Cialis

Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and CIALIS 10 mg reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil.

CIALIS 20 mg did not potentiate the increase in bleeding time caused by ASA.

CIALIS did not affect alcohol concentrations, and alcohol did not affect tadalafil concentrations. At high doses of alcohol (0.7 g/kg, mean maximum blood concentration 0.08%), the addition of CIALIS 10 or 20 mg did not induce statistically significant mean blood pressure decreases. In some subjects, postural dizziness and orthostatic hypotension were observed. When CIALIS was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed and dizziness occurred with similar frequency to alcohol alone.

Alcohol consumption may decrease the ability to attain an erection and may also temporarily decrease blood pressure. PDE5 inhibitors, including tadalafil, are vasodilators and may augment the blood-pressure-lowering effect of alcohol.

Consistent with the vasodilatory effects of alpha-blockers and PDE5 inhibitors, the concomitant use of CIALIS with non-selective alpha-blockers may lead to symptomatic hypotension in some patients. Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor (see Warnings and Precautions, Action and Clinical Pharmacology).

No significant decreases in blood pressure were observed when CIALIS 10 or 20 mg doses were administered to subjects taking the selective alpha[1]-adrenergic blocker, alfuzosin, or the selective alpha[1A]-adrenergic blocker, tamsulosin. CIALIS may be administered with selective alpha[1 or 1A] blockers such as alfuzosin or tamsulosin.

When CIALIS 20 mg was administered to healthy subjects taking the maximum recommended dose (4 mg or 8 mg daily) of the alpha[1]-adrenergic blocker, doxazosin, there was an augmentation of the blood-pressure-lowering effect of doxazosin. Caution should be exercised when prescribing CIALIS to patients who are taking alpha[1] blockers, such as doxazosin, as simultaneous administration may lead to symptomatic hypotension in some patients.

Prior to prescribing CIALIS, physicians should carefully consider whether their patients with certain underlying conditions could be adversely affected by vasodilatory effects, especially in combination with sexual activity. Patients with increased susceptibility to vasodilators include those with left ventricular outflow obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy), or those with the rare syndrome of multiple system atrophy, manifesting as severely impaired autonomic control of blood pressure.

An increase in gastric pH resulting from administration of H₂ antagonists, e.g., nizatidine, had no significant effect on the pharmacokinetics of CIALIS 10 mg dose.

In clinical pharmacology studies, the potential for CIALIS 10 or 20 mg to augment the hypotensive effects of antihypertensive agents was examined. Major classes of antihypertensive agents 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). CIALIS had no clinically significant interaction with any of these classes. Analysis of Phase 3 clinical trial data also showed no difference in adverse events in patients taking CIALIS with or without antihypertensive medications.

The recommended dose of CIALIS is 20 mg taken prior to anticipated sexual activity, without regard to food. The dose may be adjusted based on individual tolerability and effectiveness. The maximum recommended dosing frequency is once per day. CIALIS doses of 10 mg and 20 mg are intended for use prior to anticipated sexual activity and are not recommended for continuous daily use.

CIALIS has been shown to be effective within 30 minutes of taking the tablet, and up to 36 hours later. Patients may initiate sexual activity at varying time points relative to dosing, in order to determine their own optimal window of responsiveness.

For On-Demand dosing, CIALIS may be administered with selective alpha-[1 or 1A] blockers such as alfuzosin or tamsulosin, and no dosage adjustment of CIALIS is required. However, when prescribing CIALIS to patients who are taking non-selective alpha-blockers such as doxazosin, the recommended starting dose is 10 mg.

Daily use of CIALIS 10 or 20 mg should be avoided in patients with renal or hepatic impairment and those taking protease inhibitors (e.g., ritonavir) or other potent CYP3A4 inhibitors (e.g., ketoconazole). A starting dose of 10 mg prior to anticipated sexual activity should be considered for these patients, but no more frequently than on alternate days, and not exceeding 3 times a week. If the 10 mg dose is tolerated but insufficiently effective, the dose may be increased to 20 mg. If the 10 mg dose is not tolerated, CIALIS On-Demand dosing should be discontinued (see Action and Clinical Pharmacology, Pharmacokinetics in Special Populations and Conditions and Warnings and Precautions, Drug Interactions).

