`
`
`
`
`
`
`
` 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---------------------------
`
` Contraindications, Concomitant Guanylate Cyclase (GC) Stimulators
`
` 09/2015
`
` (4.3)
` ----------------------------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)
`
`
`
`•
`
`
`If CIALIS is used with finasteride to initiate BPH treatment, such use is
`
`
`
`
`recommended for up to 26 weeks (1.4).
`
`
`-----------------------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).
`
`History of known serious hypersensitivity reaction to CIALIS or
`
`
`
`ADCIRCA® (4.2).
`
`
`Administration with guanylate cyclase (GC) stimulators, such as
`
`
`riociguat (4.3).
`
`
`------------------------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).
`
`
`
`
`
`
`
`
`
`
`•
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
` 1
` INDICATIONS AND USAGE
` Erectile Dysfunction
`
`
` 1.1
`
`
` 1.2
` Benign Prostatic Hyperplasia
` Erectile Dysfunction and Benign Prostatic Hyperplasia
`
` 1.3
`
`
` 1.4
` Limitation of Use
` 2 DOSAGE AND ADMINISTRATION
`
`
`
`
`
`
` 2.1
` CIALIS for Use as Needed for Erectile Dysfunction
`
`
` 2.2
`
` CIALIS for Once Daily Use for Erectile Dysfunction
`
` 2.3
`
` CIALIS for Once Daily Use for Benign Prostatic
`
` Hyperplasia
`
`CIALIS for Once Daily Use for Erectile Dysfunction and
`Benign Prostatic Hyperplasia
`
`
`
` 2.5
` Use with Food
` Use in Specific Populations
`
` 2.6
`Concomitant Medications
`2.7
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
`2.4
`
`
`
`
`Reference ID: 3820620
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`
`
`
`•
`
`
`
`1
`
`
`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 (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 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 (5.4, 6.2).
`
`
`
`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 (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 (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: 09/2015
`
`
`
`
`
`
`
`
`
`
`
`
`
` Nitrates
`
`
` 4.1
` Hypersensitivity Reactions
`
`
` 4.2
` Concomitant Guanylate Cyclase (GC) Stimulators
`
` 4.3
`
`
` 5 WARNINGS AND PRECAUTIONS
` Cardiovascular
`
`
` 5.1
`
` 5.2
` Potential for Drug Interactions When Taking CIALIS for
`
` Once Daily Use
`
` Prolonged Erection
`
` 5.3
`
`
` Effects on the Eye
`
` 5.4
` Sudden Hearing Loss
`
`
` 5.5
`Alpha-blockers and Antihypertensives
`5.6
`
`
`
`
`Renal Impairment
`5.7
`
`
`Hepatic Impairment
`5.8
`
`
`Alcohol
`5.9
`
`
`
`5.10 Concomitant Use of Potent Inhibitors of Cytochrome P450
`
`3A4 (CYP3A4)
`
`0001
`
` DRL - EXHIBIT 1010
`
`

