`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` These highlights do not include all the information needed to use
`
`
` ADCIRCA safely and effectively. See full prescribing information
`
`
`
`
` for ADCIRCA.
`
`
`
`
`
`
`
`
`
`
` ADCIRCA (tadalafil) tablets for oral administration
`
`
`
`
`
`
`
` Initial U.S. Approval: 2003
`
`
`
`
`
` ---------------------------RECENT MAJOR CHANGES---------------------------
`
`Warnings and Precautions (5.5)
`
`
`
`
`
`
`
` 05/2017
`
`
`
`
`
`
`
`
`
` --------------------------INDICATIONS AND USAGE-----------------------------
`
`
`
`
`
`
`
`
`
`
`
`
` ADCIRCA is a phosphodiesterase 5 (PDE5) inhibitor indicated for the
`
`
`
` treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to
`
`
`
`
`
` improve exercise ability. Studies establishing effectiveness included
`
`
`
`
`
`
`
`predominately patients with NYHA Functional Class II – III symptoms
`
`
`
`
`
`
`
`
`
` and etiologies of idiopathic or heritable PAH (61%) or PAH associated
`
`
`
`
`
`
`
`
` with connective tissue diseases (23%). (1.1)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` ------------------------DOSAGE AND ADMINISTRATION----------------------
`•
`
` 40 mg once daily, with or without food. (2.1)
`
`
`
`
`
`
`
`
`
`•
`
` Dividing the dose (40 mg) over the course of the day is not
`
`
`
`
`
`
`
`
` recommended. (2.1)
`
`
` Use with ritonavir requires dosage adjustments. (2.3)
`
`
`
`•
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` -------------------------DOSAGE FORMS AND STRENGTHS------------------
`
`
`
`
`
`
`
`
`
`
`
`
`
` Tablets (not scored): 20 mg (3)
`
`------------------------------CONTRAINDICATIONS-------------------------------
`•
`
`
`
`
`
` Concomitant organic nitrates (4.1)
`•
`
`
`
`
`
` Concomitant Guanylate Cyclase (GC) Stimulators (4.2)
`
`
`•
`
`
` History of known serious hypersensitivity reaction to ADCIRCA or
`
`
`
`
`
`
`
` CIALIS (4.3)
`
`
`
`
`
`
`
`
`
` -------------------------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)
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS *
`
`
`
`1
`
`
`INDICATIONS AND USAGE
`
`
`
`1.1
`Pulmonary Arterial Hypertension
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1
`Pulmonary Arterial Hypertension
`
`
`
`2.2
`Use in Special Populations
`
`
`
`2.3
`Use with Ritonavir
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`4 CONTRAINDICATIONS
`
`
`4.1
`Concomitant Organic Nitrates
`
`
`
`
`4.2
`Concomitant Guanylate Cyclase (GC) Stimulators
`
`
`
`
`
`
`4.3
`Hypersensitivity Reactions
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1
`Cardiovascular Effects
`
`
`
`5.2
`Use with Potent CYP3A Inhibitors or Inducers
`
`
`
`
`
`
`
`
`5.3
`Use in Renal Impairment
`
`
`
`
`5.4
`Use in Hepatic Impairment
`
`
`
`
`5.5
`Visual Loss
`
`
`
`5.6
`Hearing Impairment
`
`
`
`5.7
`Combination with Other PDE5 Inhibitors
`
`
`
`
`
`
`5.8
`Prolonged Erection
`
`
`
`5.9
`Effects on Bleeding
`
`
`
`
`6 ADVERSE REACTIONS
`
`
`
`6.1
`Clinical Trials Experience
`
`
`
`
`6.2
`Postmarketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1
`Potential for Pharmacodynamic Interactions with
`
`
`
`
`
`ADCIRCA
`
`Potential for Other Drugs to Affect ADCIRCA
`
`
`
`
`
`
`Potential for ADCIRCA to Affect Other Drugs
`
`
`
`
`
`
`
`7.2
`
`7.3
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`Reference ID: 4094299
`
`
`
` 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)
`
`
`
`
`
`
`
`
`---------------------------------ADVERSE REACTIONS----------------------------
`
`
`
`
`The most common adverse reaction is headache. (6.1)
`
`
`
`
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly
`
`
`
`
`
`
`
`and Company at 1-800-545 5979 or FDA at 1-800-FDA-1088 or
`
`
`
`
`
`
`
`www.fda.gov/medwatch.
`
`
`--------------------------USE IN SPECIFIC POPULATIONS---------------------
`
`
`
`
`
`
`Renal Impairment (2.2, 5.3, 8.6, 12.3)
`
`
`
`
`
`• Mild or moderate: Start with 20 mg once daily. (2.2, 5.3, 8.6)
`
`
`
`
`
`
`
`
`
`
`
`
`
`•
`Severe: Avoid use of ADCIRCA. (2.2, 5.3, 8.6)
`
`
`
`
`
`
`
`
`
`Hepatic Impairment (2.2, 5.4, 8.7, 12.3)
`
`
`
`
`
`
`• Mild or moderate: Consider starting dose of 20 mg once daily.
`
`
`
`
`
`
`
`
`
`
`
`(2.2, 5.4, 8.7)
`
`
`
`Severe: Avoid use of ADCIRCA. (2.2, 5.4, 8.7)
`
`
`
`
`
`
`
`
`•
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`
`
`
`
`approved patient labeling
`
`
`
`Revised: 05/2017
`
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`
`
`8.1
`Pregnancy
`
`
`8.3
`Nursing Mothers
`
`
`
`8.4
`Pediatric Use
`
`
`
`8.5
`Geriatric Use
`
`
`
`8.6
`Renal Impairment
`
`
`8.7
`Hepatic Impairment
`
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`
`
`
`13.3 Reproductive Toxicology Studies
`
`
`
`
`14 CLINICAL STUDIES
`
`
`14.1 ADCIRCA for Pulmonary Arterial Hypertension
`
`
`
`
`
`14.2
`
`
`
`
`
`
`Long-Term Treatment of Pulmonary Arterial Hypertension
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`16.1 How Supplied
`
`
`
`16.2 Storage
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`
`
`
`
`
`
`* Sections or subsections omitted from the full prescribing information
`
`
`
`are not listed
`
`
`
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1074, p. 1 of 14
`
`

