Tadalafil (Page 3 of 11)

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 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 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 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 for once daily use for the treatment of BPH.

5.7 Renal Impairment

Tadalafil for Use as Needed

Tadalafil 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 in patients with creatinine clearance 30 to 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 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 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 for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min. In patients with creatinine clearance 30 to 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 for Use as Needed

In patients with mild or moderate hepatic impairment, the dose of tadalafil should not exceed 10 mg. Because of insufficient information in patients with severe hepatic impairment, use of tadalafil in this group is not recommended [see Use in Specific Populations ( 8.6)].

Tadalafil for Once Daily Use

Tadalafil for once daily use has not been extensively evaluated in patients with mild or moderate hepatic impairment. Therefore, caution is advised if tadalafil for once daily use is prescribed to these patients. Because of insufficient information in patients with severe hepatic impairment, use of tadalafil 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, 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 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 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 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 has not been administered to patients with bleeding disorders or significant active peptic ulceration. Although tadalafil 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.

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