomly allocated to one of three 12-week treatment arms: tadalafil 10 mg ( n = 73) or 20 mg ( n = 72) or placebo ( n = 71) taken up to once daily as needed. Men were instructed to take one dose of their treatment orally at any time before anticipated sexual activity, with no restrictions on food or alcohol intake.
The effects of tadalafil on erectile function were evaluated using the International Index of Erectile Function (IIEF) (17), a 15-item questionnaire that assesses five domains of male sexual function using 5- to 6-point Likert scales, with 0 or 1 signifying a low frequency or ability and 5 signifying a high frequency or ability. These domains include erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction.
The erectile function domain consists of six questions concerning erection frequency (question [Q]1), erection firmness (Q2), frequency of partner penetration (Q3), frequency of maintaining erection after penetration (Q4), ability to maintain erection to completion of intercourse (Q5), and confidence in achieving and maintaining erection (Q15), all during the previous 4 weeks. One coprimary efficacy variable consisted of the change in mean erectile function domain score from baseline to end point.
Patients also used Sexual Encounter Profile (SEP) diaries to record their sexual experiences. Other coprimary efficacy outcome measures consisted of the changes from baseline to end point in the mean proportions of “yes” responses to SEP-Q2 and SEP-Q3, respectively: “Were you able to insert your penis into your partner’s vagina? (yes/no)” and “Did your erection last long enough to have successful intercourse? (yes/no).”
Secondary outcome measures included the changes from baseline to end point in mean scores on IIEF-Q3 (penetration ability) and IIEF-Q4 (maintenance ability) in each treatment group. In addition, at study end point or early discontinuation, each patient was asked a global assessment question (GAQ), “Has the treatment you have been taking improved your erections? (yes/no).” Proportions of patients achieving more than a five-point gain from baseline to end point in the erectile function domain of the IIEF were also determined for all treatment groups.
Post hoc analyses were also performed to determine the effect of tadalafil treatment on HbA 1c levels, the effect of baseline HbA 1c level on response to treatment, and the effect of antihypertensive medications on response to treatment.
A medical history was obtained at the first visit; physical examination, 12-lead electrocardiogram (ECG), and urinalysis were performed at visit 1 and end point or early discontinuation; vital signs and clinical laboratory tests were evaluated at every visit or early discontinuation. Patients were also seen within 1–2 weeks after the 12-week end point for appropriate follow-up of adverse events.
The study protocol and informed consent form were reviewed and approved by ethical review boards. Patients and their partners provided written informed consent.
Statistical methods.
Each randomized patient was eligible for the efficacy analysis. The analysis of safety included all randomized patients. All analyses were performed with the patients included in the groups to which they were assigned by random allocation, even if the patient did not take the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol.
Patient baseline characteristics were summarized for each treatment group. For continuous patient characteristics, means were compared using ANOVA. Incidences of categorical variables were compared using Pearson’s χ 2 test.
For efficacy analyses, all patients with baseline and postbaseline observations on all variables in the statistical model were included. The IIEF erectile function domain, other domains, and individual items were analyzed using the last-observation-carried-forward convention, applied to each of the baseline and the postbaseline periods. The baseline and end point score for each SEP question was the patient’s percentage of “yes” responses to that question during the run-in and postbaseline periods, respectively.
ANCOVA models of change from baseline in the IIEF (domains and individual items) and SEP variables included terms for baseline value of the efficacy variable, treatment group, investigator site, and the baseline-by-treatment-group interaction. In any model, if the interaction was not significant (i.e., if P ≥ 0.10), then it was removed from the model and the between-treatment-group P value was obtained from the reduced model.
Because there were two tadalafil doses being studied, 10 and 20 mg, there were also two separate primary null hypotheses concerning the comparison of 10 mg to placebo and 20 mg to placebo. To reject the null hypothesis of no treatment effect relative to placebo, statistical significance at P P values from primary-efficacy treatment-group contrasts were adjusted by the method of Dunnett for the comparison of two doses with placebo. Accordingly, rejection of either of the null hypotheses concerning 10 mg tadalafil versus placebo or 20 mg tadalafil versus placebo was interpretable as statistically significant, due to the Dunnett correction for multiple comparisons with respect to dose.
