HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`REVATIO safely and effectively. See full prescribing information for
`REVATIO.
`
`REVATIO (sildenafil) tablets, for oral use
`REVATIO (sildenafil) for oral suspension
`REVATIO (sildenafil) injection, for intravenous use
`
`Initial U.S. Approval: 1998
`
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Indication and Use (1)
`08/2012
`
`
`
`
`
`Dosage and Administration (2.3)
`08/2012
`
`
`
`
`
`Contraindications (4)
`08/2012
`
`
`
`
`
`
`Warnings and Precautions (5)
`08/2012
`
`
`
`
`
`
`
`-----------------------------INDICATIONS AND USAGE--------------------------
`REVATIO is a phosphodiesterase-5 (PDE-5) inhibitor indicated for the
`
`treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in adults
`
`to improve exercise ability and delay clinical worsening. Studies establishing
`effectiveness were short-term (12 to 16 weeks), and included predominately
`
`
`patients with NYHA Functional Class II-III symptoms. Etiologies were
`idiopathic (71%) or associated with connective tissue disease (25%). (1)
`
`
`Limitation of Use: The efficacy of REVATIO has not been adequately
`evaluated in patients taking bosentan concurrently. (1)
`
`
`
`----------------------------DOSAGE AND ADMINISTRATION------------------
`
`Tablet and oral suspension: 20 mg three times a day, 4-6 hours apart (2.1)
`
`Injection: 10 mg (12.5 mL) three times a day administered as an intravenous
`bolus injection (2.2)
`
`
`----------------------------DOSAGE FORMS AND STRENGTHS---------------
`
` Tablets: 20 mg (3)
`
`
`Injection: 10 mg (12.5 mL) single use vial (3)
`
`
`
`
` For Oral Suspension: 10 mg/mL (3)
`
`
`
`
`
`------------------------------------CONTRAINDICATIONS-------------------------
`
` Use with organic nitrates (4)
`
` History of hypersensitivity reaction to sildenafil or any component of the
`
`tablet, injection, or oral suspension (4)
`
`
`-------------------------WARNINGS AND PRECAUTIONS----------------------
`
`Increased mortality with increasing doses in pediatric patients. Not
`
`recommended for use in pediatric patients. (5.1)
`
`
` Vasodilation effects may be more common in patients with hypotension or
`
`on antihypertensive therapy. (5.2)
`
` Use in pulmonary veno-occlusive disease may cause pulmonary edema
`
`
`and is not recommended. (5.3)
`
`
` Hearing or visual impairment: Seek medical attention if sudden decrease
`or loss of vision or hearing occurs. (5.5, 5.6)
`
`
` Pulmonary hypertension secondary to sickle cell disease: REVATIO may
`
`cause serious vaso-occlusive crises. (5.9)
`
`
`----------------------------------ADVERSE REACTIONS---------------------------
`Most common adverse reactions greater than or equal to 3% and more
`
`frequent than placebo were epistaxis, headache, dyspepsia, flushing, insomnia,
`
`erythema, dyspnea, and rhinitis. (6.1, 6.2)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at 1-
`
`800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`------------------------------------DRUG INTERACTIONS-------------------------
`
` Concomitant alpha-blockers or amlodipine: Note additive blood pressure
`lowering effects. (7)
`
` Use with ritonavir and other potent CYP3A inhibitors: Not recommended.
`(7, 12.3)
`
`
` Concomitant PDE-5 inhibitors: Avoid use with Viagra or other PDE-5
`
`inhibitors. (5.7)
`
`
`See 17 for PATIENT COUNSELING INFORMATION AND
`
`FDA-approved patient labeling
`
`
`
`
`Revised: August 2012
`
`
`
`
`
`
`________________________________________________________________________________________________________________________
`7 DRUG INTERACTIONS
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`8 USE IN SPECIFIC POPULATIONS
`
` Pregnancy
`8.1
`1
`INDICATIONS AND USAGE
`
`Labor and Delivery
`8.2
`2 DOSAGE AND ADMINISTRATION
`
`
`8.3
` Nursing Mothers
`REVATIO Tablets and Oral Suspension
`2.1
`
`8.4
` Pediatric Use
`REVATIO Injection
`2.2
`
`8.5
` Geriatric Use
`Reconstitution of the Powder for Oral Suspension
`2.3
`8.6
`Patients with Hepatic Impairment
`3 DOSAGE FORMS AND STRENGTHS
`8.7
`Patients with Renal Impairment
`4 CONTRAINDICATIONS
`10 OVERDOSAGE
`5 WARNINGS AND PRECAUTIONS
`
`Mortality with Pediatric Use
`5.1
`11 DESCRIPTION
`5.2
` Hypotension
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`5.3
`Worsening Pulmonary Vascular Occlusive Disease
`
`12.2
`Pharmacodynamics
`5.4
` Epistaxis
`12.3
`Pharmacokinetics
`5.5
` Visual Loss
`
`5.6
` Hearing Loss
`13 NONCLINICAL TOXICOLOGY
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`5.7
`Combination with other PDE-5 Inhibitors
`
`
` Priapism
`5.8
`14 CLINICAL STUDIES
`
`Vaso-occlusive Crisis in Patients with Pulmonary Hypertension
`5.9
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`Secondary to Sickle Cell Anemia
`17 PATIENT COUNSELING INFORMATION
`
`6 ADVERSE REACTIONS
`
`*Sections or subsections omitted from the Full Prescribing Information are not
`Clinical Trials Experience
`6.1
`
`listed.
`6.2
` Postmarketing Experience
`
`
`_________________________________________________________________________________________________________
`
`Reference ID: 3182925
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1137, p. 1 of 28
`
`