`

`
`
` 1
`
`
`
` INDICATIONS AND USAGE
`
`
`
`
`
` 2
`
`
`
` 1.1
`
` Pulmonary Arterial Hypertension
`
`
` ADCIRCA® is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve
`
`
`
`
`
`exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class II – III
`
`
`
`symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%).
`
`
`
`
`
`
`
`2
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
`2.1
`
`
`Pulmonary Arterial Hypertension
`
`The recommended dose of ADCIRCA is 40 mg (two 20 mg tablets) taken once daily with or without food. Dividing
`
`
`
`
`
`
`
`the dose (40 mg) over the course of the day is not recommended.
`
`
`
`
`Use in Special Populations
`2.2
`
`
`
`Renal Impairment
`
`• Mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min): Start dosing at
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`20 mg once daily. Increase to 40 mg once daily based on individual tolerability.
`• Severe (creatinine clearance <30 mL/min and on hemodialysis): Avoid use of ADCIRCA because of increased
`
`
`
`
`
`
`
`
`
`
`tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis [see
`
`
`
`Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].
`
`Hepatic Impairment
`• Mild or moderate (Child Pugh Class A or B): Because of limited clinical experience in patients with mild to moderate
`
`
`
`
`
`hepatic cirrhosis, consider a starting dose of 20 mg once per day.
`• Severe (Child Pugh Class C): Patients with severe hepatic cirrhosis have not been studied. Avoid use of ADCIRCA
`
`
`
`
`
`[see Warnings and Precautions (5.4) and Use in Specific Populations (8.7)].
`
`
`
`Geriatric Patients
`
`
`
`• No dose adjustment is required in patients >65 years of age without renal impairment or hepatic impairment.
`
`
`
`
`
`
`
`
`
`
`Use with Ritonavir
`2.3
`
`
`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 Warnings and Precautions (5.2), 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 Warnings and Precautions (5.2), Drug Interactions (7.2) and Clinical
`
`Pharmacology (12.3)].
`
`
`3
`
`
`4
`
`
`
`DOSAGE FORMS AND STRENGTHS
`20 mg, orange, film-coated, almond-shaped tablets (not scored) debossed with “4467”.
`
`
`
`
`
`
`CONTRAINDICATIONS
`
`
`4.1
`
`
`
`
`Concomitant Organic Nitrates
`
`
`
`
`
`Do not use ADCIRCA in patients who are using any form of organic nitrate, either regularly or intermittently.
`
`
`
`
`ADCIRCA potentiates the hypotensive effect of nitrates. This potentiation is thought to result from the combined effects of
`
`
`
`
`nitrates and ADCIRCA on the nitric oxide/cGMP pathway [see Clinical Pharmacology (12.2)].
`
`
`4.2
`
`
`
`Concomitant Guanylate Cyclase (GC) Stimulators
`
`
`
`
`
`
`
`Do not use ADCIRCA in patients who are using a GC stimulator, such as riociguat. ADCIRCA may potentiate the
`
`
`hypotensive effects of GC stimulators.
`
`
`4.3
`
`
`Hypersensitivity Reactions
`
`
`
`
`
`ADCIRCA is contraindicated in patients with a known serious hypersensitivity to tadalafil (ADCIRCA or CIALIS).
`
`
`
`Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis [see
`
`Adverse Reactions (6.2)].
`
`
`5
`
`
`
`WARNINGS AND PRECAUTIONS
`
`
`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
`
`
`
`
`
`
`
`Reference ID: 4094299
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1074, p. 2 of 14
`
`