`

`
`
`
`
` 5.11 Combination With Other PDE5 Inhibitors or Erectile
`
` Dysfunction Therapies
`
`
`
`5.12 Effects on Bleeding
`
`
`
`5.13 Counseling Patients About Sexually Transmitted Diseases
`5.14 Consideration of Other Urological Conditions Prior to
`
`
`
`Initiating Treatment for BPH
`
`
`
`
`
`6 ADVERSE REACTIONS
`
`
`
`Clinical Trials Experience
`6.1
`
`
`6.2
`Postmarketing Experience
`
`
`
`7 DRUG INTERACTIONS
`Potential for Pharmacodynamic Interactions with CIALIS
`7.1
`
`
`
`
`
`7.2
`Potential for Other Drugs to Affect CIALIS
`
`
`
`
`7.3
`Potential for CIALIS to Affect Other Drugs
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`
`
`8.5
`Geriatric Use
`
`
`8.6
`Hepatic Impairment
`
`
`
`
`8.7
`Renal Impairment
`10 OVERDOSAGE
`
`
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`
`2
`
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`14 CLINICAL STUDIES
`
`
`
`
`14.1 CIALIS for Use as Needed for ED
`
`
`
`14.2 CIALIS for Once Daily Use for ED
`
`
`
`
`14.3 CIALIS 5 mg for Once Daily Use for Benign Prostatic
`
`Hyperplasia (BPH)
`
`
`
`
`14.4 CIALIS 5 mg for Once Daily Use for ED and BPH
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`16.1 How Supplied
`
`
`16.2 Storage
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`17.1 Nitrates
`
`
`17.2 Guanylate Cyclase (GC) Stimulators
`
`
`
`17.3 Cardiovascular Considerations
`17.4 Concomitant Use with Drugs Which Lower Blood Pressure
`
`
`
`17.5 Potential for Drug Interactions When Taking CIALIS for
`
`
`
`
`Once Daily Use
`
`
`
`17.6 Priapism
`
`
`
`17.7 Sudden Loss of Vision
`
`
`17.8 Sudden Hearing Loss
`
`
`17.9 Alcohol
`17.10 Sexually Transmitted Disease
`
`
`
`17.11 Recommended Administration
`
`
`
`
`*Sections or subsections omitted from the full prescribing information
`
`
`are not listed
`
`
`
`1.2
`
`
`1.3
`
`
`1.4
`
`
`2.1
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`1.1
`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 [see Clinical Studies (14.3)].
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`Do not split CIALIS tablets; entire dose should be taken.
`
`
`
`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
`
`
`2.2
`
`
`2.3
`
`
`2.4
`
`Reference ID: 3820620
`
`0002
`
`

`

`3
`
`
`
`
`
`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.
`
`
`2.5
`Use with Food
`
`CIALIS may be taken without regard to food.
`
`
`
`Use in Specific Populations
`2.6
`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)].
`
`
`
`Concomitant Medications
`2.7
`
`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)].
`
`3
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`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
`
`
`4
`
`4.1
`
`
`
`Reference ID: 3820620
`
`0003
`
`

`

`
`5.1
`
`4
`
`
`
`
`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)].
`
`
`
`Hypersensitivity Reactions
`4.2
`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)].
`
`
`
`Concomitant Guanylate Cyclase (GC) Stimulators
`4.3
`
`
`
`
`Do not use CIALIS in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including CIALIS,
`
`
`
`may potentiate the hypotensive effects of GC stimulators.
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`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)].
`
`
`Prolonged Erection
`5.3
`
`
`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).
`
`
`
`5.4
`Effects on the Eye
`
`
`Reference ID: 3820620
`
`0004
`
`

`

`5
`
`
`
`
`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 study evaluated whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of
`
`
`
`
`NAION. The results suggest an approximate 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use.
`
`
`
`
`From this information, it is not possible to determine whether these events are related directly to the use of PDE5
`
`
`inhibitors or other factors [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 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.
`
`
`5.5
`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 [see Adverse
`
`
`Reactions (6.1, 6.2)].
`
`
`
`
`Alpha-blockers and Antihypertensives
`5.6
`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 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. [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.
`
`
`Renal Impairment
`5.7
`
`
`
`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
`
`•
`
`
`•
`
`
`
`
`Reference ID: 3820620
`
`0005
`
`

`

`6
`
`
`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)].
`
`
`Hepatic Impairment
`5.8
`
`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)].
`
`
`5.9
`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 [see Clinical Pharmacology (12.2)].
`
`
`
`
`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
`
`
`
`Reference ID: 3820620
`
`0006
`
`

`

`7
`
`
`
`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:
`
`
`
` Tadalafil 20 mg
`
` (N=635)
`
` 15%
`
` 10%
`
` 6%
`
` 3%
`
` 3%
`
` 3%
`
` 3%
`
`
`
`
`
`
`
` Adverse Reaction
`
`
`
`
`
` 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 5 mg
` Tadalafil 10 mg
`
` Placebo
`
`
` (N=476)
`
`
` (N=151)
` (N=394)
` Headache
`
`
` 5%
`
` 11%
` 11%
`
`
` Dyspepsia
`
` 1%
`
` 4%
`
` 8%
`
` Back pain
`
` 3%
`
` 3%
`
` 5%