The recommended dose of CIALIS is 5 mg per day, taken at approximately the same time each day, and without regard to food.

The dosage may be decreased to 2.5 mg once a day, based on individual tolerability.

No dose adjustment is required when CIALIS Once-a-Day is used in combination with alpha-blockers.

No dose adjustment is required in patients with mild to moderate renal or hepatic impairment, and those taking protease inhibitors (e.g., ritonavir) or other potent CYP3A4 inhibitors (e.g., ketoconazole). CIALIS for Once-a-Day use is not recommended for patients with severe renal impairment.

The management of erectile dysfunction should be individualized. Dosage and regimen should be discussed between the physician and the patient based on effectiveness and tolerability.

abdominal pain and gastroesophageal reflux.

In post-marketing surveillance, adverse events that have been reported very rarely in temporal association in patients taking tadalafil include:

migraine.

Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular arrhythmia, stroke, transient ischemic 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.

Hypotension (more commonly reported when tadalafil is given to patients who are already taking antihypertensive agents), hypertension, and syncope.

priapism, prolonged erection, spontaneous penile erection.

Additional reported adverse events where a causal relationship is uncertain (but plausible) and which occurred in <2% of patients receiving CIALIS included dizziness (1.7%), swelling of eyelids (0.3%), sensations described as eye pain (0.3%), and conjunctival hyperemia (0.3%). Across all clinical studies, reports of changes in colour vision were rare (<0.1%).

epistaxis (nose bleed).

blurred vision, nonarteritic anterior ischemic optic neuropathy, retinal vein occlusion, visual field defect.

hypersensitivity reactions including rash, urticaria, facial edema, Stevens-Johnson syndrome, and exfoliative dermatitis.

hyperhidrosis (sweating).

CIALIS has not been evaluated in individuals less than 18 years old.

No dosage adjustment is required in male elderly patients (see Warnings and Precautions, Geriatrics).

Place the patient in the supine position and assure local anesthesia of the penis. The penile shaft should be punctured at either the 2 o'clock or the 10 o'clock position, and 20-30 mL of blood aspirated from the corpus cavernosum. If detumescence has occurred, the penis should be dressed with an elasticized bandage to ensure continued emptying of the corpora and to compress the puncture site(s). If procedure 2 is unsuccessful, proceed to procedure 3.

All patients should be counselled to contact a physician if they experience any erection persisting for more than 4 hours. Priapism should be treated according to established medical practice. One algorithm aimed primarily at treating priapism secondary to pharmacological agents is presented below:

Although frequently unsuccessful, the use of prolonged external perineal compression, including ice, may be applied as a temporizing measure. If procedure 1 is unsuccessful, proceed to procedure 2.

Single doses of up to 500 mg tadalafil have been given to healthy subjects, and multiple doses of 100 mg/day for 21 days have been given to patients. Adverse events (e.g., headache, dyspepsia) were similar to those seen at lower doses.

In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance, as tadalafil is highly bound to plasma proteins.

If aspiration alone fails to achieve detumescence, the corpus cavernosum can be injected with a solution of phenylephrine (10 mg in 19 mL of 0.9% saline=500 µg/mL, and inject 0.1-0.2 mL every 2-5 minutes, for up to 10 doses). Clinicians should refer to the prescribing information for phenylephrine prior to its use.

If the above algorithm fails to detumesce the patient, a urologist should be consulted immediately. Penile tissue damage and/or permanent loss of potency may result if priapism is not treated immediately.

Each yellow-orange, almond-shaped, film-coated tablet, debossed on one side with “C2½”, contains: tadalafil 2.5 mg. Nonmedicinal ingredients: croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide and triacetin. Blister packages of 28.

