Sildenafil

1. INDICATION S AND USAGE SILDENAFIL ORAL FILM is indicated for the treatment of erectile dysfunction. SILDENAFIL ORAL FILM is a phosphodiesterase-5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction (ED). ( 1 )

2. DOSAGE AND ADMINISTRATION Dosage For most patients, the recommended dosage is 50 mg orally, taken as needed, approximately 1 hour before sexual activity. However, SILDENAFIL ORAL FILM may be taken anywhere from 30 minutes to 4 hours before sexual activity. ( 2.1 ) Based on effectiveness and toleration, may increase to a maximum of 100 mg or decrease to 25 mg. ( 2.1 ) Maximum recommended dosing frequency is once per day. ( 2.1 ) Dosage Modifications for Drug Interactions: Refer to the full prescribing information for recommended dosage. ( 2.2 ) Recommended Dosage in Specific Populations: Refer to the full prescribing information for recommended dosage. ( 2.3 ) Administration Administer with or without food. Place oral film directly onto the tongue where it will disintegrate and can then be swallowed with saliva without the need for water or other liquids. Do not cut or chew SILDENAFIL ORAL FILM. 2.1 Recommended Dosage For most patients, the recommended dosage is 50 mg orally administered on the tongue, taken as needed, approximately 1 hour before sexual activity. However, SILDENAFIL ORAL FILM may be taken anywhere from 30 minutes to 4 hours before sexual activity. The maximum recommended dosing frequency is once per day. Based on effectiveness and tolerability the dosage may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg, not to exceed once per day. For administration instructions, see Dosage and Administration ( 2.4 ) . 2.2 Dosage Modifications for Drug Interactions Nitrates Concomitant use of nitrates in any form is contraindicated [ see Contraindications ( 4.1 ), Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.2 ) ]. Alpha Blockers Initiate SILDENAFIL ORAL FILM at 25 mg orally in patients on concomitant therapy with an alpha-blocker. Patients should be stable on alpha-blocker therapy prior to initiating SILDENAFIL ORAL FILM [see Warnings and Precautions ( 5.5 ), Drug Interactions ( 7.2 ), and Clinical Pharmacology ( 12.2 ) ] . For administration instructions, see Dosage and Administration ( 2.4 ) . Ritonavir The maximum recommended dose and dosing frequency is 25 mg orally taken once within a 48-hour period in ritonavir-treated patients. Concomitant administration of ritonavir increased the blood levels of sildenafil by 11-fold [ see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7.4 ), and Clinical Pharmacology ( 12.3 ) ] . For administration instructions, see Dosage and Administration ( 2.4 ) . Other CYP3A4 Inhibitors The recommended starting dosage is 25 mg orally, in patients taking strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or saquinavir) or erythromycin. Clinical data have shown that co-administration with saquinavir or erythromycin increased blood levels of sildenafil by about 3-fold [see Drug Interactions ( 7.4 ) and Clinical Pharmacology ( 12.3 ) ] . For administration instructions, see Dosage and Administration ( 2.4 ) . 2.3 Recommended Dosage in Specific Populations Age G reater than 6 5 years The recommended starting dosage is 25 mg orally in patients greater than 65 years of age [see Use in Specific Populations ( 8.5 ) ]. For administration instructions, see Dosage and Administration ( 2.4 ) . Renal Impairment The recommended starting dosage is 25 mg orally, in patients with severe renal impairment (creatinine clearance less than 30 mL/minute). The recommended starting dosage is 50 mg, in patients with mild (creatinine clearance 50 to 80 mL/min) and moderate (creatinine clearance 30 to 49 mL/min) renal impairment [see Use in Specific Populations( 8.6 ) and Clinical Pharmacology ( 12.3 ) ]. For administration instructions, see Dosage and Administration ( 2.4 ) . Hepatic Impairment The recommended starting dosage is 25 mg orally in patients with any degree of hepatic impairment. In volunteers with mild and moderate degrees of hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in higher plasma exposure of sildena …

3. DOSAGE FORMS AND STRENGTHS Oral Film: 25 mg sildenafil, opaque light blue, thin, flexible oral film imprinted with identification code S 25 50 mg sildenafil, opaque light blue, thin, flexible oral film imprinted with identification code S 50 75 mg sildenafil, opaque light blue, thin, flexible oral film imprinted with identification code S 75 100 mg sildenafil, opaque light blue, thin, flexible oral film imprinted with identification code S 100 Oral film: 25 mg, 50 mg, 75 mg, 100 mg of sildenafil ( 3 )

