CIALIS (tadalafil) is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C 22 H 19 N 3 O 4 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 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. Chemical Structure

CIALIS ® is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of: erectile dysfunction (ED) the signs and symptoms of benign prostatic hyperplasia (BPH) ED and the signs and symptoms of BPH (ED/BPH) If CIALIS is used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks

Erectile Dysfunction CIALIS ® is indicated for the treatment of erectile dysfunction (ED)

Benign Prostatic Hyperplasia CIALIS is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH)

Erectile Dysfunction and Benign Prostatic Hyperplasia CIALIS is indicated for the treatment of ED and the signs and symptoms of BPH (ED/BPH)

Limitation of Use If CIALIS is used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks because the incremental benefit of CIALIS decreases from 4 weeks until 26 weeks, and the incremental benefit of CIALIS beyond 26 weeks is unknown .

Three strengths of almond-shaped tablets are available in different sizes and different shades of yellow: 5 mg tablets debossed with “C 5” 10 mg tablets debossed with “C 10” 20 mg tablets debossed with “C 20” Tablets: 5 mg, 10 mg, 20 mg.

Do not split CIALIS tablets; entire dose should be taken. CIALIS for use as needed: ED: Starting dose: 10 mg as needed prior to sexual activity. Increase to 20 mg or decrease to 5 mg based upon efficacy/tolerability. Improves erectile function compared to placebo up to 36 hours post dose. Not to be taken more than once per day. CIALIS for once daily use: ED: 2.5 mg taken once daily, without regard to timing of sexual activity. May increase to 5 mg based upon efficacy and tolerability. BPH: 5 mg, taken at approximately the same time every day ED and BPH: 5 mg, taken at approximately the same time every day CIALIS may be taken without regard to food

CIALIS for Use as Needed for Erectile Dysfunction The recommended starting dose of CIALIS for use as needed in most patients is 10 mg, taken prior to anticipated sexual activity. The dose may be increased to 20 mg or decreased to 5 mg, based on individual efficacy and tolerability. The maximum recommended dosing frequency is once per day in most patients. CIALIS for use as needed was shown to improve erectile function compared to placebo up to 36 hours following dosing. Therefore, when advising patients on optimal use of CIALIS, this should be taken into consideration

CIALIS for Once Daily Use for Erectile Dysfunction The recommended starting dose of CIALIS for once daily use is 2.5 mg, taken at approximately the same time every day, without regard to timing of sexual activity. The CIALIS dose for once daily use may be increased to 5 mg, based on individual efficacy and tolerability

CIALIS for Once Daily Use for Benign Prostatic Hyperplasia The recommended dose of CIALIS for once daily use is 5 mg, taken at approximately the same time every day. When therapy for BPH is initiated with CIALIS and finasteride, the recommended dose of CIALIS for once daily use is 5 mg, taken at approximately the same time every day for up to 26 weeks

CIALIS for Once Daily Use for Erectile Dysfunction and Benign Prostatic Hyperplasia The recommended dose of CIALIS for once daily use is 5 mg, taken at approximately the same time every day, without regard to timing of sexual activity

Use with Food CIALIS may be taken without regard to food

Use in Specific Populations Renal Impairment CIALIS for Use as Needed Creatinine clearance 30 to 50 mL/min: A starting dose of 5 mg not more than once per day is recommended, and the maximum dose is 10 mg not more than once in every 48 hours. Creatinine clearance less than 30 mL/min or on hemodialysis: The maximum dose is 5 mg not more than once in every 72 hours . CIALIS for Once Daily Use Erectile Dysfunction Creatinine clearance less than 30 mL/min or on hemodialysis: CIALIS for once daily use is not recommended . Benign Prostatic Hyperplasia and Erectile Dysfunction/Benign Prostatic Hyperplasia Creatinine clearance 30 to 50 mL/min: A starting dose of 2.5 mg is recommended. An increase to 5 mg may be considered based on individual response. Creatinine clearance less than 30 mL/min or on hemodialysis: CIALIS for once daily use is not recommended . Hepatic Impairment CIALIS for Use as Needed Mild or moderate (Child Pugh Class A or B): The dose should not exceed 10 mg once per day. The use of CIALIS once per day has not been extensively evaluated in patients with hepatic impairment and therefore, caution is advised. Severe (Child Pugh Class C): The use of CIALIS is not recommended . CIALIS for Once Daily Use Mild or moderate (Child Pugh Class A or B): CIALIS for once daily use has not been extensively evaluated in patients with hepatic impairment. Therefore, caution is advised if CIALIS for once daily use is prescribed to these patients. Severe (Child Pugh Class C): The use of CIALIS is not recommended