`

`
`
` 3
`
`
`
` 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 anticipate d. 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)].
`
`
`
`
`Use with Potent CYP3A Inhibitors or Inducers
`5.2
`
`
`
`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)].
`
`
`
`Use in Renal Impairment
`5.3
`
`
`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)].
`
`
`
`Use in Hepatic Impairment
`5.4
`
`
`
`
`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
`
`Reference ID: 4094299
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1074, p. 3 of 14
`
`

`

`
`
` 4
`
`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 case-
`
`
`
`
`
`
`crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, typical of erectile dysfunction
`
`
`treatment, 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 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.
`
`
`6
`
`
`6.1
`
`
`ADVERSE REACTIONS
`
`
`
`The following serious adverse reactions are discussed elsewhere in the labeling:
`• Hypotension [see Warnings and Precautions (5.1)]
`
`
`
`• Visual Loss [see Warnings and Precautions (5.5) and Patient Counseling Information (17)]
`
`
`
`
`
`
`• Hearing loss [see Warnings and Precautions (5.6)]
`
`
`
`
`• Priapism [see Warnings and Precautions (5.8)]
`
`
`
`
`
`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 398 patients with PAH during clinical trials worldwide. In trials of ADCIRCA, a total of
`
`
`
`
`
`
`
`
`311 and 251 subjects have been treated for at least 182 days and 360 days, respectively. The overall rates of
`
`
`
`
`discontinuation because of an adverse event (AE) in the placebo-controlled trial were 9% for ADCIRCA 40 mg and 15%
`
`
`
`
`
`
`
`
`
`for placebo. The rates of discontinuation because of AEs, other than those related to worsening of PAH, in patients
`
`
`
`
`
`
`
`treated with ADCIRCA 40 mg was 4% compared to 5% in placebo-treated patients.
`
`In the placebo-controlled study, the most common AEs were generally transient and mild to moderate in intensity.
`Table 1 presents treatment-emergent adverse events reported by ≥9% of patients in the ADCIRCA 40 mg group and
`
`
`
`
`
`
`
`occurring more frequently than with placebo.
`
`
`
`
`
`
`
`
`Table 1: Treatment-Emergent Adverse Events Reported by ≥9% of Patients in ADCIRCA and More Frequent than
`
`
`
`Placebo by 2%
`
`Reference ID: 4094299
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1074, p. 4 of 14
`
`