4. CONTRAINDICATIONS Administration of SILDENAFIL ORAL FILM to patients using nitric oxide donors, such as organic nitrates or organic nitrites in any form. SILDENAFIL ORAL FILM was shown to potentiate the hypotensive effect of nitrates. ( 4.1 , 7.1 , 12.2 ) Known hypersensitivity to sildenafil or any component of oral film. ( 4.2 ) Administration with guanylate cyclase (GC) stimulators, such as riociguat. ( 4.3 ) 4.1 Nitrates Consistent with its known effects on the nitric oxide/cGMP pathway [see Clinical Pharmacology ( 12.1 , 12.2 ) ] , SILDENAFIL ORAL FILM potentiates the hypotensive effects of nitrates, and its administration to patients who are using nitric oxide donors such as organic nitrates or organic nitrites in any form either regularly and/or intermittently is therefore contraindicated. After patients have taken SILDENAFIL ORAL FILM it is unknown when nitrates, if necessary, can be safely administered. Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [see Dosage and Administration ( 2.2 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.2 ) ]. 4.2 Hypersensitivity Reactions SILDENAFIL ORAL FILM is contraindicated in patients with a known hypersensitivity to sildenafil or any SILDENAFIL ORAL FILM component. Hypersensitivity reactions, including rash and urticaria, have been reported [see Adverse Reactions ( 6.1 )]. 4.3 Concomitant Guanylate Cyclase (GC) Stimulators Do not use SILDENAFIL ORAL FILM in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including SILDENAFIL ORAL FILM, may potentiate the hypotensive effects of GC stimulators.

6. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Cardiovascular [see Warnings and Precautions ( 5.1 )] Prolonged Erection and Priapism [see Warnings and Precautions ( 5.2 )] Effects on the Eye [see Warnings and Precautions ( 5.3 )] Hearing Loss [see Warnings and Precautions ( 5.4 )] Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives [see Warnings and Precautions ( 5.5 ) ] Adverse Reactions with the Concomitant Use of Ritonavir [see Warnings and Precautions 5.6 )] Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies [see Warnings and Precautions ( 5.7 ) ] Effects on Bleeding [see Warnings and Precautions ( 5.8 )] The most common adverse reactions reported in clinical trials (≥ 2%) of sildenafil are headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness, and rash. Most common adverse reactions (≥ 2%) include headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact YARAL Pharma Inc at 1-866-218-9009 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 clinical practice. Sildenafil was administered to over 3700 patients (aged 19-87 years) during pre-marketing clinical trials worldwide. Over 550 patients were treated for longer than one year. In placebo-controlled clinical studies, the discontinuation rate due to adverse reactions for sildenafil (2.5%) was not significantly different from placebo (2.3%). In fixed-dose studies, the incidence of some adverse reactions increased with dose. The type of adverse events in flexible-dose studies was similar to that for fixed dose studies. At doses above the recommended dose range, adverse reactions were similar to those detailed in Table 1 but generally were reported more frequently. Table 1: Adverse Reactions Reported by ≥2% of Patients Treated with Sildenafil and More Frequent than Placebo in Fixed-Dose Clinical Studies Adverse Reaction 25 mg (n=312) 50 mg (n=511) 100 mg (n=506) Placebo (n=607) Headache 16% 21% % 28 % 7 Flushing 10% 19% 18% 2% Dyspepsia 3% 9% 17% 2% Abnormal vision† 1% 2% 11% 1% Nasal congestion 4% 4% 9% 2% Back pain 3% 4% 4% 2% Myalgia 2% 2% 4% 1% Nausea 2% 3% 3% 1% Dizziness 3% 4% 3% 2% Rash 1% 2% 3% 1% †Abnormal Vision: Mild to moderate in severity and transient, predominantly color tinge to vision, but also increased sensitivity to light, or blurred vision. When sildenafil was taken as recommended (on an as-needed basis) in flexible-dose, placebo-controlled clinical trials of two to twenty-six weeks duration, patients took sildenafil at least once weekly, and the following adverse reactions were reported: Table 2 : Adverse Reactions Reported by ≥2% of Patients Treated with Sildenafil and More Frequent than Placebo in Flexible-Dose Clinical Studies Adverse Reaction Sildenafil N=734 Placebo N=725 Headache 16% 4% Flushing 10% 1% Dyspepsia 7% 2% Nasal Congestion 4% 2% Abnormal Vision† 3% 0% Back pain 2% 2% Dizziness 2% 1% Rash 2% 1% †Abnormal Vision: Mild to moderate in severity and transient, predominantly color tinge to vision, but also increased sensitivity to light or blurred vision. In these studies, only one patient discontinued due to abnormal vision. When SILDENAFIL ORAL FILM was taken as recommended (on an as-needed basis) in a flexible-dose, placebo-controlled clinical trial of twelve weeks duration, patients took SILDENAFIL ORAL FILM at least once weekly, not more than once per day, and the following adverse reactions were reported: Table 3: Adverse Reactions Reported by ≥2% of Patients Treated with SILDENAFIL ORAL FILM and More …