Concomitant Medications Nitrates Concomitant use of nitrates in any form is contraindicated . Alpha-Blockers ED — When CIALIS is coadministered with an alpha-blocker in patients being treated for ED, patients should be stable on alpha-blocker therapy prior to initiating treatment, and CIALIS should be initiated at the lowest recommended dose . BPH — CIALIS is not recommended for use in combination with alpha-blockers for the treatment of BPH . CYP3A4 Inhibitors CIALIS for Use as Needed — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose of CIALIS is 10 mg, not to exceed once every 72 hours . CIALIS for Once Daily Use — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose is 2.5 mg .

Evaluation of erectile dysfunction and BPH should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options. Before prescribing CIALIS, it is important to note the following: Patients should not use CIALIS if sex is inadvisable due to cardiovascular status. Use of CIALIS with alpha-blockers, antihypertensives or substantial amounts of alcohol (≥5 units) may lead to hypotension. CIALIS is not recommended in combination with alpha-blockers for the treatment of BPH because efficacy of the combination has not been adequately studied and because of the risk of blood pressure lowering. Caution is advised when CIALIS is used as a treatment for ED in men taking alpha-blockers. ( 2.7 , 5.6 , 7.1 , 12.2 ) Patients should seek emergency treatment if an erection lasts >4 hours. Use CIALIS with caution in patients predisposed to priapism. Patients should stop CIALIS and seek medical care if a sudden loss of vision occurs in one or both eyes, which could be a sign of non-arteritic anterior ischemic optic neuropathy (NAION). CIALIS should be used with caution, and only when the anticipated benefits outweigh the risks, in patients with a history of NAION. Patients with a "crowded" optic disc may also be at an increased risk of NAION. Patients should stop CIALIS and seek prompt medical attention in the event of sudden decrease or loss of hearing. Prior to initiating treatment with CIALIS for BPH, consideration should be given to other urological conditions that may cause similar symptoms

Cardiovascular Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Therefore, treatments for erectile dysfunction, including CIALIS, should not be used in men for whom sexual activity is inadvisable as a result of their underlying cardiovascular status. Patients who experience symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and seek immediate medical attention. Physicians should discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of CIALIS. In such a patient, who has taken CIALIS, where nitrate administration is deemed medically necessary for 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 still only be administered under close medical supervision with appropriate hemodynamic monitoring. Therefore, patients who experience anginal chest pain after taking CIALIS should seek immediate medical attention. . Patients with left ventricular outflow obstruction, (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators, including PDE5 inhibitors. The following groups of patients with cardiovascular disease were not included in clinical safety and efficacy trials for CIALIS, and therefore until further information is available, CIALIS is not recommended for the following groups of patients: myocardial infarction within the last 90 days unstable angina or angina occurring during sexual intercourse New York Heart Association Class 2 or greater heart failure in the last 6 months uncontrolled arrhythmias, hypotension (<90/50 mm Hg), or uncontrolled hypertension stroke within the last 6 months. As with other PDE5 inhibitors, tadalafil has mild systemic vasodilatory properties that may result in transient decreases in blood pressure. In a clinical pharmacology study, tadalafil 20 mg resulted in a mean maximal decrease in supine blood pressure, relative to placebo, of 1.6/0.8 mm Hg in healthy subjects . While this effect should not be of consequence in most patients, prior to prescribing CIALIS, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects. Patients with severely impaired autonomic control of blood pressure may be particularly sensitive to the actions of vasodilators, including PDE5 inhibitors

Potential for Drug Interactions When Taking CIALIS for Once Daily Use Physicians should be aware that CIALIS for once daily use provides continuous plasma tadalafil levels and should consider this when evaluating the potential for interactions with medications (e.g., nitrates, alpha-blockers, anti-hypertensives and potent inhibitors of CYP3A4) and with substantial consumption of alcohol

