Tadalafil

What is Tadalafil?

Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).This crystalline solid is almost not soluble in water and slightly soluble in ethanol. Tadalafil is approved by FDA (Food and Drug Administration) since October 2011 to treat Benign Prostate Hyperplasia (BPH) which is a condition in males where the prostate gland becomes enlarged obstructing the free way of urine. The symptoms that are characteristic to Benign Prostate Hyperplasia (BPH) include difficulty starting urination process (hesitancy), frequent urination (mostly during night time), sudden urges to urinate, weak urine stream, also Tadalafil is approved by FDA (Food and Drug Administration) to treat Benign Prostate Hyperplasia (BPH) and Erectile Dysfunction (ED) where the two co-exists.

The most common use of Tadalafil is in Erectile Dysfunction (ED). It causes vasodilatation and increases blood flow and produces erection, however sexual stimulation is required to initiate the process. To obtain the effect is necessary to stimulate the penis as if there were no drug administered. Tadalafil cannot be combined with other drugs for Erectile Dysfunction (ED) such as sildenafil or vardenafil because they can potentiate each other and it can lead to unpleasant side effects such as priapism that can cause permanent damage to the penis (see Side Effects). Tadalafil is known to be the most prolonged drug prescribed for Erectile Dysfunction (ED) compared to other analogs such as sildenafil or vardenafil, it results in a lot longer duration of action, up to 36 hours, and this is why Tadalafil is known as “The Weekend pill”. Tadalafil is a prescription medication which means can be purchased only with a prescription from a health care provider.

Tadalafil uses

Tadalafil is commonly used to help with Erectile Dysfunction (ED). It is not meant to treat Erectile Dysfunction; it has a temporary effect due to vasodilatation in specific area for the amount of time when drug is active in the system. Therefore there are two ways to use Tadalafil. First one is to use Tadalafil when needed in a higher dose, or to use Tadalafil in a lower dose on a daily basis. Consult your doctor to see which of the uses is more appropriate for you, also please notify your doctor if you have or had the following condition in order to minimize probability of bad results and to obtain the desired effect:

  • Heart disease or heart rhythm problems, coronary artery disease;
  • Heart attack within the past 90 days;
  • Angina (chest pain), uncontrollably high or low blood pressure;
  • A recent history (in the past 6 months) of a stroke, or congestive heart failure;
  • If you are on dialysis or have kidney or liver problems;
  • A blood cell disorder such as sickle cell anemia, multiple myeloma, or leukemia;
  • Stomach ulcer;
  • A physical deformity of the penis (such as Peyronie’s disease);
  • If you have been told you should not have sexual intercourse for health reasons;
  • Bleeding disorder such as hemophilia;
  • Retinitis pigmentosa (an inherited condition of the eye);

Tadalafil can cause vision loss due to decreased blood flow to the optic nerve of the eye,
(This has occurred in a small number of people taking sildenafil or other drugs similar to Tadalafil. Most of these people also had some pre-existing eye problems or risk factors for blood vessel disorders (such as heart disease, diabetes, high blood pressure, high cholesterol, coronary artery disease, smoking, or being over 50 years old).

Lastly, do not share your prescription with others. Not everyone experiences the same conditions as such each patient should be given a unique treatment regimen.

Another use of Tadalafil is for Benign Prostatic Hyperplasia (BPH), also called benign prostatic hypertrophy, benign enlargement of the prostate (BEP), or adenofibromyomatous hyperplasia, are all terms which refer to an increase in the size of the prostate gland. Signs and symptoms can include difficulty in starting urination, a weakened urine flow which causes stopping and starting, strain when passing urine, urinating too frequently, waking up in the night often to urinate (Nocturia), sudden urges to urinate which can result in incontinence if a toilet is not found immediately, inability to fully empty the bladder during urination, and sometimes blood in urine. Two human studies demonstrated that patients with Benign Prostatic Hyperplasia (BPH) who were prescribed 5 mg of Tadalafil once a day had statistically significant improvements in BPH symptoms compared to those on a placebo. Another study reviewed by the FDA showed that males with both BPH and ED combined who were given 5 mg of Tadalafil had improvements in both conditions, compared to those in the placebo group.

