Sildenafil (Pharmascience) Product Monograph

RECENT MAJOR LABEL CHANGES

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TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ........................................................................................... 2

TABLE OF CONTENTS ............................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ..................................................................... 4

1 INDICATIONS .............................................................................................................. 4

1.1 Pediatrics ............................................................................................................... 4

1.2 Geriatrics ............................................................................................................... 4

2 CONTRAINDICATIONS ................................................................................................ 4

4 DOSAGE AND ADMINISTRATION ................................................................................ 5

4.1 Dosing Considerations ........................................................................................... 5

4.2 Recommended Dose and Dosage Adjustment ...................................................... 5

4.4 Administration ....................................................................................................... 6

5 OVERDOSAGE ............................................................................................................. 6

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................ 7

7 WARNINGS AND PRECAUTIONS ................................................................................. 8

7.1 Special Populations .............................................................................................. 11

7.1.3 Pediatrics ......................................................................................................................... 11

7.1.4 Geriatrics ............................................................................................................. 11

8 ADVERSE REACTIONS ............................................................................................... 12

8.1 Adverse Reaction Overview ................................................................................. 12

8.2 Clinical Trial Adverse Reactions ........................................................................... 12

8.3 Less Common Clinical Trial Adverse Reactions .................................................... 13

8.5 Post-Market Adverse Reactions .......................................................................... 16

9 DRUG INTERACTIONS ............................................................................................... 17

9.1 Serious Drug Interactions .................................................................................... 17

9.2 Drug Interactions Overview ................................................................................. 17

9.4 Drug Drug Interactions ........................................................................................ 17

9.5 Drug-Food Interactions ........................................................................................ 24

9.6 Drug-Herb Interactions ........................................................................................ 24

9.7 Drug-Laboratory Test Interactions ....................................................................... 24

10 CLINICAL PHARMACOLOGY ...................................................................................... 24

10.1 Mechanism of Action ........................................................................................... 24

10.2 Pharmacodynamics ............................................................................................. 25

10.3 Pharmacokinetics ................................................................................................ 26

11 STORAGE, STABILITY AND DISPOSAL ........................................................................ 27

12 SPECIAL HANDLING INSTRUCTIONS .......................................................................... 27

PART II: SCIENTIFIC INFORMATION ...................................................................................... 28

13 PHARMACEUTICAL INFORMATION ........................................................................... 28

14 CLINICAL TRIALS ....................................................................................................... 29

14.1 Trial Design and Study Demographics ................................................................. 29

14.2 Study Results ....................................................................................................... 29

14.3 Comparative Bioavailability Studies..................................................................... 32

15 MICROBIOLOGY ....................................................................................................... 32

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 33

17 SUPPORTING PRODUCT MONOGRAPHS ................................................................... 49

PATIENT MEDICATION INFORMATION ................................................................................. 50

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

SILDENAFIL (sildenafil) is indicated for:

• the treatment of erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance.

1.1 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics: Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness.

2 CONTRAINDICATIONS

• Sildenafil has been shown to potentiate the hypotensive effects of nitrates in healthy volunteers and in patients, and is therefore contraindicated in patients who are taking any type of nitrate drug therapy, or who utilize short-acting nitrate-containing medications, due to the risk of developing potentially life-threatening hypotension. The use of organic nitrates, either regularly and/or intermittently, in any form (e.g. oral, sublingual, transdermal, by inhalation) is absolutely contraindicated (see 10 CLINICAL PHARMACOLOGY, 4 DOSAGE AND ADMINISTRATION).
• After patients have taken SILDENAFIL, it is unknown when nitrates, if necessary, can be safely administered. Plasma levels of sildenafil at 24 hours post-dose are much lower (2 ng/mL) than at peak concentration (440 ng/mL). In the following patients: age > 65, hepatic impairment (e.g. cirrhosis), severe renal impairment (e.g. CL_cr < 30 mL/min), and concomitant use of potent cytochrome P-450 3A4 inhibitors (erythromycin), plasma levels of sildenafil at 24 hours post-dose have been found to be 3 to 8 times higher than those seen in healthy volunteers. 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 coadministered at this time point.
• Treatments for erectile dysfunction should not be generally used in men for whom sexual activity is inadvisable (see also 7 WARNINGS AND PRECAUTIONS).
• SILDENAFIL is contraindicated in patients with a known hypersensitivity to any component of the tablet (see 13 PHARMACEUTICAL INFORMATION).
• SILDENAFIL is contraindicated in patients with erectile dysfunction with previous episode of non-arteritic anterior ischaemic optic neuropathy (NAION) (see 7 WARNINGS AND PRECAUTIONS).
• The co-administration of PDE5 inhibitors, including SILDENAFIL, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may lead to potentially life- threatening episodes of symptomatic hypotension or syncope.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