Prolonged Erection There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. 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), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease)

Effects on the Eye Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including CIALIS, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision, including permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged ≥50. An observational case-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of "crowded" optic disc, may have contributed to the occurrence of NAION in these studies. Neither the rare postmarketing reports, nor the association of PDE5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE5 inhibitor use and NAION . Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including CIALIS, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with "crowded" optic disc are also considered at greater risk for NAION compared to the general population; however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including CIALIS, for this uncommon condition. Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended

Sudden Hearing Loss Physicians should advise patients to stop taking PDE5 inhibitors, including CIALIS, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including CIALIS. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors

Alpha-blockers and Antihypertensives Physicians should discuss with patients the potential for CIALIS to augment the blood-pressure-lowering effect of alpha-blockers and antihypertensive medications . 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 , which may lead to symptomatic hypotension (e.g., fainting). Consideration should be given to the following: ED 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 who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended dose. 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. . BPH The efficacy of the coadministration of an alpha-blocker and CIALIS for the treatment of BPH has not been adequately studied, and due to the potential vasodilatory effects of combined use resulting in blood pressure lowering, the combination of CIALIS and alpha-blockers is not recommended for the treatment of BPH. . Patients on alpha-blocker therapy for BPH should discontinue their alpha-blocker at least one day prior to starting CIALIS for once daily use for the treatment of BPH

Renal Impairment CIALIS for Use as Needed CIALIS should be limited to 5 mg not more than once in every 72 hours in patients with creatinine clearance less than 30 mL/min or end-stage renal disease on hemodialysis. The starting dose of CIALIS in patients with creatinine clearance 30 – 50 mL/min should be 5 mg not more than once per day, and the maximum dose should be limited to 10 mg not more than once in every 48 hours. . CIALIS for Once Daily Use ED Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, CIALIS for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min . BPH and ED/BPH Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, CIALIS for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min. In patients with creatinine clearance 30 – 50 mL/min, start dosing at 2.5 mg once daily, and increase the dose to 5 mg once daily based upon individual response

Hepatic Impairment CIALIS for Use as Needed In patients with mild or moderate hepatic impairment, the dose of CIALIS should not exceed 10 mg. Because of insufficient information in patients with severe hepatic impairment, use of CIALIS in this group is not recommended . CIALIS for Once Daily Use CIALIS for once daily use has not been extensively evaluated in patients with mild or moderate hepatic impairment. Therefore, caution is advised if CIALIS for once daily use is prescribed to these patients. Because of insufficient information in patients with severe hepatic impairment, use of CIALIS in this group is not recommended

Alcohol Patients should be made aware that both alcohol and CIALIS, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., 5 units or greater) in combination with CIALIS can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache

Concomitant Use of Potent Inhibitors of Cytochrome P450 3A4 (CYP3A4) CIALIS is metabolized predominantly by CYP3A4 in the liver. The dose of CIALIS for use as needed should be limited to 10 mg no more than once every 72 hours in patients taking potent inhibitors of CYP3A4 such as ritonavir, ketoconazole, and itraconazole . In patients taking potent inhibitors of CYP3A4 and CIALIS for once daily use, the maximum recommended dose is 2.5 mg

Combination With Other PDE5 Inhibitors or Erectile Dysfunction Therapies The safety and efficacy of combinations of CIALIS and other PDE5 inhibitors or treatments for erectile dysfunction have not been studied. Inform patients not to take CIALIS with other PDE5 inhibitors, including ADCIRCA

Effects on Bleeding Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in platelets. When administered in combination with aspirin, tadalafil 20 mg did not prolong bleeding time, relative to aspirin alone. CIALIS has not been administered to patients with bleeding disorders or significant active peptic ulceration. Although CIALIS has not been shown to increase bleeding times in healthy subjects, use in patients with bleeding disorders or significant active peptic ulceration should be based upon a careful risk-benefit assessment and caution

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

Consideration of Other Urological Conditions Prior to Initiating Treatment for BPH Prior to initiating treatment with CIALIS for BPH, consideration should be given to other urological conditions that may cause similar symptoms. In addition, prostate cancer and BPH may coexist.

