warnings and cautions
5 WARNINGS AND PRECAUTIONS Cardiovascular effects: Carefully consider whether patients with certain underlying conditions (e.g., cardiovascular disease, impaired autonomic control of blood pressure, aortic stenosis) could be adversely affected by vasodilatory effects of ADCIRCA. Not recommended in patients with pulmonary veno-occlusive disease. ( 5.1 ) Concomitant alpha-blockers or alcohol: Note additive blood pressure-lowering effects. ( 5.1 ) Use with Ritonavir: Requires dosage adjustment. ( 2.3 , 5.2 ) Other concomitant potent CYP3A inhibitors: Avoid use with ADCIRCA. ( 5.2 ) Potent Inducers of CYP3A: Avoid use of ADCIRCA in patients chronically taking potent inducers of CYP3A (e.g., rifampin). ( 5.2 , 7.2 ) Effects on the eye: Patients should seek immediate medical attention if sudden loss of vision occurs, which could be a sign of non-arteritic ischemic optic neuropathy (NAION). ( 5.5 ) Hearing impairment: Advise patients to seek immediate medical attention if sudden decrease or loss of hearing occurs. ( 5.6 ) Concomitant PDE5 inhibitors: Avoid use with CIALIS or other PDE5 inhibitors. ( 5.7 ) Prolonged erection: Advise patients to seek emergency treatment if an erection lasts >4 hours. ( 5.8 ) 5.1 Cardiovascular Effects Discuss with patients the appropriate action to take in the event that they experience anginal chest pain requiring nitroglycerin following intake of ADCIRCA. At least 48 hours should elapse after the last dose of ADCIRCA before taking nitrates. If a patient has taken ADCIRCA within 48 hours, administer nitrates under close medical supervision with appropriate hemodynamic monitoring. Patients who experience anginal chest pain after taking ADCIRCA should seek immediate medical attention. PDE5 inhibitors, including tadalafil, have mild systemic vasodilatory properties that may result in transient decreases in blood pressure. Prior to prescribing ADCIRCA, carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects. Patients with severely impaired autonomic control of blood pressure or with left ventricular outflow obstruction, (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) may be particularly sensitive to the actions of vasodilators, including PDE5 inhibitors. Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of ADCIRCA to patients with veno-occlusive disease, administration of ADCIRCA to such patients is not recommended. Should signs of pulmonary edema occur when ADCIRCA is administered, the possibility of associated PVOD should be considered. There is a lack of data on safety and efficacy in the following groups who were specifically excluded from the PAH clinical trials: Patients with clinically significant aortic and mitral valve disease Patients with pericardial constriction Patients with restrictive or congestive cardiomyopathy Patients with significant left ventricular dysfunction Patients with life-threatening arrhythmias Patients with symptomatic coronary artery disease Patients with hypotension (<90/50 mm Hg) or uncontrolled hypertension Use with Alpha Blockers and Antihypertensives PDE5 inhibitors, including ADCIRCA, and alpha–adrenergic blocking agents are 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). Safety of combined use of PDE5 inhibitors and alpha blockers may be affected by other variables, including intravascular volume depletion and use of other antihypertensive drugs [see Drug Interactions ( 7.1 )] . Use with Alcohol Both alcohol and tadalafil are mild vasodilators. When mild vasodilators are taken in combination, blood pressure-lowering effects are increased [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.2 )] . 5.2 Use with Potent CYP3A Inhibitors or Inducers Co-administration of ADCIRCA in Patients on Ritonavir In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability [see Dosage and Administration ( 2.3 ), Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )] . Co-administration of Ritonavir in Patients on ADCIRCA Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability [see Dosage and Administration ( 2.3 ), Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )] . Other Potent Inhibitors of CYP3A Tadalafil is metabolized predominantly by CYP3A in the liver. In patients taking potent inhibitors of CYP3A such as ketoconazole and itraconazole, avoid use of ADCIRCA [see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )] . Potent Inducers of CYP3A For patients chronically taking potent inducers of CYP3A, such as rifampin, avoid use of ADCIRCA [see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )] . 5.3 Use in Renal Impairment In patients with mild or moderate renal impairment Start dosing at 20 mg once daily. Increase the dose to 40 mg once daily based upon individual tolerability [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )] . In patients with severe renal impairment Avoid use of ADCIRCA because of increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )] . 5.4 Use in Hepatic Impairment In patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) Because of limited clinical experience in patients with mild to moderate hepatic cirrhosis, consider a starting dose of 20 mg once daily ADCIRCA [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )] . In patients with severe hepatic cirrhosis (Child-Pugh Class C) Patients with severe hepatic cirrhosis have not been studied. Avoid use of ADCIRCA [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )] . 5.5 Visual Loss Physicians should advise patients to seek immediate 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 cause of decreased vision, including permanent loss of vision, that has been reported postmarketing in temporal association with the use of all PDE5 inhibitors. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged ≥50 in the general population. An observational study evaluated whether recent episodic use of PDE5 inhibitors, as a class, typical of erectile dysfunction treatment, was associated with acute onset of NAION. The results suggest an approximate 2-fold increase in the risk of NAION within 1 to 4 days of PDE5 inhibitor use. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or other factors. Physicians should also discuss with patients the increased risk of 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 with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended. 5.6 Hearing Impairment Physicians should advise patients to seek immediate 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 ADCIRCA. 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 ( 6.2 )] . 5.7 Combination with Other PDE5 Inhibitors Tadalafil is also marketed as CIALIS. The safety and efficacy of taking ADCIRCA together with CIALIS or other PDE5 inhibitors have not been studied. Inform patients taking ADCIRCA not to take CIALIS or other PDE5 inhibitors. 5.8 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. ADCIRCA 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). 5.9 Effects on Bleeding PDE5 is found in platelets. When administered in combination with aspirin, tadalafil 20 mg did not prolong bleeding time, relative to aspirin alone. ADCIRCA has not been administered to patients with bleeding disorders or significant active peptic ulceration. Although ADCIRCA 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.