The following factors are associated with increased plasma levels (AUC) of sildenafil:

• age 65 years or over (40%)
• hepatic impairment (e.g. cirrhosis: 84%)
• severe renal impairment (e.g. creatinine clearance < 30 mL/min: 100%)
• concomitant use of potent cytochrome P-450 3A4 inhibitors (e.g. erythromycin: 182%; saquinavir: 210%; ritonavir: 1000%). It can also be expected that more potent cytochrome P-450 3A4 inhibitors such as ketoconazole and itraconazole would result in increased levels of sildenafil.

(see 4.2 Recommended Dose and Dose Adjustment, 10 CLINICAL PHARMACOLOGY, 7 WARNINGS AND PRECAUTIONS).

Sildenafil has been shown to potentiate the hypotensive effects of nitrates in healthy volunteers and in patients, and is therefore contraindicated in patients who are taking any type of nitrate drug therapy, or who utilize short-acting nitrate-containing medications, due to the risk of developing potentially life-threatening hypotension. The use of organic nitrates, either regularly and/or intermittently, in any form (e.g. oral, sublingual, transdermal, by inhalation) is absolutely contraindicated (see 10 CLINICAL PHARMACOLOGY, 2 CONTRAINDICATIONS).

4.2 Recommended Dose and Dosage Adjustment

For most patients, the recommended dose of SILDENAFIL is 50 mg taken as needed. The maximum recommended dose is 100 mg. Dosage may be decreased to 25 mg if necessary.

Since higher plasma levels may increase both efficacy and the incidence of adverse events, a starting dose of 25 mg should be considered in patients, age 65 years or over, on concomitant CYP3A4 inhibitors, with severe renal impairment, with hepatic impairment and on ritonavir (see 4.1 Dosing Considerations above, 10 CLINICAL PHARMACOLOGY, 7 WARNINGS AND PRECAUTIONS).

The concomitant use of the potent cytochrome P-450 3A4 inhibitor, ritonavir is associated with a 1000% (11-fold) increase in plasma levels (AUC) of sildenafil. Given the extent of the interaction with patients receiving concomitant therapy with ritonavir, it is recommended not to exceed a maximum single dose of 25 mg of sildenafil in a 48-hour period (see 7 WARNINGS AND PRECAUTIONS).

4.4 Administration

To be taken as needed approximately 30 – 60 minutes before sexual activity. However, SILDENAFIL may be taken anywhere from 0.5 hour to 4 hours before sexual activity. The maximum recommended dosing frequency is once per day.

SILDENAFIL tablets should be swallowed whole with water.

5 OVERDOSAGE

In studies with healthy volunteers of single doses of up to 800 mg, adverse events 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 not eliminated in the urine.

Treatment of Priapism

Patients should be instructed to report any erections persisting for more than 4 hours to a health professional. The treatment of priapism/prolonged erection should be according to established medical practice. Health professionals may refer to two suggested protocols for detumescence presented below.

Detumescence Protocols

1. 1) Aspirate 40 to 60 mL blood from either left or right corpora using vacutainer and holder for drawing blood. Patient will often detumesce while aspirating. Apply ice for 20 minutes post aspiration if erection remains.

If procedure 1) is unsuccessful, then try procedure 2).

1. 2)

   Put patient in supine position. Dilute 10 mg phenylephrine into 20 mL distilled water for injection (0.05%). With an insulin syringe, inject 0.1 to 0.2 mL (50-100 µg) into the corpora every 2 to 5 minutes, until the detumescence occurs. The occasional patient may experience transient bradycardia and hypertension when given phenylephrine injections, therefore monitor patient’s blood pressure and pulse every 10 minutes. Patients at risk include those with cardiac arrhythmias and diabetes. Refer to the prescribing information for phenylephrine before use. Do not give phenylephrine to patients on MAO inhibitors. When phenylephrine is used within the first 12 hours of erection, the majority of patients

   1. will respond.

If procedure 2) is unsuccessful, then try procedure 3).