CIALIS can potentiate the hypotensive effects of nitrates, alpha-blockers, antihypertensives or alcohol. CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) increase CIALIS exposure ( 2.7 , 5.10 , 7.2 ) requiring dose adjustment: CIALIS for use as needed: no more than 10 mg every 72 hours CIALIS for once daily use: dose not to exceed 2.5 mg CYP3A4 inducers (e.g. rifampin) decrease CIALIS exposure

Potential for Pharmacodynamic Interactions with CIALIS Nitrates — Administration of CIALIS to patients who are using any form of organic nitrate, is contraindicated. In clinical pharmacology studies, CIALIS was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken CIALIS, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of CIALIS before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring . Alpha-Blockers — 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. Clinical pharmacology studies have been conducted with coadministration of tadalafil with doxazosin, tamsulosin or alfuzosin. . Antihypertensives — PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of tadalafil on the potentiation of the blood-pressure-lowering effects of selected antihypertensive medications (amlodipine, angiotensin II receptor blockers, bendrofluazide, enalapril, and metoprolol). Small reductions in blood pressure occurred following coadministration of tadalafil with these agents compared with placebo. . Alcohol — Both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with CIALIS can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations.

Potential for Other Drugs to Affect CIALIS . Antacids — Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil. H 2 Antagonists (e.g. Nizatidine) — An increase in gastric pH resulting from administration of nizatidine had no significant effect on pharmacokinetics. Cytochrome P450 Inhibitors — CIALIS is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase tadalafil exposure. CYP3A4 (e.g., Ketoconazole) — Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4, increased tadalafil 20 mg single-dose exposure (AUC) by 312% and C max by 22%, relative to the values for tadalafil 20 mg alone. Ketoconazole (200 mg daily) increased tadalafil 10-mg single-dose exposure (AUC) by 107% and C max by 15%, relative to the values for tadalafil 10 mg alone . Although specific interactions have not been studied, other CYP3A4 inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure. HIV Protease inhibitor — Ritonavir (500 mg or 600 mg twice daily at steady state), an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil 20-mg single-dose exposure (AUC) by 32% with a 30% reduction in C max , relative to the values for tadalafil 20 mg alone. Ritonavir (200 mg twice daily), increased tadalafil 20-mg single-dose exposure (AUC) by 124% with no change in C max , relative to the values for tadalafil 20 mg alone. Although specific interactions have not been studied, other HIV protease inhibitors would likely increase tadalafil exposure . Cytochrome P450 Inducers — Studies have shown that drugs that induce CYP3A4 can decrease tadalafil exposure. CYP3A4 (e.g., Rifampin) — Rifampin (600 mg daily), a CYP3A4 inducer, reduced tadalafil 10-mg single-dose exposure (AUC) by 88% and C max by 46%, relative to the values for tadalafil 10 mg alone. Although specific interactions have not been studied, other CYP3A4 inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease tadalafil exposure. No dose adjustment is warranted. The reduced exposure of tadalafil with the coadministration of rifampin or other CYP3A4 inducers can be anticipated to decrease the efficacy of CIALIS for once daily use; the magnitude of decreased efficacy is unknown

Potential for CIALIS to Affect Other Drugs Aspirin — Tadalafil did not potentiate the increase in bleeding time caused by aspirin. Cytochrome P450 Substrates — CIALIS is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms. Studies have shown that tadalafil does not inhibit or induce P450 isoforms CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. CYP1A2 (e.g. Theophylline) — Tadalafil had no significant effect on the pharmacokinetics of theophylline. When tadalafil was administered to subjects taking theophylline, a small augmentation (3 beats per minute) of the increase in heart rate associated with theophylline was observed. CYP2C9 (e.g. Warfarin) — Tadalafil had no significant effect on exposure (AUC) to S-warfarin or R-warfarin, nor did tadalafil affect changes in prothrombin time induced by warfarin. CYP3A4 (e.g. Midazolam or Lovastatin) — Tadalafil had no significant effect on exposure (AUC) to midazolam or lovastatin. P-glycoprotein (e.g. Digoxin) — Coadministration of tadalafil (40 mg once per day) for 10 days did not have a significant effect on the steady-state pharmacokinetics of digoxin (0.25 mg/day) in healthy subjects.