Cialis - Treatment for Impotence

DESCRIPTION

CIALIS^® (tadalafil), an oral treatment for erectile dysfunction, is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C₂₂H₁₉N₃O₄ representing a molecular weight of 389.41. The structural formula is:

The chemical designation is pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-
benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-. It is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol.
CIALIS is available as film-coated, almond-shaped tablets for oral administration. Each tablet contains 5, 10, or 20 mg of tadalafil and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.

CLINICAL PHARMACOLOGY

Mechanism of Action
Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal 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 causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP.
Tadalafil inhibits PDE5. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect in the absence of sexual
stimulation.
Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is
found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, cerebellum, and pancreas.
In vitro studies have shown that the effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. These 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 heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, tadalafil is 700-fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. Tadalafil is >9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10 and 14-fold more potent for PDE5 than for PDE11A1, an enzyme found in human skeletal muscle. Tadalafil inhibits human recombinant PDE11A1 activity at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.

Pharmacokinetics
Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. Steady-state plasma concentrations are attained within 5 days of once-daily dosing, and exposure is approximately 1.6-fold greater than after a single dose.
Tadalafil is eliminated predominantly by hepatic metabolism, mainly by cytochrome P450 3A4 (CYP3A4). The concomitant use of potent CYP3A4 inhibitors such as ritonavir or ketoconazole resulted in significant increases in tadalafil AUC values (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Mean tadalafil
concentrations measured after the administration of a single oral dose of 20 mg to healthy
male subjects are depicted in Figure 1.

Absorption - After single oral-dose administration, the maximum observed plasma
concentration (C_max) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours). 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.

Distribution - The mean apparent volume of distribution following oral administration is
approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic
concentrations, 94% of tadalafil in plasma is bound to proteins.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Metabolism - Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite.
The catechol metabolite undergoes extensive methylation and glucuronidation to form the
methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.
Elimination - The mean oral clearance for tadalafil is 2.5 L/hr and the mean terminal half-life is 17.5 hours in healthy subjects. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).

Pharmacokinetics in Special Populations
Geriatric - Healthy male elderly subjects (65 years or over) had a lower oral clearance of
tadalafil, resulting in 25% higher exposure (AUC) with no effect on Cmax relative to that
observed in healthy subjects 19 to 45 years of age. No dose adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered (see Geriatric Use under PRECAUTIONS).
Pediatric - Tadalafil has not been evaluated in individuals less than 18 years old.
Hepatic Impairment - In clinical pharmacology studies, tadalafil exposure (AUC) in subjects with mild or moderate hepatic impairment (Child-Pugh Class A or B) was comparable to exposure in healthy subjects when a dose of 10 mg was administered. There are no available data for doses higher than 10 mg of tadalafil in patients with hepatic impairment. Insufficient data are available for subjects with severe hepatic impairment (Child-Pugh Class C). Therefore, for patients with mild or moderate hepatic impairment, the maximum dose should not exceed 10 mg, and use in patients with severe hepatic impairment is not recommended (see DOSAGE AND ADMINISTRATION).
Renal Insufficiency - In clinical pharmacology studies using single-dose tadalafil (5 to 10 mg), tadalafil exposure (AUC) doubled in subjects with mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min) renal insufficiency. In subjects with end-stage renal disease on hemodialysis, there was a two-fold increase in Cmax and 2.7- to 4.1-fold increase in AUC following single-dose administration of 10 or 20 mg tadalafil. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2- to 4-fold higher in subjects with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24 and 30 hours post-dose) contributed negligibly to tadalafil or metabolite elimination. In a clinical pharmacology study (N=28) at a dose of 10 mg, back pain was reported as a limiting adverse event in male patients with moderate renal impairment. At a dose of 5 mg, the incidence and severity of back pain was not significantly different than in the general population. In patients on hemodialysis taking 10- or 20-mg tadalafil, there were no reported cases of back pain. The dose of tadalafil should be limited to 5 mg not more than once daily in patients with severe renal insufficiency or end-stage renal disease. A starting dose of 5 mg not more than once daily is recommended for patients with moderate renal insufficiency; the maximum recommended dose is 10 mg not more than once in every 48 hours. No dose adjustment is required in patients with mild renal insufficiency (see DOSAGE AND ADMINISTRATION).
Patients with Diabetes Mellitus - In male patients with diabetes mellitus after a 10 mg
tadalafil dose, exposure (AUC) was reduced approximately 19% and Cmax was 5% lower than that observed in healthy subjects. No dose adjustment is warranted.

