10/2011
`
`
`10/2011
`10/2011
`
`
`10/2011
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use CIALIS
`safely and effectively. See full prescribing information for CIALIS.
`CIALIS (tadalafil) tablets, for oral use
`
`Initial U.S. Approval: 2003
`---------------------------RECENT MAJOR CHANGES---------------------------
`Indications and Usage:
`
`10/2011
` Benign Prostatic Hyperplasia (1.2)
`
` Erectile Dysfunction and Benign Prostatic
`Hyperplasia (1.3)
`Dosage and Administration:
` Dosage and Administration (2)
`
` CIALIS for Once Daily Use for Benign Prostatic
`Hyperplasia (2.3)
`
` CIALIS for Once Daily Use for Erectile Dysfunction
`and Benign Prostatic Hyperplasia (2.4)
`
`
` Use in Specific Populations (2.6)
`
` Concomitant Medications (2.7)
`
`Warnings and Precautions:
`Warnings and Precautions (5)
`
`
` Alpha-blockers and Antihypertensives (5.6)
`
` Renal Impairment (5.7)
`
` Consideration of Other Urological Conditions Prior to
`Initiating Treatment for BPH (5.14)
`----------------------------INDICATIONS AND USAGE---------------------------
`CIALIS® is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment
`of:
`• erectile dysfunction (ED) (1.1)
`the signs and symptoms of benign prostatic hyperplasia (BPH) (1.2)
`•
`
`• ED and the signs and symptoms of BPH (ED/BPH) (1.3)
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`• 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 (2.1).
`• 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
`(2.2).
`
`• BPH: 5 mg, taken at approximately the same time every day (2.3)
`
`• ED and BPH: 5 mg, taken at approximately the same time every day
`(2.3, 2.4)
`
`• CIALIS may be taken without regard to food (2.5).
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`Tablets: 2.5 mg, 5 mg, 10 mg, 20 mg (3).
`----------------------------CONTRAINDICATIONS---------------------------------
`• Administration of CIALIS to patients using any form of organic nitrate is
`
`contraindicated. CIALIS was shown to potentiate the hypotensive effect of
`
`nitrates (4.1).
`
`10/2011
`10/2011
`
`10/2011
`10/2011
`10/2011
`
`10/2011
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1
` Erectile Dysfunction
`1.2
`Benign Prostatic Hyperplasia
`1.3
`Erectile Dysfunction and Benign Prostatic Hyperplasia
`DOSAGE AND ADMINISTRATION
`CIALIS for Use as Needed for Erectile Dysfunction
`2.1
`2.2
`CIALIS for Once Daily Use for Erectile Dysfunction
`2.3
`CIALIS for Once Daily Use for Benign Prostatic Hyperplasia
`2.4
`CIALIS for Once Daily Use for Erectile Dysfunction and
`Benign Prostatic Hyperplasia
`Use with Food
`
`2.5
`
`2
`
`
`
`Reference ID: 3024692
`
`
`
`•
`
`• History of known serious hypersensitivity reaction to CIALIS or
`ADCIRCA® (4.2).
`
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`
`
`• Patients should not use CIALIS if sex is inadvisable due to cardiovascular
`status (5.1).
`• Use of CIALIS with alpha blockers, antihypertensives or substantial
`
`
`amounts of alcohol (≥5 units) may lead to hypotension (5.6, 5.9).
`• 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)
`
`If taking potent inhibitors of CYP3A4, dose should be adjusted: CIALIS
`for use as needed: ≤10 mg every 72 hours. For once daily use: dose not to
`exceed 2.5 mg (5.10).
`
`• Patients should seek emergency treatment if an erection lasts >4 hours.
`
`Use CIALIS with caution in patients predisposed to priapism (5.3).
`
`
`• 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
`
`Ischemic Optic Neuropathy (NAION). Discuss increased risk of NAION
`
`in patients with history of NAION (5.4).
`• Patients should stop CIALIS and seek prompt medical attention in the
`
`event of sudden decrease or loss of hearing (5.5).
`
`• Prior to initiating treatment with CIALIS for BPH, consideration should be
`
`
`given to other urological conditions that may cause similar symptoms
`
`(5.14).
`------------------------------ADVERSE REACTIONS-------------------------------
`
`Most common adverse reactions (≥2%) include headache, dyspepsia, back
`
`
`pain, myalgia, nasal congestion, flushing, and pain in limb (6.1).
`
`To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and
`
`Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088
`or www.fda.gov/medwatch
`
`-------------------------------DRUG INTERACTIONS------------------------------
`
`• CIALIS can potentiate the hypotensive effects of nitrates, alpha blockers,
`
`antihypertensives or alcohol (7.1).
`• CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) increase CIALIS
`exposure. For concomitant use with potent CYP3A4 inhibitors, dose
`
`
`adjustment may be needed (2.7, 5.10, 7.2).
`
`• CYP3A4 inducers (e.g. rifampin) decrease CIALIS exposure (7.2).
`---------------------------USE IN SPECIFIC POPULATIONS--------------------
`Hepatic Impairment (2.6, 5.8, 8.6):
`
`
`• Mild or Moderate: Dosage adjustment may be needed.
`
`• Severe: Use is not recommended.
`Renal Impairment (2.6, 5.7, 8.7):
`• Patients with creatinine clearance 30 to 50 mL/min: Dosage adjustment
`
`may be needed.
`• Patients with creatinine clearance less than 30 mL/min or on hemodialysis:
`
`For use as needed: Dose should not exceed 5 mg every 72 hours. Once
`
`daily use is not recommended.
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling
`
`
`
`Revised: 10/2011
`
`3
`4
`
`Use in Specific Populations
`2.6
`Concomitant Medication s
`2.7
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`4.1
` Nitrates
`4.2
` Hypersensitivity Rea ctions
`5 WARNINGS AND PRECAUTIONS
` Cardiovasc ular
`5.1
`
`Potential for Drug Interac tions When Taking CIALIS for Once
`5.2
`Daily Use
`
` Prolonged Erection
`
`5.3
`
`ATI 1007-0001
`
`ATI v. ICOS
`IPR2018-01183
`
`