Logistic regression models were used to evaluate GAQ at the end point and the proportion of patients achieving a greater than five-point gain in the erectile function domain of the IIEF. The models included terms for baseline value of the IIEF erectile function domain, treatment group, investigator site, and baseline-by-treatment-group interaction. If the interaction was not significant (i.e., if P ≥ 0.10), then it was removed from the model and the between-treatment-group P value was obtained from the reduced model.
Change of HbA 1c from baseline to end point was evaluated by a ranked ANOVA model. The effect of baseline HbA 1c level and concomitant antihypertensive medication use on response to treatment was determined using a model including investigator site, therapy, and baseline HbA 1c or antihypertensive medication status.
The analysis of safety included all enrolled patients. Safety was assessed by evaluating all reported adverse events and changes in clinical laboratory values, vital signs, physical examination results, and ECG results. Treatment-emergent adverse events were defined as events that first occurred or worsened after baseline and were summarized by the COSTART preferred term for severity and the relationship to the study drug. Analyses comparing the incidence of treatment-emergent adverse events among treatment groups were performed using Fisher’s exact test across all treatment groups in the study. Treatment-emergent events with incidences of >3% in tadalafil-treated patients or statistically significant differences between active treatment and control groups are presented.
Changes in continuous laboratory analytes, vital signs, and ECG measurements were evaluated by a ranked ANOVA model with a term for treatment group. Categorical changes in laboratory analytes by treatment group were evaluated by summarizing the proportion of patients whose test values were outside the reference ranges at their final visit and at their maximum and minimum value recorded during the study, as appropriate, for each individual analyte.
RESULTS.
Of the 216 men enrolled, 191 (88%) completed treatment. A total of six (3%) patients discontinued because of treatment-emergent adverse events. Of these six, four were randomized to tadalafil treatment: one man in the tadalafil 10-mg group experienced mild pain and three patients in the 20-mg group experienced either moderate myalgia, moderate headache, or severe flushing. The other two patient discontinuations were due to myocardial infarctions: one in the placebo group and one who was randomized to the 20-mg group but never took the study drug. Five patients (2%) randomized to tadalafil discontinued because of perceived lack of efficacy, including three in the 10-mg arm and two in the 20-mg arm. Protocol violations or failure to meet entry criteria accounted for four (2%) discontinuations, including two men in the placebo arm, while eight patients (4%) discontinued because of physician decision ( n = 4, two in placebo group) or personal conflict/patient decision ( n = 4; two in placebo group).
Therapy with tadalafil (particularly at 20 mg) significantly enhanced erectile function across all three coprimary efficacy outcome variables: IIEF erectile function domain, erection vaginal penetration rates (SEP-Q2), and successful intercourse rates (SEP-Q3) (all P.
Tadalafil treatment did not significantly change HbA 1c levels from baseline to end point (−0.2% both in the tadalafil 10- and 20-mg groups vs. 0% in the placebo group; P = 0.083), and baseline HbA 1c level did not influence response to tadalafil treatment (Table 2). However, concomitant antihypertensive medication use did influence response to treatment. Those who were treated with concomitant antihypertensive medications appeared to respond better to tadalafil 20 mg than those who were not (Table 2).
At end point, each dose of tadalafil also significantly enhanced patients’ erections according to responses to the GAQ. The proportions of positive responses to the GAQ in the tadalafil 10- and 20-mg groups were 56 and 64%, respectively, compared with 25% in the control group (both P.
Tadalafil at 10 and 20 mg improved erectile function irrespective of the type of diabetes, presence of microvascular complications, or type of diabetes treatment. Treatment with tadalafil was well tolerated, with the majority of events being mild or moderate and transient. The most common treatment-emergent events in the tadalafil groups were dyspepsia and headache (Table 3). Only the incidence of dyspepsia was significantly different across treatment groups: ∼11% in either the 10- or 20-mg group, compared with 0% in the control arm ( P = 0.005). No treatment-related visual disturbances were reported. Electrocardiograms, clinical laboratory values, and vital signs exhibited no clinically significant changes.
CONCLUSIONS.
Therapy with tadalafil consistently enhanced erectile function, significantly improving patients’ ability to achieve and maintain erections.