`

`INDICATIONS AND USAGE
`
`
`FULL PRESCRIBING INFORMATION
`
`
`1
`
`REVATIO is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in adults to improve
`
`exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when REVATIO
`
`
`
`
`was added to background epoprostenol therapy [see Clinical Studies (14)].
`
`
`
`
`Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New
`
`York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic etiology (71%) or associated with
`
`
`connective tissue disease (CTD) (25%).
`
`Limitation of Use
`
`The efficacy of REVATIO in the treatment of pulmonary arterial hypertension (PAH) has not been adequately
`
`evaluated in patients taking bosentan.
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`The recommended dose of REVATIO is 20 mg three times a day (TID). Administer REVATIO doses 4-6 hours
`
`
`
`
`
`apart.
`
`In the clinical trial no greater efficacy was achieved with the use of higher doses. Treatment with doses higher than
`
`
`
`20 mg TID is not recommended.
`
`
`
`2.1 REVATIO Tablets and Oral Suspension
`
`2.2 REVATIO Injection
`
`
`
`REVATIO injection is for the continued treatment of patients with PAH who are currently prescribed oral
`REVATIO and who are temporarily unable to take oral medication.
`
`
`
`The recommended dose is 10 mg (12.5 mL) administered as an intravenous bolus injection three times a day (TID).
`
`The dose of REVATIO injection does not need to be adjusted for body weight.
`
`A 10 mg dose of REVATIO injection is predicted to provide pharmacological effect of sildenafil and its
`
`N-desmethyl metabolite equivalent to that of a 20 mg oral dose.
`
`
`2.3 Reconstitution of the Powder for Oral Suspension
`
`
`
`
`1. Tap the bottle to release the powder.
`
`
`2. Remove the cap.
`
`3. Accurately measure out 60 mL of water and pour the water into the bottle. (Figure 1)
`
`
`Reference ID: 3182925
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1137, p. 2 of 28
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 1
`
`
`4. Replace the cap and shake the bottle vigorously for a minimum of 30 seconds. (Figure 2)
`
`
`Figure 2
`
`
`
`
`5. Remove the cap.
`
`6. Accurately measure out another 30 mL of water and add this to the bottle. You should always add a total of
`
`
`90 mL of water irrespective of the dose prescribed. (Figure 3)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 3
`
`
`7. Replace the cap and shake the bottle vigorously for a minimum of 30 seconds. (Figure 4)
`
`
`Reference ID: 3182925
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1137, p. 3 of 28
`
`