Tadalafil Mechanism of action

The erection during sexual stimulation is due to increased blood flow in the area resulting from the relaxation of arteries and penis smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP increases blood flow and smooth muscles to relax. Increasing the amount of cGMP enchases erection. Tadalafil inhibits PDE5. Stimulation is required to begin the release of nitric oxide. And absence of stimulation will not start the process. The effect of PDE5 inhibition on cGMP is also present in other smooth muscle such as bladder, muscle of prior vascular supply. PDE5 is found in other smooth muscles of the body: urethra, kidneys, lungs, cerebellum, liver, heart, pancreas and others. The mechanism for reducing BPH symptoms has not been established.

Studies showed that Tadalafil is a selective inhibitor of PDE5. Studies have shown that the effect of Tadalafil is more potent on PDE5 than on other phosphodiesterases. Studies have shown that Tadalafil is >10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the brain, liver, blood vessels, heart, leukocytes and other organs. Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme in the heart and blood vessels. Also, Tadalafil is 700-fold more potent for PDE5 than for PDE6 found in the retina and responsible for photo transduction. Tadalafil is > 9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14-fold more potent for PDE5 than for PDE11A1 and 40-fold more potent for PDE5 than for PDE11A4, two of the four known forms of PDE11. PDE11 is an enzyme in human prostate and in other tissues (e.g., testes, skeletal muscle, and adrenal cortex). In vitro, Tadalafil inhibits human PDE11A1 and, to a lesser degree, PDE11A4 activities at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.

Tadalafil is well absorbed after per oral ingestion and the maximum concentration observed plasma (Cmax) is obtained at aproximately 2 hours after administering. Absolute bioavailability of Tadalafil following oral dosing has not been determined. The absorption of Tadalafil is not influenced by food. The time of administering (AM vs PM) showed no difference on the rate and extent of absorption.

The volume of distribution is approximately 63 l, which indicates that Tadalafil is distributed into tissues. Tadalafil is bound to proteins in plasma at therapeutic concentration of 94%. . 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. Metabolite concentrations does not have pharmaceutical effect. The mean oral clearance for Tadalafil is 2.5 l/h and the mean half-life is 17.5 hours in persons with no medical condition. Tadalafil is excreted mostly as inactive metabolites, mainly in the faeces (approximately 61% of the dose) and to a lesser in the urine (approximately 36% of the dose).

Healthy elderly patients, over age of 65 or over showed a lower oral clearance of Tadalafil, resulting in 25% higher exposure (AUC) relative to healthy patients aged between 19 and 45 years old. This effect of age is not clinically significant and does not warrant a dose adjustment.

Tadalafil Dosage & different forms

Tadalafil can be found as film coated tablets or liquid for per oral use.
The tablet form it is known to have better results in patients with Erectile Dysfunction (ED) versus the liquid form. It was found to be more effective, last longer and have fewer side effects (see Side Effects). The tablet form is a very accurate way to administrate the exact dosage and prevent under dose or overdose and is found to be more preferred by the patients. For patient convenience Tadalafil is produced in different dosages to approach patients’ needs and to avoid halving the pill in order improve the exact amount of substance that is desired to be administered.

Common doses: Tablets: 2.5 mg, 5 mg, 10mg, 20 mg. Liquid – 30mg/ml.

Cialis (USA)

2.5 mg, 5 mg, 10 mg, 20 mg,
Each 2.5 mg tablet contains 2.5 mg tadalafil.
Excipient with known effect: Each coated tablet contains 87 mg of lactose (as monohydrate).
Each 5 mg tablet contains 5 mg tadalafil.
Excipient with known effect: Each coated tablet contains 121 mg of lactose (as monohydrate).
Each 10 mg tablet contains 10 mg tadalafil.
Excipient with known effect: Each coated tablet contains 170 mg of lactose (as monohydrate).
Each 20 mg tablet contains 20 mg tadalafil.
Excipient with known effect: Each coated tablet contains 233 mg of lactose (as monohydrate).
Excipients used: Tablet core: lactose monohydrate, croscarmellose sodium, hydroxypropylcellulose, microcrystalline cellulose, sodium laurel sulfate, magnesium stearate.

2.5 mg Film-coat: lactose monohydrate, hypromellose ,triacetin, titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172), talc.
5 mg, 10 mg and 20 mg Film-coat: lactose monohydrate, hypromellose, triacetin, titanium dioxide (E171), iron oxide yellow (E172), talc.
Nature and contents of container: Aluminium/PVC blisters in cartons of 2, 4, 8, 10, 12, 14, 28 and 84 film-coated tablets. Not all pack sizes may be marketed.