1. 3) If the above measures fail to detumesce the patient, a urologist should be consulted as soon as possible, especially if the erection has been present for many hours. If priapism is not treated immediately, penile tissue damage and/or permanent loss of potency may result.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1– Dosage Forms, Strengths, Composition and Packaging

Description

25 mg: Each blue, diamond-shaped, biconvex, coated tablet, debossed with “SD” and “25" on one side and plain on the other side, contains the equivalent of 25 mg of sildenafil (as sildenafil citrate). Available in HDPE bottles of 30 tablets, and blister packs of 4 and 6 tablets.

50 mg: Each blue, diamond-shaped, biconvex, coated tablet, debossed with “SD” and “50" on one side and plain on the other side, contains the equivalent of 50 mg of sildenafil (as sildenafil citrate). Available in blister packs of 4 and 6 tablets.

100 mg: Each blue, diamond-shaped, biconvex, coated tablet, debossed with “SD” and “100" on one side and plain on the other side, contains the equivalent of 100 mg of sildenafil (as sildenafil citrate). Available in blister packs of 4 and 6 tablets.

7 WARNINGS AND PRECAUTIONS

General

The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assessment.

Cardiovascular

As with all treatments for erectile dysfunction, there is a potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease, including hypertension (BP>140/90).

Therefore, treatments for erectile dysfunction, including SILDENAFIL, should not be generally administered in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.

There are no controlled clinical data on the safety or efficacy of SILDENAFIL in the following groups, if prescribed, this should be done with caution.

• Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months
• Patients with resting hypotension (BP < 90/50 at rest) or hypertension (BP > 170/110 at rest)
• Patients with cardiac failure or coronary artery disease causing unstable angina

(see 10 CLINICAL PHARMACOLOGY)

Caution is advised when sildenafil is administered to patients taking an alpha-blocker, as the coadministration may lead to symptomatic hypotension in a few susceptible individuals (see 9 DRUG INTERACTIONS). In order to minimize the potential for developing postural hypotension, patients should be hemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Initiation of sildenafil at lower doses should be considered. In addition, health professionals should advise patients what to do in the event of postural hypotensive symptoms.

Driving and Operating Machinery

As dizziness and altered vision were reported in clinical trials with sildenafil, patients should be aware of how they react to SILDENAFIL, before driving or operating machinery. The effect of sildenafil on the ability to drive and use machinery has not been studied.

Ear/Nose/Throat

Sudden decrease or loss of hearing has been reported in a few number of postmarketing and clinical trial cases with the use of PDE5 inhibitors, including sildenafil. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including sildenafil. 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 events are related directly to the use of PDE5 inhibitors or to other factors (see 8 ADVERSE REACTIONS, 8.5 Post-Market Adverse Reactions and PATIENT MEDICATION INFORMATION). Health professionals should advise patients to stop taking SILDENAFIL and seek prompt medical attention in case of sudden decrease or loss of hearing.

Hematologic

In clinical trials, sildenafil has been shown to have systemic vasodilatory properties that result in transient decreases in blood pressure. This is of little or no consequence in most patients. However, prior to prescribing sildenafil, health professionals should carefully consider whether their patients with certain underlying conditions could be adversely affected by such vasodilatory effects, especially in combination with sexual activity. Patients with increased susceptibility to vasodilators include those with left ventricular outflow obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy), or those with the rare syndrome of multiple system atrophy manifesting as severely impaired autonomic control of blood pressure.

In humans, sildenafil has no effect on bleeding time when taken alone or with acetylsalicylic acid. In vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor). The combination of heparin and sildenafil had an additive effect on bleeding time in the anesthetized rabbit, but this interaction has not been studied in humans (see 10 CLINICAL PHARMACOLOGY).

There is no safety information on the administration of sildenafil to patients with bleeding disorders or active peptic ulceration. Therefore, SILDENAFIL should be administered with caution to these patients.

Hepatic/Biliary/Pancreatic

In volunteers with hepatic cirrhosis (Child-Pugh A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C_max (47%) compared to age-matched volunteers with no hepatic impairment.

A starting dose of 25 mg should be considered in patients with hepatic impairment (see 10 CLINICAL PHARMACOLOGY, 4 DOSAGE AND ADMINISTRATION).

Ophthalmologic

Patients should stop taking PDE5 inhibitors, including SILDENAFIL, and consult their health professional immediately if they experience a decrease in, or sudden loss of, vision in one or both eyes. Postmarketing reports of sudden loss of vision have occurred rarely, in temporal association with the use of PDE5 inhibitors. 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.