Pharmacodynamics
Effects on Blood Pressure - Tadalafil 20 mg administered to healthy male subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (difference in the mean maximal decrease of 1.6/0.8 mm Hg, respectively) and in standing systolic and diastolic blood pressure (difference in the mean maximal decrease of 0.2/4.6 mm Hg, respectively). In addition, there was no significant effect on heart rate. Effects on Blood Pressure when CIALIS is Administered with Nitrates - In clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Therefore, the use of CIALIS in patients taking any form of nitrates is contraindicated (see CONTRAINDICATIONS).

A study was conducted to assess the degree of interaction between nitroglycerin and tadalafil, should nitroglycerin be required in an emergency situation after tadalafil was taken. This was a double-blind, placebo-controlled, crossover study in 150 male subjects at least 40 years of age (including subjects with diabetes mellitus and/or controlled hypertension) and receiving daily doses of tadalafil 20 mg or matching placebo for 7 days. Subjects were administered a single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre-specified timepoints, following their last dose of tadalafil (2, 4, 8, 24, 48, 72, and 96 hours after tadalafil). The objective of the study was to determine when, after tadalafil dosing, no apparent blood pressure interaction was observed.
In this study, a significant interaction between tadalafil and NTG was observed at each timepoint up to and including 24 hours. At 48 hours, by most hemodynamic measures, the interaction between tadalafil and NTG was not observed, although a few more tadalafil subjects compared to placebo experienced greater blood-pressure lowering at this timepoint. After 48 hours, the interaction was not detectable.

Patient Information CIALIS

Read the Patient Information about CIALIS before you start taking it and again each time you get a refill. There may be new information. You may also find it helpful to share this information with your partner. This leaflet does not take the place of talking with your doctor. You and your doctor should talk about CIALIS when you start taking it and at regular checkups. If you do not understand the information, or have questions, talk with your doctor or pharmacist.

What important information should you know about CIALIS?

CIALIS can cause your blood pressure to drop suddenly to an unsafe level if it is taken with certain other medicines. You could get dizzy, faint, or have a heart attack or stroke.

Do not take CIALIS if you:

• take any medicines called "nitrates."
• use recreational drugs called "poppers" like amyl nitrate and butyl nitrate.
• take medicines called alpha blockers, other than Flomax® (tamsulosin HCl) 0.4 mg daily.

(See "Who should not take CIALIS?")

Tell all your healthcare providers that you take CIALIS. If you need emergency medical care for a heart problem, it will be important for your healthcare provider to know when you last took CIALIS.

After taking a single tablet, some of the active ingredient of CIALIS remains in your body for more than 2 days. The active ingredient can remain longer if you have problems with your kidneys or liver, or you are taking certain other medications (see "Can other medications affectCIALIS?").

What is CIALIS?

CIALIS is a prescription medicine taken by mouth for the treatment of erectile dysfunction (ED) in men.

ED is a condition where the penis does not harden and expand when a man is sexually excited, or when he cannot keep an erection. A man who has trouble getting or keeping an erection should see his doctor for help if the condition bothers him. CIALIS may help a man with ED get and keep an erection when he is sexually excited.

CIALIS does not:

• cure ED
• increase a man's sexual desire
• protect a man or his partner from sexually transmitted diseases, including HIV. Speak to your doctor about ways to guard against sexually transmitted diseases.
• serve as a male form of birth control

CIALIS is only for men with ED. CIALIS is not for women or children. CIALIS must be used only under a doctor's care.

How does CIALIS work?

When a man is sexually stimulated, his body's normal physical response is to increase blood flow to his penis. This results in an erection. CIALIS helps increase blood flow to the penis and may help men with ED get and keep an erection satisfactory for sexual activity. Once a man has completed sexual activity, blood flow to his penis decreases, and his erection goes away.

Who can take CIALIS?

Talk to your doctor to decide if CIALIS is right for you.

CIALIS has been shown to be effective in men over the age of 18 years who have erectile dysfunction, including men with diabetes or who have undergone prostatectomy.

Who should not take CIALIS?

Do not take CIALIS if you:

• take any medicines called "nitrates" (See "What important information should you know about CIALIS?"). Nitrates are commonly used to treat angina. Angina is a symptom of heart disease and can cause pain in your chest, jaw, or down your arm. Medicines called nitrates include nitroglycerin that is found in tablets, sprays, ointments, pastes, or patches. Nitrates can also be found in other medicines such as isosorbide dinitrate or isosorbide mononitrate. Some recreational drugs called "poppers" also contain nitrates, such as amyl nitrate and butyl nitrate. Do not use CIALIS if you are using these drugs. Ask your doctor or pharmacist if you are not sure if any of your medicines are nitrates.
• take medicines called "alpha blockers", other than Flomax® 0.4 mg daily. Alpha blockers are sometimes prescribed for prostate problems or high blood pressure. If CIALIS is taken with alpha blockers other than Flomax® 0.4 mg daily, your blood pressure could suddenly drop to an unsafe level. You could get dizzy and faint.
• you have been told by your healthcare provider to not have sexual activity because of health problems. Sexual activity can put an extra strain on your heart, especially if your heart is already weak from a heart attack or heart disease.
• are allergic to CIALIS or any of its ingredients. The active ingredient in CIALIS is called tadalafil. See the end of this leaflet for a complete list of ingredients.