After 12 weeks of treatment taken whenever patients anticipated sexual activity, without restrictions on food or alcohol intake, nearly two-thirds (64%) of patients in the tadalafil 20-mg group and more than half (56%) in the tadalafil 10-mg group reported improved erections. Similarly, increases in the proportions of positive responses to SEP questions concerning patients’ ability to penetrate their partner and maintain erection to successful completion of intercourse in the present trial were significantly higher in the tadalafil 10- and 20-mg groups than in the placebo arm. Treatment with tadalafil at 10 and 20 mg improved these outcomes regardless of baseline HbA 1c level.
These findings, taken together with the observed mean improvements of 6.4 and 7.3 points on the erectile function domain of the IIEF, warrant comment given the level of morbidity in this patient population. At baseline, >72% of men had moderate or severe ED, >80% had HbA 1c >7.0%, and >20% had microvascular complications, including 23 (11%) men with retinopathy and 14 (6%) with neuropathy. The percentage of men reporting improved erections in this study (56 and 64% for 10 and 20 mg, respectively) is consistent with data from a previous, flexible, dose-escalation study (10) with sildenafil, in which 56% of diabetic men responded at 12 weeks that treatment had improved their erections. The sildenafil study excluded men with either diabetic retinopathy or autonomic neuropathy.
Further, patients in the present trial were included irrespective of previous response to ED therapy, including sildenafil. The fact that tadalafil therapy improved erectile function domain scores by more than five points, which is consistent with an improvement from, for instance, severe to moderate ED (18), in a significant proportion of men with long-standing fairly advanced diabetes is clinically noteworthy.
The pathophysiology of diabetic ED has yet to be completely elucidated, but in vitro work (14) demonstrated that corporal smooth muscle from men with diabetes exhibited diminished autonomically mediated or endothelium-dependent relaxation compared with tissues from nondiabetic counterparts. A more recent immunohistochemical study (19) suggested that advanced glycation end products (e.g., pentosidine and pyrraline) in diabetic men, when deposited within the penile tunica and corporal collagen, might result in downregulation of NO synthesis through modulation of endothelial and/or inducible NO synthase enzymatic activity. Therefore, treatment with a PDE5 inhibitor, which potentiates the effects of NO, is a rational therapeutic alternative in a setting of potentially attenuated NO output. However, improvements in erectile function were not as pronounced in this population as in ED patients without diabetes in other studies. A recent placebo-controlled trial (15) involving 179 men with ED and no history of diabetes that also included a tadalafil 10-mg arm demonstrated positive response rates of 81% on the GAQ at end point at this dose (vs. 56% in the 10-mg group within the present trial).
We observed that nearly 40% of men also had baseline hypertension, a condition that could substantially alter endothelium-dependent relaxation in penile resistance arteries. Antihypertensive medications themselves have also been implicated in ED (20). In this study, men taking concomitant antihypertensive medications had greater improvements in erectile function with tadalafil at 20 mg than those not taking antihypertensives. These results may indicate that men with more severe endothelial dysfunction derive a greater benefit from the NO-potentiating effect of tadalafil at 20 mg. It is clear that hypercholesterolemia (e.g., oxidized LDL cholesterol) can also compromise NO production by endothelial NO synthase (21,22). A total of 38 (18%) men had hypercholesterolemia in the present study.
Tadalafil was well tolerated in this study. The chief adverse events were mild-to-moderate dyspepsia and headache, and the incidences of these events were consistent with data from a previous study in a general population (15). Even in these patients, who are more prone to ophthalmic sequelae of diabetes, no patient reported treatment-related visual (i.e., color discrimination) defects.
When taken as needed with no restrictions on either food or alcohol intake or the timing of dose administration relative to the onset of sexual intercourse, tadalafil significantly enhanced erectile function and was well tolerated in men with diabetes and ED.