`

`Figure 4
`
`
`
`
`8. Remove the cap.
`
`
`
`9. Press the bottle adaptor into the neck of the bottle (as shown on Figure 5, below). The adaptor is provided
`
`so that you can fill the oral syringe with medicine from the bottle. Replace the cap on the bottle.
`
`
`Figure 5
`
`
`
`
`
`
`
`
`
`
`10. Write the expiration date of the constituted oral suspension on the bottle label (the expiration date of the
`
`
`
`
`constituted oral suspension is 30 days from the date of constitution).
`
`
`
`
`Incompatibilities
`Do not mix with any other medication or additional flavoring agent.
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`REVATIO Tablets
`REVATIO tablets are supplied as white, film-coated, round tablets engraved with “RVT20” containing sildenafil
`
`
`
`citrate equivalent to 20 mg of sildenafil.
`
`
`REVATIO Injection
`REVATIO injection is supplied as a single use vial containing 10 mg (12.5 mL) of sildenafil.
`
`
`
`REVATIO for Oral Suspension
`REVATIO for oral suspension is supplied in 125 mL bottles containing 32.27 g of a white to off-white powder.
`
`
`
`Following constitution with water, the volume of the oral suspension is 112 mL and each bottle contains 1.57 g of
`
`
`
`
`
`sildenafil citrate (1.12 g sildenafil). A 2 mL oral syringe and a press-in bottle adaptor are also provided.
`
`
`
`
`
`Reference ID: 3182925
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1137, p. 4 of 28
`
`

`

`
`
` 4 CONTRAINDICATIONS
`
`REVATIO is contraindicated in patients with:
`
`
`
`
` Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of
`
`
`
`hypotension [see Warnings and Precautions (5.2)].
`
`
`
`
` Known hypersensitivity to sildenafil or any component of the tablet, injection, or oral suspension.
`Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been
`reported in association with the use of sildenafil.
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Mortality with Pediatric Use
`
`
`
`In a long-term trial in pediatric patients with PAH, an increase in mortality with increasing REVATIO dose was
`
`observed. Deaths were first observed after about 1 year and causes of death were typical of patients with PAH. Use
`
`
`
`
`of REVATIO, particularly chronic use, is not recommended in children. [see Use in Specific Populations (8.4)].
`
`
`
`
`
`
`5.2 Hypotension
`
`
`REVATIO has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before
`
`prescribing REVATIO, carefully consider whether patients with certain underlying conditions could be adversely
`
`
`affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension [BP less
`
`than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood
`
`
`
`
`
`
`
`
`
`pressure when co-administering blood pressure lowering drugs with REVATIO.
`
`
`5.3 Worsening Pulmonary Vascular Occlusive Disease
`
`
`
`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 REVATIO to patients with veno­
`occlusive disease, administration of REVATIO to such patients is not recommended. Should signs of pulmonary
`
`
`
`
`edema occur when REVATIO is administered, consider the possibility of associated PVOD.
`
`
`
`5.4 Epistaxis
`
`
`The incidence of epistaxis was 13% in patients taking REVATIO with PAH secondary to CTD. This effect was not
`
`
`
`seen in idiopathic PAH (REVATIO 3%, placebo 2%) patients. The incidence of epistaxis was also higher in
`REVATIO-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with
`
`
`concomitant vitamin K antagonist).
`
`
`
`The safety of REVATIO is unknown in patients with bleeding disorders or active peptic ulceration.
`
`
`
`
`
`
`5.5 Visual Loss
`
`
`When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of
`
`
`decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with
`
`
`
`
`
`the use of phosphodiesterase type 5 (PDE-5) inhibitors, including sildenafil. Most, but not all, of these patients had
`
`
`underlying anatomic or vascular risk factors for developing 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. It is not possible to determine whether these events are related directly to the use of PDE-5 inhibitors, to
`
`
`the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other
`factors.
`
`
`Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while
`
`
`taking PDE-5 inhibitors, including REVATIO. Physicians should also discuss the increased risk of NAION with
`
`patients who have already experienced NAION in one eye, including whether such individuals could be adversely
`
`
`affected by use of vasodilators, such as PDE-5 inhibitors.
`
`There are no controlled clinical data on the safety or efficacy of REVATIO in patients with retinitis pigmentosa, a
`
`minority whom have genetic disorders of retinal phosphodiesterases. Prescribe REVATIO with caution in these
`patients.
`
`Reference ID: 3182925
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1137, p. 5 of 28
`
`

