Tadalafil: What to Know Before You Take It

5 WARNINGS AND PRECAUTIONS Evaluation of erectile dysfunction and BPH should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options. Before prescribing tadalafil tablets, it is important to note the following: Patients should not use tadalafil tablets if sex is inadvisable due to cardiovascular status ( 5.1 ). Use of tadalafil tablets with alpha-blockers, antihypertensives or substantial amounts of alcohol (≥5 units) may lead to hypotension ( 5.6 , 5.9 ). Tadalafil tablets are 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 tadalafil tablets are 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 tadalafil tablets with caution in patients predisposed to priapism ( 5.3 ). Patients should stop tadalafil tablets 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). Tadalafil tablets 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 ( 5.4 , 6.2 ). Patients should stop tadalafil tablets and seek prompt medical attention in the event of sudden decrease or loss of hearing ( 5.5 ). Prior to initiating treatment with tadalafil tablets for BPH, consideration should be given to other urological conditions that may cause similar symptoms ( 5.14 ). 5.1 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 tadalafil tablets, 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 tadalafil tablets. In such a patient, who has taken tadalafil tablets, where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should have elapsed after the last dose of tadalafil tablets 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 tadalafil tablets should seek immediate medical attention. [see Contraindications ( 4.1 ) and Patient Counseling Information ( 17.1 )] . 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 tadalafil tablets, and therefore until further information is available, tadalafil tablets are 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 [see Clinical Pharmacology ( 12.2 )] . While this effect should not be of consequence in most patients, prior to prescribing tadalafil tablets, 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. 5.2 Potential for Drug Interactions When Taking Tadalafil Tablets for Once Daily Use Physicians should be aware that tadalafil tablets 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 [see Drug Interactions ( 7.1 , 7.2 , 7.3 )] . 5.3 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. Tadalafil tablets 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). 5.4 Effects on the Eye Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including tadalafil, 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 [see Adverse Reactions ( 6.2 )] . 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 tadalafil, 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 tadalafil, 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. 5.5 Sudden Hearing Loss Physicians should advise patients to stop taking PDE5 inhibitors, including tadalafil, 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 tadalafil. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions ( 6.1 , 6.2 )] . 5.6 Alpha-blockers and Antihypertensives Physicians should discuss with patients the potential for tadalafil tablets to augment the blood-pressure-lowering effect of alpha-blockers and antihypertensive medications [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.2 )] . Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers. PDE5 inhibitors, including tadalafil, 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 ( 7.1 ) and Clinical Pharmacology ( 12.2 )] , 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. [see Dosage and Administration ( 2.7 ) and Drug Interactions ( 7.1 )] . BPH The efficacy of the coadministration of an alpha-blocker and tadalafil tablets 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 tadalafil tablets and alpha-blockers is not recommended for the treatment of BPH. [see Dosage and Administration ( 2.7 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.2 .)] . Patients on alpha-blocker therapy for BPH should discontinue their alpha-blocker at least one day prior to starting tadalafil tablets for once daily use for the treatment of BPH. 5.7 Renal Impairment Tadalafil Tablets for Use as Needed Tadalafil tablets 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 tadalafil tablets 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. [see Use in Specific Populations ( 8.7 )] . Tadalafil Tablets for Once Daily Use ED Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, tadalafil tablets for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min [see Use in Specific Populations ( 8.7 )] . BPH and ED/BPH Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, tadalafil tablets 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 [see Dosage and Administration ( 2.6 ), Use in Specific Populations ( 8.7 ), and Clinical Pharmacology ( 12.3 )] . 5.8 Hepatic Impairment Tadalafil Tablets for Use as Needed In patients with mild or moderate hepatic impairment, the dose of tadalafil tablets should not exceed 10 mg. Because of insufficient information in patients with severe hepatic impairment, use of tadalafil tablets in this group is not recommended [see Use in Specific Populations ( 8.6 )] . Tadalafil Tablets for Once Daily Use Tadalafil tablets for once daily use has not been extensively evaluated in patients with mild or moderate hepatic impairment. Therefore, caution is advised if tadalafil tablets for once daily use is prescribed to these patients. Because of insufficient information in patients with severe hepatic impairment, use of tadalafil tablets in this group is not recommended [see Use in Specific Populations ( 8.6 )] . 5.9 Alcohol Patients should be made aware that both alcohol and tadalafil tablets, 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 tadalafil tablets can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache [see Clinical Pharmacology ( 12.2 )] . 5.10 Concomitant Use of Potent Inhibitors of Cytochrome P450 3A4 (CYP3A4) Tadalafil is metabolized predominantly by CYP3A4 in the liver. The dose of tadalafil tablets 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 [see Drug Interactions ( 7.2 )] . In patients taking potent inhibitors of CYP3A4 and tadalafil tablets for once daily use, the maximum recommended dose is 2.5 mg [see Dosage and Administration ( 2.7 )] . 5.11 Combination With Other PDE5 Inhibitors or Erectile Dysfunction Therapies The safety and efficacy of combinations of tadalafil tablets and other PDE5 inhibitors or treatments for erectile dysfunction have not been studied. Inform patients not to take tadalafil tablets with other PDE5 inhibitors, including ADCIRCA. 5.12 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. Tadalafil tablets have not been administered to patients with bleeding disorders or significant active peptic ulceration. Although tadalafil tablets have 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. 5.13 Counseling Patients About Sexually Transmitted Diseases The use of tadalafil tablets 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. 5.14 Consideration of Other Urological Conditions Prior to Initiating Treatment for BPH Prior to initiating treatment with tadalafil tablets for BPH, consideration should be given to other urological conditions that may cause similar symptoms. In addition, prostate cancer and BPH may coexist.