7. DRUG INTERACTIONS SILDENAFIL ORAL FILM can potentiate the hypotensive effects of nitrates, alpha blockers, and antihypertensives. ( 4.1 , 5.5 , 7.1 , 7.2 , 7.3 , 12.2 ) With concomitant use of alpha blockers, initiate SILDENAFIL ORAL FILM at 25 mg dose. ( 2.2 ) CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, erythromycin) increase SILDENAFIL ORAL FILM exposure. ( 2.2 , 7.4 , 12.3 ) Ritonavir: Do not exceed a maximum single dose of 25 mg in a 48- hour period. ( 2.2 , 5.6 ) Erythromycin or strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, saquinavir): Consider a starting dose of 25 mg. ( 2.2 , 7.4 ) 7.1 Nitrates Administration of sildenafil with nitric oxide donors such as organic nitrates or organic nitrites in any form is contraindicated. Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates [see Dosage and Administration ( 2.2 ), Contraindications ( 4.1 ), Clinical Pharmacology ( 12.2 ) ] . 7.2 Alpha-blockers Use caution when co-administering alpha-blockers with sildenafil because of potential additive blood pressure lowering effects. When sildenafil is co-administered with an alpha-blocker, patients should be stable on alpha blocker therapy prior to initiating sildenafil treatment and sildenafil should be initiated at the lowest dose [see Dosage and Administration ( 2.2 ),Warnings and Precautions ( 5.5 ), Clinical Pharmacology ( 12.2 ) ]. 7.3 Amlodipine When sildenafil 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic [see Warnings and Precautions ( 5.5 ), Clinical Pharmacology ( 12.2 ) ]. 7.4 Ritonavir and other CYP3A4 inhibitors Co-administration of ritonavir, a strong CYP3A4 inhibitor, greatly increased the systemic exposure of sildenafil (11-fold increase in AUC). It is therefore recommended not to exceed a maximum single dose of 25 mg of sildenafil in a 48 hour period [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.6 ), Clinical Pharmacology ( 12.3 ) ]. Co-administration of erythromycin, a moderate CYP3A4 inhibitor, resulted in 160% and 182% increases in sildenafil Cmax and AUC, respectively. Co-administration of saquinavir, a strong CYP3A4 inhibitor, resulted in 140% and 210% increases in sildenafil Cmax and AUC, respectively. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole could be expected to have greater effects than seen with saquinavir. A starting dose of 25 mg of sildenafil should be considered in patients taking erythromycin or strong CYP3A4 inhibitors (such as saquinavir, ketoconazole, itraconazole) [see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 ) ]. 7.5 Alcohol In a drug-drug interaction study of sildenafil 50 mg given with alcohol 0.5 g/kg, in which mean maximum blood alcohol levels of 0.08% was achieved, sildenafil did not potentiate the hypotensive effect of alcohol in healthy volunteers [see Clinical Pharmacology ( 12.2 ) ] .