`

`
`
` 5.6 Hearing Loss
`
`
`Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been
`
`reported in temporal association with the use of PDE-5 inhibitors, including REVATIO. In some of the cases,
`
`
`
`
`medical conditions and other factors were reported that may have played a role. 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 REVATIO, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other
`factors.
`
`
`
`
`Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking
`PDE-5 inhibitors, including REVATIO.
`
`
`
`5.7 Combination with other PDE-5 inhibitors
`
`
`Sildenafil is also marketed as VIAGRA®. The safety and efficacy of combinations of REVATIO with VIAGRA or
`
`other PDE-5 inhibitors have not been studied. Inform patients taking REVATIO not to take VIAGRA or other PDE­
`5 inhibitors.
`
`
`5.8
`
`Priapism
`
`
`
`
`Use REVATIO with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal
`
`
`fibrosis, or Peyronie’s disease) or in patients who have conditions, which may predispose them to priapism (e.g.,
`sickle cell anemia, multiple myeloma, or leukemia). In the event of an erection that persists longer than 4 hours, the
`
`
`
`patient should seek immediate medical assistance. If priapism (painful erection greater than 6 hours in duration) is
`
`not treated immediately, penile tissue damage and permanent loss of potency could result.
`
`
`
`5.9 Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Anemia
`
`
`In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell
`
`
`disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received
`
`REVATIO than by those randomized to placebo. The effectiveness and safety of REVATIO in the treatment of PAH
`
`secondary to sickle cell anemia has not been established.
`
`6 ADVERSE REACTIONS
`
`The following serious adverse events are discussed elsewhere in the labeling:
`
`
`
`
` Mortality with pediatric use[see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)]
`
`
`
` Hypotension [see Warnings and Precautions (5.2)]
`
`
`
` Vision loss [see Warnings and Precautions (5.5)]
`
`
`
`
` Hearing loss [see Warnings and Precautions (5.6)]
`
`
`
`
` Priapism [see Warnings and Precautions (5.8)]
`
`
`
`
` Vaso-occlusive crisis [see Warnings and Precautions (5.9)]
`
`
`
`
`
`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.
`
`Safety data of REVATIO in adults were obtained from the 12-week, placebo-controlled clinical study (Study 1) and
`an open-label extension study in 277 REVATIO-treated patients with PAH, WHO Group I Diagnostic Classification
`
`
`
`[see Clinical Studies (14)].
`
`The overall frequency of discontinuation in REVATIO-treated patients 20 mg TID was 3% and was the same for the
`
`
`placebo group.
`
`In Study 1, the adverse reactions that were reported by at least 3% of REVATIO-treated patients (20 mg TID) and
`
`
`were more frequent in REVATIO-treated patients than in placebo-treated patients are shown in Table 1. Adverse
`
`reactions were generally transient and mild to moderate in nature.
`
`
`Reference ID: 3182925
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1137, p. 6 of 28
`
`