Each yellow, almond-shaped, film-coated tablet, debossed on one side with “C20”, contains: tadalafil 20 mg. Nonmedicinal ingredients: croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide and triacetin. Blister packages of 4.

Each yellow, almond-shaped, film-coated tablet, debossed on one side with “C10”, contains: tadalafil 10 mg. Nonmedicinal ingredients: croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide and triacetin. Blister packages of 4.

Each yellow, almond-shaped, film-coated tablet, debossed on one side with “C5”, contains: tadalafil 5 mg. Nonmedicinal ingredients: croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide and triacetin. Blister packages of 28.

In a clinical pharmacology study, administration of CIALIS 10 mg to patients with mild and moderate hepatic impairment (Child-Pugh Class A and B) did not result in increased exposure (AUC) to tadalafil, in comparison to healthy subjects. Daily use of CIALIS 10 or 20 mg should be avoided in patients with hepatic impairment. A starting dose of 10 mg prior to anticipated sexual activity should be considered for these patients, but no more frequently than on alternate days, and not exceeding 3 times a week. If the 10 mg dose is tolerated but insufficiently effective, the dose may be increased to 20 mg. If the 10 mg dose is not tolerated, CIALIS On-Demand dosing should be discontinued (see Dosage and Administration).

CIALIS 5 mg for Once-a-Day use may be considered for patients with hepatic impairment. The dosage may be decreased to 2.5 mg Once-a-Day, based on individual tolerability.

Of the total number of patients in the primary efficacy and safety studies of CIALIS, 27% were ages 65 and over. No differences in safety or effectiveness were observed between these patients and younger patients. No dose adjustment is required in elderly patients.

The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following an appropriate medical assessment.

CIALIS should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

Agents for the treatment of erectile dysfunction should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease).

Post-marketing reports of sudden loss of vision have occurred rarely, in temporal association with the use of PDE5 inhibitors. It is not clear whether these are related directly to the use of PDE5 inhibitors or to other factors. There may be an increased risk to patients who have already experienced Non-Arteritic Ischemic Optic Neuropathy (NAION).

In humans, CIALIS has no effect on bleeding time when taken alone or with acetylsalicylic acid (ASA).

There is no safety information on the administration of CIALIS to patients with bleeding disorders or active peptic ulceration. Therefore, CIALIS should be administered with caution to these patients.

Caution is advised when PDE5 inhibitors are coadministered with alpha blockers. PDE5 inhibitors, including CIALIS, and alpha adrenergic blocking agents are both vasodilators with blood pressure lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly (see Drug Interactions, Action and Clinical Pharmacology), which may lead to symptomatic hypotension (e.g., fainting). Consideration should be given to the following:

Patients should be stable on alpha blocker therapy prior to initiating a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.

In those patients already taking an optimized dose of PDE5 inhibitor, alpha blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor.

Safety of combined use of PDE5 inhibitors and alpha blockers may be affected by other variables, including intravascular volume depletion and other antihypertensive drugs.

In a clinical pharmacology study, administration of CIALIS 10 mg to patients with moderate renal failure (creatinine clearance=31 to 50 mL/min) was less well tolerated, with more back pain experienced, than in patients with mild renal failure (creatinine clearance=51 to 80 mL/min) and healthy subjects. However, when CIALIS 20 mg was administered to patients undergoing hemodialysis there were no complaints of back pain. Hemodialysis contributed negligibly to tadalafil elimination. Daily use of CIALIS 10 or 20 mg should be avoided in patients with renal impairment. A starting dose of 10 mg prior to anticipated sexual activity should be considered for these patients, but no more frequently than on alternate days, and not exceeding 3 times a week. If the 10 mg dose is tolerated but insufficiently effective, the dose may be increased to 20 mg. If the 10 mg dose is not tolerated, CIALIS On-Demand dosing should be discontinued (see Dosage and Administration).

CIALIS 5 mg for Once-a-Day use may be considered for patients with mild to moderate renal impairment. The dosage may be decreased to 2.5 mg Once-a-Day, based on individual tolerability.