8. USE IN SPECIFIC POPULATIONS Geriatric use: Recommended starting dose is 25 mg. ( 2.3 , 8.5 ) Severe renal impairment: Recommended starting dose is 25 mg. ( 2.3 , 8.6 ) Hepatic impairment: Recommended starting dose is 25 mg. ( 2.3 , 8.7 ) 8.1 Pregnancy Risk Summary SILDENAFIL ORAL FILM is not indicated for use in females. There are no data with the use of SILDENAFIL ORAL FILM in pregnant women to inform any drug-associated risks for adverse developmental outcomes. Animal reproduction studies conducted with sildenafil did not show adverse developmental outcomes when administered during organogenesis in rats and rabbits at oral doses up to 16 and 32 times, respectively, the maximum recommended human dose (MRHD) of 100 mg/day on a mg/m2 basis ( see Data ). Data Animal Data No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received oral doses up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 16 and 32 times the MRHD on a mg/m2 basis in a 50 kg subject. In the rat pre- and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days, about 2 times the MRHD on a mg/m2 basis in a 50 kg subject. 8.2 Lactation Risk Summary SILDENAFIL ORAL FILM is not indicated for use in females. Limited data indicate that sildenafil and its active metabolite are present in human milk. There is no information on the effects on the breastfed child, or the effects on milk production. 8.4 Pediatric Use SILDENAFIL ORAL FILM is not indicated for use in pediatric patients. Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy young volunteers (18-45 years) [see Clinical Pharmacology ( 12.3 ) ] . Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively [see Clinical Pharmacology ( 12.3 ) ]. Of the total number of subjects in clinical studies of sildenafil, 18% were 65 years and older, while 2% were 75 years and older. No overall differences in safety or efficacy were observed between older (≥ 65 years of age) and younger adult (< 65 years of age) subjects. Of the total number of subjects in the clinical study of SILDENAFIL ORAL FILM, 31% were 65 years and older. No overall differences in safety or efficacy were observed between older (≥ 65 years of age) and younger (< 65 years of age) subjects. A starting dose of SILDENAFIL ORAL FILM 25 mg is recommended in patients 65 years of age and older due to the higher systemic exposure in older subjects, and larger decreases in blood pressure observed in older subjects in a clinical pharmacology study [see Dosage and Administration ( 2.3 ) , Warning s and Precautions ( 5.1 ), Clinical Pharmacology ( 12.2 ] . 8.6 Renal Impairment No dose adjustment is required for mild (CLcr=50-80 mL/min) and moderate (CLcr=30-49 mL/min) renal impairment. In volunteers with severe renal impairment (Clcr<30 mL/min), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (~2 fold), approximately doubling of Cmax and AUC. A starting dose of 25 mg should be considered in patients with severe renal impairment [see Dosage and Administration ( 2.3 ) , Clinical Pharmacology ( 12.3 ) ] . 8.7 Hepatic Impairment In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (47% for Cmax and 85% for AUC). The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied. A starting dose of 25 mg should be considered in patients with any …

12.1 Mechanism of Action The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation. Binding Characteristics Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3. PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision [see Clinical Pharmacology ( 12.2 ) ]. In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo .

11 DESCRIPTION SILDENAFIL ORAL FILM (sildenafil) oral film is for treatment of erectile dysfunction and contains sildenafil citrate, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). 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, has the molecular formula C 22 H 39 N 6 O 4 S ‧ C 6 H 8 O 7 , and the following structural formula: 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. SILDENAFIL ORAL FILM is formulated as an opaque light blue, thin, flexible oral film with the characteristic lemon and grapefruit scent. The product is available in four different strengths 25, 50, 75, or 100 mg of sildenafil equivalent to 35, 70, 105, 140 mg sildenafil citrate respectively for oral administration. In addition to the active ingredient, sildenafil citrate, each oral film contains the following inactive ingredients: Blue Videojet ink, FD&C Blue No.2, glycerin, grapefruit flavor, lemon flavor, maltodextrin, polysorbate 20, polyvinyl acetate dispersion, propylene glycol monocaprylate, sucralose, titanium dioxide. SILDENAFIL ORAL FILM contains no ingredient made from a gluten-containing grain (wheat, barley, or rye). 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, has the molecular formu

10 OVERDOSAGE In studies in healthy volunteers administered single sildenafil doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but incidence 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.

16 HOW SUPPLIED/STORAGE AND HANDLING SILDENAFIL ORAL FILM is supplied as oral films in individually sealed foil pouches in four dosage strengths. Each carton contains 4 or 8 pouches. The product is an opaque light blue, thin, flexible oral film with film imprint code, and characteristic lemon and grapefruit flavor with the following dimensions: Strengths (mg ) of sildenafil Film Imprint Code Film Dimensions ( shape ) NDC for Carton of 4 Pouches NDC for Carton of 8 Pouches 25 mg S25 30 mm x 15 mm (rectangular) 82347-0205-5 82347-0205-6 50 mg S50 30 mm x 30 mm (square) 82347-0210-5 82347-0210-6 75 mg S75 30 mm x 45 mm (rectangular) 82347-0215-5 82347-0215-6 100 mg S100 45 mm x 40 mm (rectangular) 82347-0220-5 82347-0220-6 Recommended Storage: Store at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].