`

`5.11
`
` Eye
`5.4
`Sudden Hearing Loss
`5.5
`Alpha-blocker s and Antihypertensives
`5.6
` Renal Impairment
`5.7
` Hepatic Impair ment
`5.8
` Alcohol
`5.9
`5.10 Concomitant Use of Pot ent Inhibitors of Cytochrome P450 3A4
`
`(CYP3A4)
`
`Combination With Other PDE5 Inhibitors or Erectile
`
`Dysfunction Therapies
`Effects on Bleeding
`
`5.12
`5.13 Counseling Patients Abo ut Sexually Transmitted Diseases
`
`
`Consideration of Other Urological Conditions Prior to Initiating
`5.14
`Treatment for BPH
` ADVERSE REACTIONS
`Clinical Trials Experience
`6.1
`6.2
` Postmarketing Experience
` DRUG INTERACTIONS
`
`7.1
`Potential for Pharmacodynamic Interactions with CIALIS
`7.2
`Potential for Oth er Drugs to Affect CI ALIS
`
`Potential for CIALIS to Affect Other Drugs
`7.3
`USE IN SPECIFIC POPU LATIONS
` Pregnancy
`8.1
`
` Nursing Mothers
`8.3
`8.4
` Pediatric Use
` Geriatric Use
`8.5
`
` Hepatic Impa irment
`8.6
`8.7
` Renal Impair ment
`10 OVERDOSAGE
`
` DESCRIPTION
`11
`12 CLINICAL PHARMACOLOGY
`
`
`6
`
`7
`
`8
`
`
`
`14
`
`13
`
`12.1 Mechanism of Action
`
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
` NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mu tagenesis, Impairment of Fertility
`
`13.2 Animal Toxicology and/or Pharmac ology
`
`
`CLIN CAL STUDIES
`I
`CIALIS for Use as Needed for ED
`14.1
`CIALIS for Once Da ily Use for ED
`14.2
`14.3 CIALIS 5 mg for Once Daily Use for Benign Prosta tic
`
`Hyperplasia (BPH)
`CIALIS 5 mg for O nce Daily Use for ED and BPH
`14.4
`16 HOW SUPPLIED/S TORAGE AND HANDLING
`16.1 How Supplied
`Storage
`16.2
`17 PATIENT COUNSELING INFORMATI ON
`
`17.1
` Nitrates
`Cardiovascular Considerations
`17.2
`
`17.3 Concomitan t Use with Drugs Which Lower Blood Pressure
`
`
`17.4
`Potential for Dr ug Interactions When Taking CIALIS for Once
`
`Daily Use
`Priapism
`17.5
`
`17.6 Vision
`17.7
`Sudden Hearing Loss
`
`17.8 Alcohol
`Sexually Transmitted Disease
`17.9
`17.10 Recommended Administration
`*Sections or subsections omitted from the full prescribing information are not
`
`listed
`
`
`
`
`
`
`
`
`Reference ID: 3024692
`
`FULL PRESCRIBING INFORMATION
`1
` INDICATIONS AND USA GE
`1.1
` Erectile Dysfunction
`CIALIS® is indicated for the trea tment 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).
`
`
`DOSAGE AND ADMINISTRATION
`
`
`Do not split CIALIS tablets; entire dose should be ta ken.
`
`CIALIS for Use as Needed for Erectile Dysfunction
`
`
`
`• The recom mended 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 o n 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.
`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
`2.5
` CIALIS may be taken without regard to food.
`
`
`
` 1.2
`
`1.3
`
`
`2
`
`2.1
`
`2.2
`
`2.3
`
`2.4
`
`ATI 1007-0002
`
`
`
`