`

`
`
` EVENT
`
`
` Placebo (%)
`
` (N=82)
`
`
` ADCIRCA 20 mg (%)
` (N=82)
`
`
`
`
`
` ADCIRCA 40 mg (%)
` (N=79)
`
`
`
`
`
`
` 5
`
`
`
`
`
`
`
`
` 15
`
` 4
`
` 7
`
` 2
`
` 6
`
` 2
`
` 6
`
` 6
`
` 2
`
` 1
`
`
` 32
`
` 9
`
` 2
`
` 6
`
` 7
`
` 5
`
` 10
`
` 12
`
` 13
`
` 0
`
`
` 42
`
` 14
`
` 13
`
` 13
`
` 13
`
` 11
`
` 11
`
` 10
`
` 10
`
` 9
`
`
` Headache
`
` Myalgia
` Nasopharyngitis
`
` Flushing
` Respiratory Tract Infection (Upper and Lower)
`
` Pain in Extremity
`
` Nausea
`
` Back Pain
`
` Dyspepsia
` Nasal Congestion (Including sinus congestion)
`
`
`
`
`6.2
`
`
`Postmarketing Experience
`
`
`The following adverse reactions have been identified during post-approval use of tadalafil. These events have
`
`
`
`been chosen for inclusion either because of their seriousness, reporting frequency, lack of clear alternative causation, or a
`
`
`
`combination of these factors. Because these reactions are reported voluntarily from a population of uncertain size, it is not
`
`always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. The list does not
`
`
`
`
`
`include adverse events that are reported from clinical trials and that are listed elsewhere in this section.
`Cardiovascular and cerebrovascular — Serious cardiovascular events, including myocardial infarction, sudden
`
`
`
`
`
`
`cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported postmarketing in temporal association
`
`with the use of tadalafil. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these
`
`
`
`
`
`events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use
`
`
`
`
`
`
`
`
`
`of tadalafil without sexual activity. Others were reported to have occurred hours to days after the use of tadalafil and
`
`
`
`
`
`
`sexual activity. It is not possible to determine whether these events are related directly to tadalafil, to sexual activity, to the
`patient’s underlying cardiovascular disease, to a combination of these factors, or to other factors [see Warnings and
`
`
`
`Precautions (5.1)].
`Body as a whole — Hypersensitivity reactions including urticaria, Stevens–Johnson syndrome, and exfoliative
`
`
`
`
`
`dermatitis
`Nervous — Migraine, seizure and seizure recurrence, and transient global amnesia
`
`
`
`Ophthalmologic — Visual field defect, retinal vein occlusion, retinal artery occlusion, and NAION [see Warnings
`
`
`
`
`
`
`
`
`
`and Precautions (5.5) and Patient Counseling Information (17)].
`Otologic — Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal
`
`
`
`
`
`
`
`
`association with the use of PDE5 inhibitors, including tadalafil. In some of the cases, medical conditions and other factors
`
`were reported that may have also played a role in the otologic adverse events. In many cases, medical follow -up
`
`
`
`
`
`information was limited. It is not possible to determine whether these reported events are related directly to the use of
`tadalafil, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors [see
`
`
`
`
`
`
`
`
`Warnings and Precautions (5.6) and Patient Counseling Information (17)].
`Urogenital — Priapism [see Warnings and Precautions (5.8)].
`
`
`
`
`
`
`7
`
`
`DRUG INTERACTIONS
`
`
`
`
`
`Potential for Pharmacodynamic Interactions with ADCIRCA
`7.1
`
`Nitrates
`
`
`
`
`
`
`Do not use ADCIRCA in patients who are using any form of organic nitrate [see Contraindications (4.1)]. In clinical
`
`
`
`
`
`
`pharmacology studies ADCIRCA potentiated the hypotensive effect of nitrates [see Clinical Pharmacology (12.2)]. In a
`
`
`
`
`
`
`patient who has taken ADCIRCA, where nitrate administration is deemed medically necessary in a life–threatening
`
`
`
`
`situation, at least 48 hours should elapse after the last dose of ADCIRCA before nitrate administration is considered. In
`
`such circumstances, nitrates should still only be administered under close medical supervision with appropriate
`
`
`hemodynamic monitoring.
`
`Alpha-Blockers
`
`PDE5 inhibitors, including ADCIRCA, 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. Clinical pharmacology studies have been conducted with coadministration of tadalafil with doxazosin,
`
`
`
`alfuzosin or tamsulosin [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].
`
`Antihypertensives
`
`
`PDE5 inhibitors, including ADCIRCA, are mild systemic vasodilators. Clinical pharmacology studies were
`
`
`
`
`conducted to assess the effect of tadalafil on the potentiation of the blood–pressure–lowering effects of selected
`
`antihypertensive medications (amlodipine, angiotensin II receptor blockers, bendroflumethiazide, enalapril, and
`
`Reference ID: 4094299
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1074, p. 5 of 14
`
`