Individuals who have already experienced NAION are at increased risk of NAION recurrence. PDE 5 inhibitors, including SILDENAFIL, are not recommended in patients with male erectile dysfunction with a previous episode of NAION (see 2 CONTRAINDICATIONS).

There are no controlled clinical data on the safety or efficacy of sildenafil in patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases). If prescribed, this should be done with caution. (see 10 CLINICAL PHARMACOLOGY).

A small percentage of patients experience visual effects (e.g. impairment of colour discrimination, increased perception to light, blurred vision, eye pain, ocular redness) after taking sildenafil. If this happens, then the patient should not operate a motor vehicle or any heavy machinery until the adverse effects disappear (see 10 CLINICAL PHARMACOLOGY).

Rare cases of central serous chorioretinopathy have been reported during the post- marketing period in temporal association with the use of sildenafil citrate. It is not known if medical and other facts were reported that may have also played a role in the development of the condition. It is not possible to determine whether the development of the condition was related directly to the use of sildenafil, to the patient’s possible underlying risk factors, a combination of these factors, or to other factors. These cases of central serous chorioretinopathy in patients receiving sildenafil did not provide evidence of serious or permanent alteration in visual function. (See 8.5 Post-Market Adverse Reactions).

Renal

In volunteers with mild (CL_cr = 50-80 mL/min) and moderate (CL_cr = 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CL_cr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in increases in AUC (100%) and C_max (88%) compared to age-matched volunteers with no renal impairment.

A starting dose of 25 mg should be considered in patients with severe renal impairment (see 10 CLINICAL PHARMACOLOGY, 4 DOSAGE AND ADMINISTRATION).

Reproductive Health: Female and Male Potential Function

Although priapism had not been reported during clinical trials, prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently during the post-marketing surveillance of sildenafil. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result (see 8 ADVERSE REACTIONS).

Agents for the treatment of erectile dysfunction should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease) or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma or leukemia).

The safety and efficacy of combinations of sildenafil with other PDE5 inhibitors, or other pulmonary arterial hypertension (PAH) treatments containing sildenafil, or other agents for the treatment of erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

Skin

Rare cases of Stevens-Johnson’s Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported during the post-marketing period.

7.1 Special Populations

Women, Nursing Mothers, Pregnancy: SILDENAFIL is not indicated for use in women. There are no adequate and well-controlled studies in pregnant or lactating women.

7.1.3 Pediatrics

SILDENAFIL is not indicated for use in children.

7.1.4 Geriatrics

(> 65 years of age): Healthy elderly volunteers had a reduced clearance of sildenafil, with free plasma concentrations approximately 40% greater than those seen in younger volunteers (18 to 45 years). Since higher plasma levels may increase both the pharmacological action and incidence of some adverse events, a starting dose of 25 mg should be considered (see 10 CLINICAL PHARMACOLOGY, 4 DOSAGE AND ADMINISTRATION).

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

During clinical trials, the most commonly observed adverse events associated with the use of sildenafil (incidence of 5% or greater) and observed at a rate on sildenafil at least three times that of placebo were headache (15.8%), flushing (10.5%) and dyspepsia (6.5%).

There have been rare post-marketing reports of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) and very rare reports of priapism.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Sildenafil was administered to over 3700 patients (aged 19-87 years) during clinical trials worldwide. Over 550 patients were treated for longer than one year.

In placebo-controlled clinical studies, the discontinuation rate due to adverse events for sildenafil (2.5%) was not significantly different from placebo (2.3%). The adverse events were generally transient and mild to moderate in nature.

In trials of all designs, adverse events reported by patients receiving sildenafil were generally similar. In fixed-dose studies, the incidence of some adverse events increased with dose. The nature of the adverse events in flexible-dose studies, which more closely reflect the recommended dosage regimen, was similar to that for fixed-dose studies.

When sildenafil was taken as recommended (on an as-needed basis) in flexible-dose, placebo- controlled clinical trials, the following adverse events were reported:

Table 2. Adverse Events Reported by ≥2% of Patients Treated with Sildenafil or Placebo in PRN Flexible-Dose Phase II/III Studies

* Abnormal Vision: Mild and transient changes, predominantly impairment of colour discrimination (blue/green), but also increased perception to light or blurred vision.

At doses above the recommended dose range, adverse events were similar to those detailed above but generally were reported more frequently.