`

`
`
`
`
`
`•
`
`
`•
`
`2.6
` 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 [see Warnings and Precautions (5.7) and Use in Specific Populations (8.7)].
`
`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 [see
`
`
`
`
`
`
`
`Warnings and Precautions (5.7) and Use in Specific Populations (8.7)].
`
`
`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 [see
`
`
`
`
`
`
`
`Warnings and Precautions (5.7) and Use in Specific Populations (8.7)].
`
`
`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 [see Warnings and Precautions (5.8) and Use in
`
`
`
`Specific Populations (8.6)].
`
`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 [see Warnings and Precautions (5.8) and Use in
`
`
`
`Specific Populations (8.6)].
`2.7
`Concomitant Medications
`
`Nitrates
`
`Concomitant use of nitrates in any form is contraindicated [see Contraindications (4.1)].
`
`
`
`
`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 [see Warnings
`
`
`
`and Precautions (5.6), Drug Interactions (7.1), and Clinical Pharmacology (12.2)].
`
`BPH — CIALIS is not recommended for use in combination with alpha blockers for the treatment of BPH [see Warnings and
`
`
`Precautions (5.6), Drug Interactions (7.1), and Clinical Pharmacology (12.2)].
`
`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 [see Warnings and Precautions (5.10) and
`
`
`Drug Interactions (7.2)].
`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 [see Warnings and Precautions (5.10) and Drug Interactions (7.2)].
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`Four strengths of almond-shaped tablets are available in different sizes and different shades of yellow:
`
`
`2.5 mg tablets debossed with “C 2 1/2”
`
`5 mg tablets debossed with “C 5”
`
`10 mg tablets debossed with “C 10”
`
`20 mg tablets debossed with “C 20”
`
`
`CONTRAINDICATIONS
`Nitrates
`
`
`Administration of CIALIS to patients who are using any form of organic nitrate, either regularly and/or intermittently, is
`
`contraindicated. In clinical pharmacology studies, CIALIS was shown to potentiate the hypotensive effect of nitrates [see Clinical
`
`Pharmacology (12.2)].
`4.2
`Hypersensitivity Reactions
`CIALIS is contraindicated in patients with a known serious hypersensitivity to tadalafil (CIALIS or ADCIRCA®).
`
`
`
`Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis [see Adverse Reactions
`
`
`(6.2)].
`
`4
`4.1
`
`
`
`Reference ID: 3024692
`
`ATI 1007-0003
`
`

`

`
`
` 5
`
`5.1
`
`
`
`
`
`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 CIALIS, it is important to note the following:
`
`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. [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
`
`
`
`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 [see Clinical Pharmacology (12.2)]. 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
`5.2
`
`
`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 [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.
`
`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).
`
`Eye
`5.4
`Physicians should advise patients to stop use of all 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 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. 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 [see Adverse Reactions (6.2)].
`
`
`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
`5.5
`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 [see Adverse Reactions (6.1, 6.2)].
`
`
`
`
`
`Reference ID: 3024692
`
`ATI 1007-0004
`
`

`

`•
`
`•
`
`•
`
`
`•
`
`
`5.6
`
`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 [see Drug Interactions (7.1) and Clinical Pharmacology (12.2)].
`
`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 (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 co-administration 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. [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
`
`
`CIALIS for once daily use for the treatment of BPH.
`5.7
`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. [See Use in Specific Populations (8.7)].
`
`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 [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, 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 [see Dosage and Administration (2.6), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].
`5.8
`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 [see Use in Specific
`
`
`Populations (8.6)].
`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 [see Use in Specific Populations (8.6)].
`
`
`Alcohol
`5.9
`
`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 [see Clinical Pharmacology (12.2)].
`
`
`
`Reference ID: 3024692
`
`ATI 1007-0005
`
`