. Placebo . Tadalafil 10 mg . Tadalafil 20 mg . Overall . n 71 73 72 216 Age (years) 55.8 ± 9.1 55.9 ± 8.8 55.5 ± 9.0 55.7 ± 9.0 Race White 70 (98.6) 73 (100) 72 (100) 215 (99.5) Black 1 (1.4) 0 0 1 (0.5) Diabetes duration (years) 11.9 ± 9.6 11.9 ± 9.4 11.2 ± 9.5 11.7 ± 9.5 Type 1 diabetes 8 (11.3) 8 (11.0) 4 (5.6) 20 (9.3) Type 2 diabetes 63 (88.7) 65 (89.0) 68 (94.4) 196 (90.7) Diabetes control Good: HbA 1c 15 (21.1) 13 (17.8) 12 (16.7) 40 (18.5) Fair: HbA 1c 7.0–9.5% 42 (59.2) 51 (69.9) 43 (59.7) 136 (63.0) Poor: HbA 1c >9.5% 14 (19.7) 9 (12.3) 17 (23.6) 40 (18.5) Microvascular complications * 14 (19.7) 15 (20.5) 19 (26.4) 48 (22.2) Current diabetic therapy Insulin only 32 (45.1) 26 (35.6) 20 (27.8) 78 (36.1) Oral only 29 (40.8) 32 (43.8) 39 (54.2) 100 (46.3) Insulin + oral 7 (9.9) 9 (12.3) 6 (8.3) 22 (10.2) None 3 (4.2) 6 (8.2) 7 (9.7) 16 (7.4) IIEF erectile function domain score 12.1 ± 6.1 12.9 ± 6.9 11.5 ± 5.6 12.2 ± 6.2 ED duration >1 year (%) 66 (93.0) 68 (93.2) 67 (93.1) 201 (93.1)
. Placebo . Tadalafil 10 mg . Tadalafil 20 mg . Overall . n 71 73 72 216 Age (years) 55.8 ± 9.1 55.9 ± 8.8 55.5 ± 9.0 55.7 ± 9.0 Race White 70 (98.6) 73 (100) 72 (100) 215 (99.5) Black 1 (1.4) 0 0 1 (0.5) Diabetes duration (years) 11.9 ± 9.6 11.9 ± 9.4 11.2 ± 9.5 11.7 ± 9.5 Type 1 diabetes 8 (11.3) 8 (11.0) 4 (5.6) 20 (9.3) Type 2 diabetes 63 (88.7) 65 (89.0) 68 (94.4) 196 (90.7) Diabetes control Good: HbA 1c 15 (21.1) 13 (17.8) 12 (16.7) 40 (18.5) Fair: HbA 1c 7.0–9.5% 42 (59.2) 51 (69.9) 43 (59.7) 136 (63.0) Poor: HbA 1c >9.5% 14 (19.7) 9 (12.3) 17 (23.6) 40 (18.5) Microvascular complications * 14 (19.7) 15 (20.5) 19 (26.4) 48 (22.2) Current diabetic therapy Insulin only 32 (45.1) 26 (35.6) 20 (27.8) 78 (36.1) Oral only 29 (40.8) 32 (43.8) 39 (54.2) 100 (46.3) Insulin + oral 7 (9.9) 9 (12.3) 6 (8.3) 22 (10.2) None 3 (4.2) 6 (8.2) 7 (9.7) 16 (7.4) IIEF erectile function domain score 12.1 ± 6.1 12.9 ± 6.9 11.5 ± 5.6 12.2 ± 6.2 ED duration >1 year (%) 66 (93.0) 68 (93.2) 67 (93.1) 201 (93.1)
Patients with microvascular complications had a history of diabetic retinopathy, laser treatment for diabetic eye disease, or a urine microalbumin-to-creatinine ratio >3.0 at visit 1.
Effects of tadalafil on efficacy variables.
Change in efficacy end points * . Treatment group . . . . . . Placebo . Tadalafil 10 mg . P † . Tadalafil 20 mg . P ‡ . n 71 73 72 ΔIIEF EF domain 0.1 6.4 7.3 By HbA 1c level 0.5068 § Good: −1.0 9.7 — 8.3 Fair: 7.0–9.5% −0.9 6.0 — 6.7 Poor: >9.5% 3.9 3.8 — 8.3 By concomitant antihypertensive medication use Yes −1.8 3.9 — 9.5 No 1.1 7.9 — 5.5 ΔSEP-Q2 (%) −4.1 22.2 22.6 By HbA 1c level 0.649 § Good: −13.7 21.0 — 30.6 Fair: 7.0–9.5% −3.3 24.1 — 21.0 Poor: >9.5% 3.7 13.0 — 21.2 By concomitant antihypertensive medication use 0.004 ‖ Yes −4.2 16.4 — 33.8 No −4.1 25.8 — 13.4 ΔSEP-Q3 (%) 1.9 28.4 29.1 By HbA 1c level 0.793¶ Good: 4.4 35.7 — 34.2 Fair: 7.0–9.5% −1.7 27.8 — 28.8 Poor: >9.5% 9.7 21.1 — 26.8 By concomitant antihypertensive medication use 0.085 ‖ Yes −4.5 21.9 — 31.9 No 5.4 32.5 — 26.9.