`

`
`
`
` Table 1. Most Common Adverse Reactions in Patients with PAH in Study 1 (More Frequent in REVATIO-
` Treated Patients than Placebo-Treated Patients and Incidence 3% in REVATIO-Treated Patients)
`
`
`REVATIO 20 mg TID, %
`Placebo-
`Placebo, %
`
`(n = 70)
`(n = 69)
`Subtracted, %
`1
`9
`8
`39
`46
`7
`7
`13
`6
`4
`10
`6
`1
`7
`6
`1
`6
`5
`3
`7
`4
`4
`0
`4
`
`3
`6
`9
`4
`7
`3
`3
`6
`3
`3
`0
`3
`
`3
`0
`3
`
`3
`0
`3
`
`Epistaxis
`Headache
`Dyspepsia
`Flushing
`
`Insomnia
`
`Erythema
`
`Dyspnea exacerbated
`
`Rhinitis
`
`Diarrhea
`Myalgia
`Pyrexia
`Gastritis
`
`Sinusitis
`Paresthesia
`
`At doses higher than the recommended 20 mg TID, there was a greater incidence of some adverse reactions
`
`
`including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and
`
`
`transient, and were predominately color-tinge to vision, but also increased sensitivity to light or blurred vision.
`
`
`
`
`
`The incidence of retinal hemorrhage with REVATIO 20 mg TID was 1.4% versus 0% placebo and for all REVATIO
`
`
`
`doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both 20 mg TID and at all doses
`
`studied was 1.4% for REVATIO versus 1.4% for placebo. The patients experiencing these reactions had risk factors
`
`
`for hemorrhage including concurrent anticoagulant therapy.
`
`
`In a placebo-controlled fixed dose titration study (Study 2) of REVATIO (starting with recommended dose of 20 mg
`
`TID and increased to 40 mg TID and then 80 mg TID) as an adjunct to intravenous epoprostenol in patients with
`
`
`PAH, the adverse reactions that were more frequent in the REVATIO + epoprostenol group than in the epoprostenol
`
`
`group (greater than 6% difference) are shown in Table 2 [see Clinical Studies (14)].
`
`
`Table 2. Adverse Reactions (%) in patients with PAH in Study 2 (incidence in REVATIO + Epoprostenol
`
`
`
`group at least 6% greater than Epoprostenol group)
`
`
`REVATIO +
`Epoprostenol
`
`(n = 134)
`57
`25
`16
`17
`25
`25
`9
`
`
`
`
`
`Epoprostenol
`
`(n = 131)
`
`(REVATIO +
`Epoprostenol)
`minus Epoprostenol
`
`
`23
`14
`14
`11
`7
`7
`7
`
`34
`13
`2
`6
`18
`18
`2
`
`Headache
`Edema^
`Dyspepsia
`Pain in extremity
`
`Diarrhea
`Nausea
`Nasal congestion
`^includes peripheral edema
`
`
`
`REVATIO Injection
`REVATIO injection was studied in a 66-patient, placebo-controlled study in patients with PAH at doses targeting
`
`plasma concentrations between 10 and 500 ng/mL (up to 8 times the exposure of the recommended dose). Adverse
`
`
`events with REVATIO injection were similar to those seen with oral tablets.
`
`
`Reference ID: 3182925
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1137, p. 7 of 28
`
`