8.3 Less Common Clinical Trial Adverse Reactions

The following events occurred in <2% of patients in in phase II/III controlled clinical trials where a causal relationship is uncertain:

Autonomic: sweating, dry mouth;

Cardiovascular: abnormal electrocardiogram, angina pectoris, arrhythmia, AV block, cardiac arrest, cardiomyopathy, heart failure, hypertension, hypotension, palpitation, postural hypotension, myocardial ischemia, syncope, tachycardia, varicose vein, vascular anomaly;

Central & Peripheral Nervous System: tremor, abnormal dreams, anxiety, agitation, ataxia, depression, insomnia, nervousness, somnolence, paresthesia, vertigo, speech disorder, reflexes decreased, hyperesthesia, neuropathy, migraine, myasthenia, oculogyric crisis, neuralgia, hypertonia;

Gastrointestinal: vomiting, gastritis, gastrointestinal disorder, flatulence, increased appetite, gastroenteritis, stomatitis, eructation, dysphagia, colitis, glossitis, constipation, rectal hemorrhage, mouth ulceration, esophagitis, rectal disorder, gingivitis, tooth disorder;

Hematopoietic: anemia and leukopenia;

Liver/Biliary: liver function tests abnormal, ALT increased;

Metabolic/Nutritional: edema, thirst, gout, hyperuricemia, hypoglycemic reaction, unstable diabetes, hyperglycemia, hyperlipidemia, hypernatremia;

Musculoskeletal: myalgia, bone disorder, arthrosis, arthritis, tendon rupture, tenosynovitis, bone pain, joint disorder, synovitis;

Respiratory: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, respiratory disorder, carcinoma of lung, sputum increased, cough increased;

Skin/Appendages: skin carcinoma, skin disorder, skin hypertrophy, skin ulcer, contact dermatitis, exfoliative dermatitis, pruritus, urticaria, photosensitivity reaction, nail disorder, acne, herpes simplex, furunculosis;

Special Senses: Sudden decrease or loss of hearing, mydriasis, conjunctivitis, photophobia, eye pain, tinnitus, ear pain, lacrimation disorder, eye disorder, eye hemorrhage, ear disorder, cataract, dry eyes;

Urogenital: penile erection, other sexual dysfunction, cystitis, nocturia, balanitis, urinary frequency, breast enlargement, prostatic disorder, testis disorder, urinary incontinence, urinary tract disorder, urine abnormality, abnormal ejaculation, genital edema and anorgasmia;

Vascular Disorders: cerebrovascular disorder, cerebral thrombosis;

General: face edema, peripheral edema, chills, allergic reaction, asthenia, pain, infection, shock, hernia, accidental fall, abdominal pain, chest pain, accidental injury, intentional overdose.

Myocardial Infarction and Cardiovascular Mortality

In an analysis of double blind placebo controlled clinical trials encompassing over 700 person- years of observation on placebo and over 1300 person-years on sildenafil, there were no differences in the incidence rate of myocardial infarction (MI) or in the rate of cardiovascular mortality for patients receiving sildenafil compared to those receiving placebo. The rates of MI were 1.1 per 100 person-years for men receiving sildenafil and for those receiving placebo.

The rates of cardiovascular mortality were 0.3 per 100 person-years for men receiving sildenafil and those receiving placebo.

Clinical Trial Adverse Drug Reactions Reported in 74 Double-Blind Placebo-Controlled Phase II/III/IV Studies

When sildenafil was taken as recommended in 74 randomized double-blind, placebo-controlled (DBPC) Phase II/III/IV studies, adverse reactions reported by ≥2% of patients treated with sildenafil (n=9,570) and more frequently than placebo (n=7,237) were headache, flushing, dyspepsia, nasal congestion and dizziness. The nature and frequency of adverse reactions reported by ≥2% of patients in this pooled dataset of 74 DBPC studies was consistent with the adverse reactions reported in the 6 flexible-dose studies detailed above in Table 2.

The following adverse reactions occurred in <2% of patients in the 74 DBPC clinical trials.

8.5 Post-Market Adverse Reactions

Reports of adverse events temporally associated with sildenafil during post-marketing surveillance that are not listed above and for which the causal relationship is unknown, include the following:

Cardiovascular:

Epistaxis; serious cardiovascular events - including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, and transient ischemic attack - have been reported. Most of these patients had pre-existing 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 the use of sildenafil 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, to combination of these factors, or to other factors (see 7 WARNINGS AND PRECAUTIONS).