`

`
`
`
`
`
`
` 5.10 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 [see Drug Interactions (7.2)]. In patients taking potent inhibitors of CYP3A4 and CIALIS 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 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.
`
`
`
`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. 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.
`
` 5.13 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.
`
` 5.14 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.
`6
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a
`
`drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
`
`
`
`
`
`Tadalafil was administered to over 9000 men during clinical trials worldwide. In trials of CIALIS for once daily use, a total of
`
`
`
`1434, 905, and 115 were treated for at least 6 months, 1 year, and 2 years, respectively. For CIALIS for use as needed, over 1300 and
`
`
`1000 subjects were treated for at least 6 months and 1 year, respectively.
`
`CIALIS for Use as Needed for ED
`In eight primary placebo-controlled clinical studies of 12 weeks duration, mean age was 59 years (range 22 to 88) and the
`
`
`discontinuation rate due to adverse events in patients treated with tadalafil 10 or 20 mg was 3.1%, compared to 1.4% in placebo
`
`
`
`
`treated patients.
`
`When taken as recommended in the placebo-controlled clinical trials, the following adverse reactions were reported (see
`
`
`Table 1) for CIALIS for use as needed:
`
`
`Adverse Reaction
`
`
`
`
`Table 1: Treatment-Emergent Adverse Reactions Reported by ≥2% of Patients Treated with CIALIS (10 or 20 mg) and More
`
`
`
`Frequent on Drug than Placebo in the Eight Primary Placebo-Controlled Clinical Studies (Including a Study in Patients with
`
`
`
`Diabetes) for CIALIS for Use as Needed for ED
`
`
`Tadalafil 10 mg
`Tadalafil 5 mg
`Placebo
`
`
`
`(N=151)
`(N=476)
`(N=394)
`Headache
`5%
`11%
`11%
`Dyspepsia
`1%
`4%
`8%
`Back pain
`3%
`3%
`5%
`Myalgia
`1%
`1%
`4%
`Nasal congestion
`1%
`2%
`3%
`1%
`2%
`3%
`
`Flushinga
`Pain in limb
`1%
`1%
`3%
`
` a The term flushing includes: facial flushing and flushing
`
`CIALIS for Once Daily Use for ED
` In three placebo-controlled clinical trials of 12 or 24 weeks duration, mean age was 58 years (range 21 to 82) and the
`
`
`
`
`
` discontinuation rate due to adverse events in patients treated with tadalafil was 4.1%, compared to 2.8% in placebo-treated patients.
` The following adverse reactions were reported (see Table 2) in clinical trials of 12 weeks duration:
`
`
`
`
`Tadalafil 20 mg
`
`(N=635)
`15%
`10%
`6%
`3%
`3%
`3%
`3%
`
`
`
`Reference ID: 3024692
`
`ATI 1007-0006
`
`

`

`
`
`
`Table 2: Treatment-Emergent Adverse Reactions Reported by ≥2% of Patients Treated with CIALIS for Once Daily Use (2.5
`
`
`or 5 mg) and More Frequent on Drug than Placebo in the Three Primary Placebo-Controlled Phase 3 Studies of 12 weeks
`
`
`
`
`
`Treatment Duration (Including a Study in Patients with Diabetes) for CIALIS for Once Daily Use for ED
`
`
`
`Placebo
`Tadalafil 2.5 mg
`Tadalafil 5 mg
`Adverse Reaction
`(N=304)
`(N=248)
`(N=196)
`5%
`3%
`6%
`2%
`4%
`5%
`4%
`4%
`3%
`1%
`3%
`3%
`1%
`3%
`3%
`1%
`1%
`3%
`1%
`2%
`2%
`0%
`4%
`2%
`0%
`1%
`2%
`0%
`2%
`2%
`0%
`1%
`2%
`0%
`2%
`0%
`0%
`2%
`1%
`0%
`2%
`1%
`
`Headache
`Dyspepsia
`Nasopharyngitis
`Back pain
`
`Upper respiratory tract infection
`Flushing
`Myalgia
`Cough
`
`Diarrhea
`Nasal congestion
`
`Pain in extremity
`Urinary tract infection
`Gastroesophageal reflux disease
`
`Abdominal pain
`
`
`
`The following adverse reactions were reported (see Table 3) over 24 weeks treatment duration in one placebo-controlled
`
`
`clinical study:
`
`
`Table 3: Treatment-Emergent Adverse Reactions Reported by ≥2% of Patients Treated with CIALIS for Once Daily Use (2.5
`
`
`
`or 5 mg) and More Frequent on Drug than Placebo in One Placebo-Controlled Clinical Study of 24 Weeks Treatment
`
`
`Duration for CIALIS for Once Daily Use for ED
`
`Placebo
`Tadalafil 2.5 mg
`(N=94)
`(N=96)
`5%
`6%
`2%
`3%
`3%
`5%
`0%
`3%
`1%
`4%
`0%
`3%
`2%
`4%
`0%
`1%
`0%
`0%
`
`
`
`Tadalafil 5 mg
`(N=97)
`6%
`5%
`2%
`4%
`1%
`2%
`1%
`3%
`4%
`
`
`CIALIS for Once Daily Use for BPH and for ED and BPH
`
`
`
`In three placebo-controlled clinical trials of 12 weeks duration, two in patients with BPH and one in patients with ED and
`
`
`
`BPH, the mean age was 63 years (range 44 to 93) and the discontinuation rate due to adverse events in patients treated with tadalafil
`
`
`
`was 3.6% compared to 1.6% in placebo-treated patients. Adverse reactions leading to discontinuation reported by at least 2 patients
`treated with tada