CIALIS is not indicated for use in newborns, children or women.

There are no studies of tadalafil in pregnant women.

See Pregnant Women.

Physicians should discuss with patients the contraindication of CIALIS with regular and/or intermittent use of organic nitrates.

Physicians should also discuss with patients the potential for CIALIS to augment the blood pressure lowering effect of alpha blockers and antihypertensive medications (see Drug Interactions, Action and Clinical Pharmacology).

Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease. Patients who experience symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and should report the episode to their physician.

Daily use of CIALIS 10 or 20 mg should be avoided in patients with renal or hepatic impairment and those taking protease inhibitors (e.g., ritonavir) or other potent CYP3A4 inhibitors (e.g., ketoconazole). A starting dose of 10 mg prior to anticipated sexual activity should be considered for these patients, but no more frequently than on alternate days, and not exceeding 3 times a week. If the 10 mg dose is tolerated but insufficiently effective, the dose may be increased to 20 mg. If the 10 mg dose is not tolerated, CIALIS On-Demand dosing should be discontinued (see Dosage and Administration).

CIALIS 5 mg for Once-a-Day use may be considered for these patients. The dosage may be decreased to 2.5 mg Once-a-Day, based on individual tolerability.

Priapism was not reported in clinical trials with CIALIS. However, priapism has been reported rarely in post-marketing surveillance with PDE5 inhibitors, including tadalafil. The incidence of priapism may increase when PDE5 inhibitors are used in combination with intrapenile injections containing vasoactive agents (e.g., Caverject). 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.

Tadalafil should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease).

Physicians should discuss with patients the increased risk of Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION) in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE5 inhibitors. Patients should stop taking CIALIS and consult their physician if they experience changes in, or loss of vision in one or both eyes.

Long-term human studies with subjects 45 years or older have shown that CIALIS therapy may decrease sperm concentration in some patients, but the clinical relevance of this to human fertility is unknown.

CIALIS works only in the presence of sexual stimulation.

The use of CIALIS offers no protection against sexually transmitted diseases. Counselling of patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV), should be considered.

See Pregnant Women.

The mean volume of distribution is approximately 64 L at steady-state, 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 rapidly absorbed after oral administration and the mean maximum observed plasma concentration (C_max of 189 µg/L at 10 mg and 378 µg/L at 20 mg) is achieved at a median time of 2 hours after dosing. The absolute bioavailability of tadalafil 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 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 feces (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.

Tadalafil is predominantly metabolized 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.

In a study to assess the effects of a single dose of tadalafil 40 mg 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 (see Action and Clinical Pharmacology, Mechanism of Action). In addition, no effects were observed on visual acuity, electroretinograms, intraocular pressure, or pupillometry. Across all clinical studies with CIALIS 10 or 20 mg, reports of changes in colour vision were rare (<0.1% of patients).

The efficacy and safety of tadalafil at doses of 2 to 100 mg have been evaluated in clinical trials up to 24 weeks duration, involving over 4000 patients. CIALIS 10 mg or 20 mg On Demand or CIALIS 2.5 mg or 5 mg for Once-a-Day use, is effective in improving erectile function in men with ED. Erectile function effects of CIALIS were dose-related. In clinical studies assessing patients’ ability to engage in successful and satisfying sexual intercourse, CIALIS demonstrated highly statistically significant improvement compared with placebo. Additionally, partners of patients on CIALIS had statistically significant greater satisfaction with sexual intercourse compared with partners of patients on placebo.

Overall, CIALIS consistently showed efficacy in a broad and representative population that included patients with ED of various severities (Mild, Moderate, Severe), etiologies (including patients with diabetes), ages (21 to 86 years), and ethnicities. Patients on CIALIS therapy demonstrated consistent and statistically significant improvement in erectile function, compared to patients on placebo. The period of responsiveness to CIALIS was evaluated in an “at-home” setting and by office-based RIGISCAN. These studies demonstrated that CIALIS 20 mg significantly improved patients' ability to have successful sexual intercourse as early as 16 minutes after dose administration and up to 36 hours after dose administration. The treatment effect did not diminish over time.