Film-coated tablet (tablet):
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 color and almond shaped tablets, marked with ‘C 5’ on one side.
The 10 mg tablets are light yellow color and almond shaped tablets, marked with ‘C 10’ on one side.
The 20 mg tablets are yellow color and almond shaped tablets, marked with ‘C 20’ on one side.

Adcirca (USA)

20 mg, Each film-coated tablet contains 20 mg tadalafil. Each film-coated tablet contains 233 mg lactose (as monohydrate). Excipients used: Film-coated tablet core: lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, microcrystalline cellulose, sodium laurilsulfate, magnesium stearate.Film-coat: lactose monohydrate, hypromellose, triacetin, titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172), talc.
Container material: Aluminium/ PVC/ PE/ PCTFE blisters in cartons of 28 and 56 film-coated tablets. Not all pack sizes may be marketed.
Film-coated tablet (tablet):
Orange and almond shaped film-coated tablets, marked with “4467” on one side.

Tadacip (India)

10 mg, 20 mg.
The recommended starting dose of Tadalafil for use as needed in most patients is 10 mg, taken prior to anticipated sexual activity. The dose may be increased as needed to the maximum dose of 20 mg or decreased to 5 mg, based on individual test results and health condition. It is recommended not to abuse on Tadalafil and maximum to use as frequent as once per day. Tadalafil for use as needed was shown to have results compared to placebo group up to 36 hours following dosing. Therefore this should be taken in consideration before administration.

Tadalafil 10 and 20 mg is intended for use prior to sexual activity and it is not recommended for continuous daily use.

In patients who anticipate a frequent use of Tadalafil (i.e., at least twice weekly) a once daily regimen with the lowest doses of Tadalafil 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 2.5 mg once a day based on individual tolerability.

Tadalafil side effects

Tadalafil has been used widely around the world. Frequency convention: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very Rare (<1/10,000) and Not known (cannot be estimated from the available data).

Common: Headache, nasal congestion, flushing, dyspepsia, back pain, myalgia, pain in extremity.

Uncommon: Hypersensitivity reactions, dizziness, blurred vision, sensations described as eye pain, tinnitus, tachycardia, palpitations, hypotension, hypertension, dyspnoea, epistaxis, abdominal pain, vomiting, nausea, gastro-oesophageal reflux, rash, haematuria, prolonged erections, chest pain, peripheral oedema, fatigue.

Rare: Angioedema, stroke(including haemorrhagic events), syncope, transient ischaemic attacks, migraine, seizures, transient amnesia, visual field defect, swelling of eyelids, conjunctival hyperaemia, non-arteritic anterior ischaemic optic neuropathy (NAION), retinal vascular occlusion , sudden hearing loss, myocardial infarction, unstable angina pectoris, ventricular arrhythmia , urticaria, Stevens-Johnson syndrome, exfoliative dermatitis, hyperhydrosis (sweating), priapism, penile haemorrhage, haematospermia, facial oedema, sudden cardiac death.

Side effects that you should report to your prescriber or health care professional as soon as possible:

  • Changes in hearing such as loss of hearing or ringing in ears;
  • Changes in vision such as loss of vision, blurred vision, eyes being more sensitive to light, or trouble telling the difference between blue and green objects or objects having a blue color tinge to them;
  • Chest pain or palpitations;
  • Difficulty breathing, shortness of breath;
  • Dizziness;
  • Eyelid swelling
  • Prolonged erection (lasting longer than 4 hours)
  • Skin rash, itching

Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome):

  • Back pain
  • Flushing
  • Headache
  • Indigestion
  • Muscle aches
  • Stuffy or runny nose

The most common adverse reactions when taking Tadalafil for the ED or benign prostatic hyperplasia were reported to be: headache (between 10 and 30 days of use), dyspepsia, back pain and myalgia, in which the incidences increase with increasing dose of Tadalafil. The intensity of reported adverse effects was mild and moderate.

Contraindication for Tadalafil uses:

One of the main contraindication is hypersensitivity to the active substance or to any of the excipients. Tadalafil was shown to augment the hypotensive effects of nitrates. In different studies was shown that Tadalafil potentiate the effect of nitrates and may result in a dangerous low blood pressure. Therefore, administration of Tadalafil to patients who are using any form of organic nitrate is contraindicated. Examples of medication that contain nitrates and should be avoided when using Tadalafil: Nitroglycerin, Isosorbide mononitrate, Isosorbide dinitrate.

Tadalafil must not be used in men with cardiac disease o where advised to avoid any sexual activity for any reason.