`

`6.2
`
`Postmarketing Experience
`
`
`
`
`The following adverse reactions have been identified during post approval use of sildenafil (marketed for both PAH
`
`
`and erectile dysfunction). Because these reactions are reported voluntarily from a population of uncertain size, it is
`
`
`
`
`not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
`
`
`Cardiovascular Events
`In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious cardiovascular,
`
`cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia,
`
`
`cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and
`
`intracerebral hemorrhages have been reported in temporal association with the use of the drug. 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 sildenafil without sexual
`
`
`
`activity. Others were reported to have occurred hours to days after use concurrent with sexual activity. It is not
`
`possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient’s
`underlying cardiovascular disease, or to a combination of these or other factors.
`
`
`Nervous system
`Seizure, seizure recurrence
`
`
`7 DRUG INTERACTIONS
`
`Nitrates
`Concomitant use of REVATIO with nitrates in any form is contraindicated [see Contraindications (4)].
`
`
`
`Ritonavir and other Potent CYP3A Inhibitors
`
`Concomitant use of REVATIO with ritonavir and other potent CYP3A inhibitors is not recommended [see Clinical
`
`Pharmacology (12.3)].
`
`Other drugs that reduce blood pressure
`Alpha blockers. In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-blocker
`
`
`
`
`doxazosin (4 mg or 8 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH)
`
`
`
`stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine systolic and
`
`
`
`diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, were observed. Mean additional
`
`
`
`reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively, were also observed.
`
`There were infrequent reports of patients who experienced symptomatic postural hypotension. These reports
`included dizziness and light-headedness, but not syncope.
`
`Amlodipine. When sildenafil 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive
`
`
`
`
`
`
`patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.
`
`
`Monitor blood pressure when co-administering blood pressure lowering drugs with REVATIO [see Warnings and
`
`
`
`Precautions (5.2)].
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.2 Labor and Delivery
`
`The safety and efficacy of REVATIO during labor and delivery has not been studied.
`
`
`Reference ID: 3182925
`
`8.1
`
`Pregnancy
`
`
`
`Pregnancy Category B
`
`There are no adequate and well-controlled studies of sildenafil in pregnant women. No evidence of teratogenicity,
`
`
`
`
`embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during
`organogenesis, a level that is, on a mg/m2 basis, 32- and 68-times, respectively, the recommended human dose
`
`(RHD) of 20 mg TID. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was
`
`
`
`
`
`30 mg/kg/day (equivalent to 5-times the RHD on a mg/m2 basis). Because animal reproduction studies are not always
`
`
`
`predictive of human response, REVATIO should be used during pregnancy only if clearly needed.
`
`
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1137, p. 8 of 28
`
`

`

`8.3 Nursing Mothers
`
`
`
`It is not known if sildenafil or its metabolites are excreted in human breast milk. Because many drugs are excreted in
`
`human milk, caution should be exercised when REVATIO is administered to a nursing woman.
`
`
`8.4
`
`
`Pediatric Use
`
`
`
`In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients
`
`
`
`
`
`with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body
`
`weight, to three dose levels of REVATIO, or placebo, for 16 weeks of treatment. Most patients had mild to moderate
`
`
`
`
`
`symptoms at baseline: WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). One-third of patients had
`
`
`
`primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 36%; surgical repair in 30%). Sixty-
`two percent of patients were female. Drug or placebo was administered TID.
`
`
`The primary objective of the study was to assess the effect of REVATIO on exercise capacity as measured by
`
`
`cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115).
`
`
`Administration of REVATIO did not result in a statistically significant improvement in exercise capacity in those
`
`patients. No patients died during the 16-week controlled study.
`
`
`
`After completing the 16-week controlled study, a patient originally randomized to REVATIO remained on his/her
`
`dose of REVATIO or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose
`
`
`REVATIO. After all patients completed 16 weeks of follow-up in the controlled study, the blind was broken and
`
`doses were adjusted as clinically indicated. Patients were followed for a median of 4 years (range 0.3 years to 7.0
`
`
`
`years). Mortality during the long-term study, by originally assigned dose, is shown in Figure 6:
`
`
`
`Figure 6: Kaplan-Meier Plot of Mortality by REVATIO Dose
`
`
`
`
`An increase in mortality was observed with increasing REVATIO doses. The hazard ratio for high dose compared to
`
`
`low dose was 3.5, p=0.015. Causes of death were typical of patients with PAH. Use of REVATIO, particularly
`
`
`
`
`
`
`
`chronic use, is not recommended in children.
`
`
`
`
`
`
`
`8.5 Geriatric Use
`
`
`
`Clinical studies of REVATIO did not include sufficient numbers of subjects aged 65 and over to determine whether
`
`
`
`
`they respond differently from younger subjects. Other reported clinical experience has not identified differences in
`
`
`
`
`
`Reference ID: 3182925
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1137, p. 9 of 28
`
`