What should you discuss with your doctor before taking CIALIS?

Before taking CIALIS, tell your doctor about all your medical problems, including if you:

• have heart problems such as angina, heart failure, irregular heartbeats, or have had a heart attack. Ask your doctor if it is safe for you to have sexual activity.
• have low blood pressure or have high blood pressure that is not controlled
• have had a stroke 
• have liver problems
• have kidney problems or require dialysis
• have retinitis pigmentosa, a rare genetic (runs in families) eye disease
• have stomach ulcers
• have a bleeding problem
• have a deformed penis shape or Peyronie's disease
• have had an erection that lasted more than 4 hours
• have blood cell problems such as sickle cell anemia, multiple myeloma, or leukemia

Can other medications affect CIALIS?

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. CIALIS and other medicines may affect each other. Always check with your doctor before starting or stopping any medicines. Especially tell your doctor if you take any of the following:

• medicines called nitrates (See "What important information should you know about CIALIS?")
• medicines called alpha blockers. These include Hytrin® (terazosin HCl), Flomax® (tamsulosin HCl), Cardura® (doxazosin mesylate), Minipress® (prazosin HCl) or Uroxatral® (alfuzosin HCl).
• ritonavir (Norvir®) or indinavir (Crixivan®)
• ketoconazole or itraconazole (such as Nizoral® or Sporanox®)
• erythromycin
• other medicines or treatments for ED

How should you take CIALIS?

Take CIALIS exactly as your doctor prescribes. CIALIS comes in different doses (5 mg, 10 mg, and 20 mg). For most men, the recommended starting dose is 10 mg. CIALIS should be taken no more than once a day. Some men can only take a low dose of CIALIS because of medical conditions or medicines they take. Your doctor will prescribe the dose that is right for you.

• If you have kidney problems, your doctor may start you on a lower dose of CIALIS.
• If you have kidney or liver problems or you are taking certain medications, your doctor may limit your highest dose of CIALIS to 10 mg and may also limit you to one tablet in 48 hours (2 days) or one tablet in 72 hours (3 days).

Take one CIALIS tablet before sexual activity. In some patients, the ability to have sexual activity was improved at 30 minutes after taking CIALIS when compared to a sugar pill. The ability to have sexual activity was improved up to 36 hours after taking CIALIS when compared to a sugar pill. You and your doctor should consider this in deciding when you should take CIALIS prior to sexual activity. Some form of sexual stimulation is needed for an erection to happen with CIALIS. CIALIS may be taken with or without meals.

Do not change your dose of CIALIS without talking to your doctor. Your doctor may lower your dose or raise your dose, depending on how your body reacts to CIALIS.

Do not drink alcohol to excess when taking CIALIS (for example, 5 glasses of wine or 5 shots of whiskey). When taken in excess, alcohol can increase your chances of getting a headache or getting dizzy, increasing your heart rate, or lowering your blood pressure.

If you take too much CIALIS, call your doctor or emergency room right away.

What are the possible side effects of CIALIS?

The most common side effects with CIALIS are headache, indigestion, back pain, muscle aches, flushing, and stuffy or runny nose. These side effects usually go away after a few hours. Patients who get back pain and muscle aches usually get it 12 to 24 hours after taking CIALIS. Back pain and muscle aches usually go away by themselves within 48 hours. Call your doctor if you get a side effect that bothers you or one that will not go away.

CIALIS may uncommonly cause:

• an erection that won't go away (priapism). If you get an erection that lasts more than 4 hours, get medical help right away. Priapism must be treated as soon as possible or lasting damage can happen to your penis including the inability to have erections.
• vision changes, such as seeing a blue tinge to objects or having difficulty telling the difference between the colors blue and green.

These are not all the side effects of CIALIS. For more information, ask your doctor or pharmacist.

How should CIALIS be stored?

• Store CIALIS at room temperature between 59° and 86°F (15° and 30°C).
• Keep CIALIS and all medicines out of the reach of children.

General Information about CIALIS:

Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use CIALIS for a condition for which it was not prescribed. Do not give CIALIS to other people, even if they have the same symptoms that you have. It may harm them.

This leaflet summarizes the most important information about CIALIS. If you would like more information, talk with your healthcare provider. You can ask your doctor or pharmacist for information about CIALIS that is written for health professionals.