In trials patients with heart conditions lower described did not participate as the use of Tadalafil is not recommended for patients with such heart conditions like:

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 (<90/50 mm Hg), or uncontrolled hypertension,
– Patients with a stroke within the last 6 months.
– Patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION);

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. Avoid drinking large amounts of grapefruit juice when using Tadalafil. Grapefruit and grapefruit juice contain a substance that may potentially interfere with Tadalafil and lead to overdose. If you have taken grapefruit juice, is advised to avoid using Tadalafil at least 3 days.

Special warnings: 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 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. 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 and as such potentiates the hypotensive effect of nitrates.

Tadalafil 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 toTadalafil before driving or using machines. Tadalafil is not intended to be used in newborns, kids and women.

Tadalafil brand name

Tadalafil can be found under the brand name Cialis and Adcirca.

Cialis is available in 4 different doses: 2.5 mg, 5mg, 10mg and 20 mg. The recommended dose for use is 10mg, but it can be lowered to 5mg or 2.5mg or increased up to 20mg if your doctor tells you so. Cialis can be found in following packages sizes: 2.5mg tabs 2 blisters x 15 tabs each tablet marked with “C 2 ½”, 5mg tab Bottles of 30 tabs or 2 blisters x 15 tabs each marked with “C 5”, 10mg tab Bottles of 30tab marked with “C10” and 20mg tab in Bottles of 30tabs each marked with “C20”.

Adcirca is more used to treat Pulmonary Arterial Hypertension. It is available with a prescription in 20mg dose. The recommended dose for Pulmonary Arterial Hypertension is 2 tab x 20mg once a day with or without food. It is recommended not to divide the dose over the course of the day. Do not take Adcirca and Cialis (or other medication for Erectile Dysfunction such as sildenafil or vardenafil) unless your doctor tells you to. Tell your doctor about all current medication that you are taking, including herbal supplements or pain killers, drug interaction can lead to unpleasant and unwanted side effects or permanent damage of the tissue (see Side effects and Overdose).

You should stop using Adcirca and get immediate emergency help if you experience sudden vision loss. Sudden vision loss is an affection caused by decreased blood flow to the optic nerve.

Tadalafil in pregnancy

Tadalafil is not recommended to be used by newborns, children or women. Tadalafil was shown to cross the placenta in studies which included rats. Tadalafil is not expected to be teratogenic, embriotoxic or fetotoxic to an unborn baby but there are no controlled studies that can show whether it is or not harmful to use Tadalafil in pregnant women. Patient should consult a health care provider as a doctor or a pharmacist to weigh all the risks and benefits before starting the medication in pregnancy. Patient must tell doctor that is expecting a baby or planning a pregnancy. No evidence of harmful potential was seen during controlled studies in pregnant rats where they were exposed with 7 times higher the maximum dosage recommended for humans, 40 mg/day. Signs of toxicity have been shown at 8 time concentration and higher. There are no controlled studies with humans. The administration of Tadalafil is not recommended in women, is suggested to be avoided and must be prescribed only if there is no other medication compatible with the patient.

Tadalafil in breastfeeding

Tadalafil is not recommended to be used by breastfeeding women. It is suggested to avoid administering Tadalafil in breastfeeding women. There are no data with humans in excretion of Tadalafil in human milk. It is known that the medication was found to be excreted in animal milk; with a concentration 2.4- fold higher than maximal maternal plasma concentration. A potential risk for the breastfed child can’t be neglected. Caution is recommended. Try avoiding administering Tadalafil with breastfeeding women and should be prescribed only after studying all the risks and benefits; and should be prescribed if there is no other medication that can replace Tadalafil in this case. The effect on nursing baby is unknown.

Does Tadalafil build up in the system?

Tadalafil stays in the body for up to 36 hours and if administer every day big doses it is possible in one moment to have a higher concentration of the medication in the body, higher than recommended by your health provider. Theoretically id you take a high dose every day it is possible at some point to have 50mg-70mg in your body, which is too much and can increase the side effects. This is why if there is a necessity to administer Tadalafil on a daily basis, it is prescribed in dose of 5 mg. this is all theoretical, even if you at some moment will have a higher concentration recommended, there is no overdose with Tadalafil. Make sure to talk to your health provider and discuss which dose is best recommended for you and your condition. Do not use somebody else’s medication and do not share medication that was prescribed for you. Different person may need different dose even if for same health condition, let the health provider decide what is best for you.

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