`

`
`
`
`
`responses between the elderly and younger patients. In general, dose selection for an elderly patient should be
`
`cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease
`or other drug therapy [see Clinical Pharmacology (12.3)].
`
`
`
`8.6
`
`Patients with Hepatic Impairment
`
`
`No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see
`
`
`Clinical Pharmacology (12.3)].
`
`
`
`8.7
`
`
`Patients with Renal Impairment
`
`
`
`
`No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [see Clinical Pharmacology
`
`
`(12.3)].
`
`
`10 OVERDOSAGE
`
`
`
`In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower
`
`doses but rates and severities were increased.
`
`
`
`In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to
`accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.
`
`
`11 DESCRIPTION
`
`
`REVATIO, phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective inhibitor of cyclic
`
`guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5). Sildenafil is also marketed as
`VIAGRA® for erectile dysfunction.
`
`
`Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d]
`pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula:
`
`
`
`
`
`
`C H 3CH 2O
`
`NH
`
`CH 3
`N
`
`N
`
`O
`
`N
`
`CH 2CH 2CH 3
`
`O 2S
`
`N
`
`N
`
`H O O C
`CH 3
`
`CO 2H
`O H
`CO 2H
`
`
`
`
`Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular
`
`
`
`
`weight of 666.7.
`
`
`
`REVATIO Tablets: REVATIO is formulated as white, film-coated round tablets with 20 mg of sildenafil for oral
`
`
`administration. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive
`ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium
`
`stearate, hypromellose, titanium dioxide, lactose monohydrate, and triacetin.
`
`REVATIO Injection: REVATIO is supplied as a clear, colorless, sterile, ready to use solution containing 10 mg (12.5
`
`
`mL) of sildenafil. Each mL of solution contains 1.124 mg sildenafil citrate, 50.5 mg dextrose and water for injection.
`
`
`REVATIO for Oral Suspension: REVATIO is supplied in an amber glass bottle as a white to off-white powder
`
`providing a white to off-white grape flavored oral suspension when constituted. Bottles containing 32.27 g powder
`
`
`for oral suspension are intended for constitution with 90 mL water to produce an oral suspension containing
`
`
`
`
`
`
`10 mg/mL sildenafil. In addition to the bottle, a press-in bottle adapter and an oral dosing syringe (2 mL) are
`
`
`
`provided. The inactive ingredients include sorbitol, citric acid anhydrous, sucralose, sodium citrate dihydrate,
`
`xanthan gum, titanium dioxide, sodium benzoate, colloidal silicon dioxide anhydrous and grape flavor.
`
`
`
`
`Reference ID: 3182925
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1137, p. 10 of 28
`
`

`

`
`12 CLINICAL PHARMACOLOGY
`
`
`
`12.1 Mechanism of Action
`
`
`
`
`Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary
`
`
`vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within
`
`
`
`
`pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation
`
`of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.
`
`
`
`
`
`
`Studies in vitro have shown that sildenafil is selective for PDE-5. Its effect is more potent on PDE-5 than on other
`
`
`known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3,
`
`PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3
`
`is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent
`for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the
`retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher
`doses or plasma levels [see Clinical Pharmacology (12.2)].
`
`
`
`
`In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues
`
`
`including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in these tissues by sildenafil
`
`
`
`may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild
`
`peripheral arterial-venous dilatation in vivo.
`
`
`12.2 Pharmacodynamics
`
`
`Effects of REVATIO on Blood Pressure
`
`
`
`Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood
`
`
`pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood
`
`
`
`pressure was most notable approximately 1-2 hours after dosing, and was not different from placebo at 8 hours.
`
`Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects
`
`
`are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients
`receiving concomitant nitrates [see Contraindications (4)].
`
`
`
`
`Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG.
`
`After chronic dosing of 80 mg TID to patients with PAH,