Tadalafil has not been evaluated in individuals less than 18 years old.

Three studies were conducted in men, ages 45-70 years, to assess the potential effect on spermatogenesis of CIALIS 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered once daily. In all 3 studies, there were no adverse effects on sperm morphology or sperm motility. There were also no significant changes in mean concentrations of the reproductive hormones, testosterone, luteinizing hormone or follicle-stimulating hormone with either 10 or 20 mg of CIALIS compared to placebo. No decrease in sperm concentration was observed in the study of 20 mg CIALIS taken for 6 months. In the study of 10 mg CIALIS for 6 months and the study of 20 mg CIALIS for 9 months, results showed a statistically significant decrease in mean sperm concentration relative to placebo. The clinical relevance of this to human fertility is unknown. In the 9-month study (n=125 [CIALIS 20 mg], n=128 [placebo]), decreases in sperm concentration were in a few patients (but not all) associated with higher ejaculatory frequency, which may have resulted from CIALIS-related improvement in sexual function.

The amount of tadalafil found in the ejaculate of most subjects on repeated CIALIS dosing was negligible; however, a few subjects showed unexplained higher levels of tadalafil in their ejaculate.

CIALIS 10 or 20 mg doses administered to healthy 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.

When CIALIS and certain oral antihypertensive medications (amlodipine, enalapril, metoprolol, bendrofluazide, angiotensin II receptor blockers) were assessed in drug interaction studies, CIALIS 10 or 20 mg doses did not result in clinically significant augmentation of the antihypertensive effects of those medications (see Drug Interactions). Analysis of Phase 3 clinical trial data also showed no difference in adverse events in patients taking CIALIS with or without antihypertensive medications.

Larger effects were recorded among subjects receiving concomitant nitrates (see Contraindications).

The potential hemodynamic interactions of CIALIS with a non-selective alpha blocker (doxazosin 4, 8 mg), a selective [1A] alpha blocker (tamsulosin 0.4 mg) and a selective [1] alpha blocker (alfuzosin 10 mg) were investigated in randomized, double-blind, crossover design studies. Blood pressure (BP) and heart rate were recorded before dosing and for 24 hours after dosing.

CIALIS 20 mg augmented the hypotensive effect of 8 mg doxazosin by producing a mean maximal decrease in standing systolic BP (SBP) that was significantly greater than placebo (a mean difference of 9.8 mm Hg). Analysis of BP outliers showed that the number of subjects with a standing SBP of less than 85 mm Hg was greater after doxazosin plus tadalafil (28%) versus doxazosin plus placebo (6%). A further clinical pharmacology study was performed in order to investigate the lower dose of 4 mg doxazosin. The changes produced in that study were comparable to those observed in the earlier study.

In subjects on tamsulosin, CIALIS 10 and 20 mg produced mean maximal decreases in standing SBP that were similar to placebo (mean difference of 1.7 and 2.3 mm Hg, respectively). No subject taking tamsulosin had a decrease in standing SBP less than 85 mm Hg. In subjects receiving alfuzosin, CIALIS 20 mg also produced a maximal decrease in SBP that was not significantly different from that after placebo (mean difference of 4.35 mm Hg). One subject taking alfuzosin had an asymptomatic SBP of less than 85 mm Hg.

No vasodilatory adverse events were observed when tadalafil was administered with tamsulosin or alfuzosin. Two such events (dizziness, vertigo) were reported following administration of CIALIS with doxazosin. No syncope was reported in these studies.

The mean AUC value (4881 µg·h/L for 10 mg dose) in male subjects aged 65 to 78 years was approximately 25% higher than AUC (3896 µg·h/L) for subjects aged 19 to 45 years, while age had negligible effect on C_max values. This effect of age is not clinically significant and does not require a dose adjustment (see Warnings and Precautions, Geriatrics).