`

`
`
` 6
`
`metoprolol). Small reductions in blood pressure occurred following coadministration of tadalafil with these agents
`
`
`
`
`
`compared with placebo [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].
`
`
`
`
`
`Alcohol
`
`
`
`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. Substantial consumption of
`
`
`
`
`
`
`alcohol (e.g., 5 units or greater) in combination with ADCIRCA can increase the potential for orthostatic signs and
`
`
`
`
`symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil
`
`
`
`(10 mg or 20 mg) did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations.
`
`[See Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].
`
`
`
`
`
`Potential for Other Drugs to Affect ADCIRCA
`7.2
`
`Ritonavir
`
`
`
`
`Ritonavir initially inhibits and later induces CYP3A, the enzyme involved in the metabolism of tadalafil. At steady
`
`
`
`
`
`
`
`state of ritonavir (about 1 week), the exposure to tadalafil is similar as in the absence of ritonavir [see Dosage and
`
`
`
`Administration (2.3), Warnings and Precautions (5.2), 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 Warnings and Precautions (5.2) 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 Warnings
`
`
`and Precautions (5.2) and Clinical Pharmacology (12.3)].
`
`
`
`
`
`Potential for ADCIRCA to Affect Other Drugs
`7.3
`
`
`Cytochrome P450 Substrates
`
`
`
`Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized
`
`by cytochrome P450 (CYP) isoforms (e.g., theophylline, warfarin, midazolam, lovastatin, bosentan) [see Clinical
`
`Pharmacology (12.3)].
`
`Aspirin
`
`
`
`
`
`
`
`Tadalafil (10 mg and 20 mg once daily) does not potentiate the increase in bleeding time caused by aspirin [see
`
`Clinical Pharmacology (12.3)].
`
`
`P-glycoprotein (e.g., digoxin)
`
`
`
`
`
`
`Coadministration of tadalafil (40 mg once daily) for 10 days did not significantly alter digoxin pharmacokinetics in
`
`
`
`
`healthy subjects [see Clinical Pharmacology (12.3)].
`
`
`8
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`
`Pregnancy
`8.1
`
`
`Pregnancy Category B
`
`
`Animal reproduction studies in rats and mice revealed no evidence of fetal harm . There are, however, no adequate
`
`
`
`and well-controlled studies of tadalafil in pregnant women. Because animal reproduction studies are not always predictive
`
`
`
`
`of human response, tadalafil should be used during pregnancy only if clearly needed.
`
`
`
`Non–teratogenic effects
`
`
`Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil
`
`
`was given to pregnant rats or mice at unbound tadalafil exposures up to 7 times the maximum recommended human dose
`
`
`
`
`
`(MRHD) of 40 mg/day during organogenesis. In one of two perinatal/postnatal developmental studies in rats, postnatal
`
`
`pup survival decreased following maternal exposure to unbound tadalafil concentrations greater than 5 times the MRHD
`
`
`
`
`
`
`
`based on AUC. Signs of maternal toxicity occurred at doses greater than 8 times the MRHD based on AUC. Surviving
`
`
`
`offspring had normal development and reproductive performance [see Nonclinical Toxicology (13.3)].
`
`
`8.3
`
`
`Nursing Mothers
`
`
`
`It is not known whether tadalafil is excreted into human milk. While tadalafil or some metabolite of tadalafil was
`
`
`
`
`excreted into rat milk, drug levels in animal breast milk may not accurately predict levels of drug in human breast milk.
`
`
`Because many drugs are excreted in human milk, caution should be exercised when ADCIRCA is administered to a
`
`
`nursing woman.
`
`
`8.4
`
`
`Pediatric Use
`
`
`
`
`
`
`Safety and effectiveness of ADCIRCA in pediatric patients have not been established.
`
`
`8.5
`
`
`Geriatric Use
`
`
`Of the total number of subjects in the clinical study of tadalafil for pulmonary arterial hypertension, 28 percent were
`
`
`
`65 and over, while 8 percent were 75 and over. No overall differences in safety were observed between subjects over 65
`
`
`
`
`
`years of age compared to younger subjects or those over 75 years of age. No dose adjustment is warranted based on age
`
`
`
`alone; however, a greater sensitivity to medications in some o