Change in efficacy end points * . Treatment group . . . . . . Placebo . Tadalafil 10 mg . P † . Tadalafil 20 mg . P ‡ . n 71 73 72 ΔIIEF EF domain 0.1 6.4 7.3 By HbA 1c level 0.5068 § Good: −1.0 9.7 — 8.3 Fair: 7.0–9.5% −0.9 6.0 — 6.7 Poor: >9.5% 3.9 3.8 — 8.3 By concomitant antihypertensive medication use Yes −1.8 3.9 — 9.5 No 1.1 7.9 — 5.5 ΔSEP-Q2 (%) −4.1 22.2 22.6 By HbA 1c level 0.649 § Good: −13.7 21.0 — 30.6 Fair: 7.0–9.5% −3.3 24.1 — 21.0 Poor: >9.5% 3.7 13.0 — 21.2 By concomitant antihypertensive medication use 0.004 ‖ Yes −4.2 16.4 — 33.8 No −4.1 25.8 — 13.4 ΔSEP-Q3 (%) 1.9 28.4 29.1 By HbA 1c level 0.793¶ Good: 4.4 35.7 — 34.2 Fair: 7.0–9.5% −1.7 27.8 — 28.8 Poor: >9.5% 9.7 21.1 — 26.8 By concomitant antihypertensive medication use 0.085 ‖ Yes −4.5 21.9 — 31.9 No 5.4 32.5 — 26.9.
Changes from baseline to end point in mean erectile function domain scores (unitless) or in proportions (%) of “yes” responses to SEP-Q2 (“Were you able to insert your penis into your partner’s vagina? [yes/no]”) or SEP-Q3 (“Did your erection last long enough to have successful intercourse? [yes/no]”).
P for comparison of tadalafil 10 mg vs. placebo;
P for comparison of tadalafil 20 mg vs. placebo;
interaction P for difference in response to therapy by baseline HbA 1c level;
interaction P for difference in response to therapy by antihypertensive medication status.
Treatment-emergent adverse events occurring in >3% of patients in all treatment groups.
. Placebo . Tadalafil 10 mg . Tadalafil 20 mg . P . n 71 73 72 ≥1 Event 22 (31.0) 29 (39.7) 32 (44.4) 0.247 Dyspepsia 0 8 (11.0) 8 (11.1) 0.005 Headache 2 (2.8) 7 (9.6) 6 (8.3) 0.234 Myalgia 1 (1.4) 4 (5.5) 3 (4.2) 0.540 Flu syndrome 3 (4.2) 3 (4.1) 3 (4.2) 1.00 Back pain 1 (1.4) 1 (1.4) 4 (5.6) 0.330 Flushing 0 2 (2.7) 3 (4.2) 0.332.
. Placebo . Tadalafil 10 mg . Tadalafil 20 mg . P . n 71 73 72 ≥1 Event 22 (31.0) 29 (39.7) 32 (44.4) 0.247 Dyspepsia 0 8 (11.0) 8 (11.1) 0.005 Headache 2 (2.8) 7 (9.6) 6 (8.3) 0.234 Myalgia 1 (1.4) 4 (5.5) 3 (4.2) 0.540 Flu syndrome 3 (4.2) 3 (4.1) 3 (4.2) 1.00 Back pain 1 (1.4) 1 (1.4) 4 (5.6) 0.330 Flushing 0 2 (2.7) 3 (4.2) 0.332.
Article Information.
Funding for this study was provided by Lilly ICOS LLC.
The authors would like to acknowledge the investigators in this study: Antonio Allona Almagro, José Luis Arrondo, Ander Odriozola Astobieta, Martín Caballero Gomez, Venancio Chantada Abal, Natalio Antonio Cruz Navarro, Luis Fiter Gomez, Rafael Gutierrez del Pozo, Fernando Jiménez Cruz, Enrique Lledó García, Antonio Martín Morales, Luis Martínez Piñeiro, Ignacio Moncada Iribarren, Jose M Pomerol Montseny, Luis Resel Estevez, Luis Rodríguez Vela, Jesús Romero Maroto, and Iñigo Sáenz de Tejada.
References.
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