In a clinical pharmacology study using CIALIS 10 mg, tadalafil exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh Class A and B) was comparable to exposure in healthy subjects. Daily use of CIALIS 10 or 20 mg should be avoided in patients with hepatic impairment. A starting dose of 10 mg prior to anticipated sexual activity should be considered for these patients, but no more frequently than on alternate days, and not exceeding 3 times a week. If the 10 mg dose is tolerated but insufficiently effective, the dose may be increased to 20 mg. If the 10 mg dose is not tolerated, CIALIS On-Demand dosing should be discontinued (see Warnings and Precautions, Use in Patients with Hepatic Impairment and Dosage and Administration).

CIALIS 5 mg for Once-a-Day use may be considered for patients with hepatic impairment. The dosage may be decreased to 2.5 mg once a day, based on individual tolerability.

When sexual stimulation causes the local release of nitric oxide in the corpus cavernosum, nitric oxide then activates the enzyme guanylyl cyclase, which results in increased levels of cGMP. The increased levels of cGMP in the corpus cavernosum produce smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. PDE5 degrades cGMP in the corpus cavernosum, and the inhibition of PDE5 by CIALIS maintains increased levels of cGMP in the corpus cavernosum. CIALIS has no effect on penile blood flow in the absence of sexual stimulation.

Studies in vitro have shown that tadalafil is a potent 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 selective on PDE5 than on other phosphodiesterases. Tadalafil is >10 000-fold more selective for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the heart, brain, blood vessels, liver, and other organs. Tadalafil is >10 000-fold more selective 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 >9000-fold more potent for PDE5 than for PDE8 through 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 found in human prostate, testes, skeletal muscle and in other tissues. In vitro, tadalafil inhibits human recombinant 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.

In patients with stable coronary artery disease (CAD) and demonstrable ischemia with exercise, CIALIS 10 mg was non-inferior to placebo with respect to effect on time to ischemia. In a separate double-blind, placebo-controlled study to evaluate the effects of CIALIS on myocardial perfusion in patients with CAD, CIALIS 20 mg had no significant effect on myocardial blood flow, both at rest and during pharmacological stress with dobutamine.

Tadalafil at doses up to 500 mg did not significantly change cardiac output and did not significantly impact patients' hemodynamic response to exercise. The effect of CIALIS has not been evaluated in cardiac catheterization studies.

No tadalafil-related changes in electrocardiographic measures, including QTc interval, were observed following administration of CIALIS single doses up to 500 mg and multiple doses of up to 100 mg once-daily for 21 days, to healthy subjects or patients. ECGs were obtained pre- and post-dose, spanning the period from the expected T_max of tadalafil (2 hours) to the expected T_max of the primary metabolite (methylcatechol glucuronide, 24 hours).

In clinical pharmacology studies, CIALIS 10 and 20 mg had no clinically significant effect on acetylsalicylic acid-induced prolongation of bleeding time or warfarin-induced changes in prothrombin time (see Drug Interactions). Also, in clinical studies there was no evidence of bleeding-related adverse events associated with CIALIS treatment.

Tadalafil exposure (AUC 3454 µg·h/L for a 10 mg dose) in patients with diabetes was 19% lower, and the mean maximum plasma concentration (C_max of 184 µg/L) was 5% lower than that observed in healthy subjects. This difference in exposure does not require a dose adjustment.

In clinical pharmacology studies using single-dose CIALIS 5 to 20 mg, 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 insufficiency, and in subjects with end-stage renal disease on dialysis. In dialysis patients, C_max was 41% higher than that observed in healthy subjects. Hemodialysis contributed negligibly to tadalafil elimination. Daily use of CIALIS 10 or 20 mg should be avoided in patients with renal impairment. A starting dose of 10 mg prior to anticipated sexual activity should be considered for these patients, but no more frequently than on alternate days, and not exceeding 3 times a week. If the 10 mg dose is tolerated but insufficiently effective, the dose may be increased to 20 mg. If the 10 mg dose is not tolerated, CIALIS On Demand dosing should be discontinued (see Warnings and Precautions, Use in Patients with Renal Impairment and Dosage and Administration).