Central & Peripheral Nervous System: seizure, seizure recurrence, transient global amnesia; Gastrointestinal: vomiting;

Urogenital: prolonged erection, priapism (see 7 WARNINGS AND PRECAUTIONS) and hematuria;

Skin / Appendages: Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

Special Senses: diplopia, temporary vision loss/decreased vision, blurred vision, Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION), retinal vein occlusion, visual field defect, eye pain, ocular redness or bloodshot appearance, ocular burning, ocular swelling/pressure, increased intraocular pressure, retinal vascular disease of bleeding, vitreous detachment/traction and paramacular edema.

Cases of sudden decrease or loss of hearing have been reported post-marketing in temporal association with the use of PDE5 inhibitors, including sildenafil. 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 events are related directly to the use of sildenafil , to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors (see 7 WARNINGS AND PRECAUTIONS, 8 ADVERSE REACTIONS and PATIENT MEDICATION INFORMATION).

Rare cases of central serous chorioretinopathy have been reported during the post-marketing period in temporal association with the use of sildenafil citrate. It is not known if medical and other facts were reported that may have also played a role in the development of the condition. It is not possible to determine whether the development of the condition was related directly to the use of sildenafil, to the patient’s possible underlying risk factors, a combination of these factors, or to other factors. These cases of central serous chorioretinopathy in patients receiving sildenafil did not provide evidence of serious or permanent alteration in visual function. (See 7 WARNINGS AND PRECAUTIONS).

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

9.2 Drug Interactions Overview

In vitro studies:

Sildenafil metabolism is principally mediated by the cytochrome P-450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route) (see 10 CLINICAL PHARMACOLOGY).

Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.

Sildenafil is a weak inhibitor of the cytochrome P-450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC₅₀>150 mcM). Given sildenafil peak plasma concentrations of approximately 1 mcM after recommended doses, it is unlikely that SILDENAFIL will alter the clearance of the substrates of these isoenzymes.

In vivo studies:

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.

9.4 Drug Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e. those identified as contraindicated).

Table 3 – Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Effects of Other Drugs on Sildenafil

Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, angiotensin converting enzyme (ACE) inhibitors, and calcium channel blockers. The AUC of the active metabolite, N-desmethyl sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence.

In healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC, C_max, T_max, elimination rate constant, or subsequent half-life of sildenafil or its principle circulating metabolite.

9.5 Drug-Food Interactions

Grapefruit juice being a weak inhibitor of CYP3A4 gut wall metabolism may give rise to modest increases in plasma levels of sildenafil.

SILDENAFIL can be taken with or without food. However, when SILDENAFIL is taken with a high-fat meal, the rate of absorption is reduced with a mean delay in T_max of 60 minutes and a mean reduction in C_max of 29%. AUC is decreased by 11%. The patient may find that it takes longer to work if taken with a high-fat meal (see 10 CLINICAL PHARMACOLOGY).

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Sildenafil is a cGMP-specific phosphodiesterase type 5 (PDE5) inhibitor, used for the treatment of male erectile dysfunction.

The physiological mechanism responsible for erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum in response to sexual stimulation. Nitric oxide 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 has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of NO by inhibiting PDE5, which is responsible for the biodegradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil produces increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and increased inflow of blood to the corpus cavernosum. Sildenafil, at recommended doses, has no effect in the absence of sexual stimulation.

Studies in vitro have shown that sildenafil has between 10 and 10,000-fold greater selectivity for PDE5 than for other phosphodiesterase isoforms namely PDEs 1, 2, 3, 4, and 6 and greater than 700-fold effect on PDE7-PDE11. In particular, sildenafil has greater than 4,000-fold selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility. Sildenafil is about 10-fold as potent for PDE5 compared to PDE6, an isoenzyme found in the retina; this lower selectivity is thought to be the basis for colour vision abnormalities observed with higher doses or plasma levels of sildenafil (see 7 WARNINGS AND PRECAUTIONS).

PDE5 is also found in lower concentrations in platelets, vascular and visceral smooth muscles, and skeletal muscle. The sildenafil-induced inhibition of PDE5 in these tissues appears to be the basis for the enhanced platelet antiaggregatory activity of nitric oxide observed in vitro, and inhibition of platelet thrombus formation in vivo, and peripheral arterial-venous dilation in vivo (see 7 WARNINGS AND PRECAUTIONS).

10.2 Pharmacodynamics

Effects of Sildenafil on Blood Pressure (BP):

Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease of 8.3/5.3 mm Hg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing. The effects are not related to dose or plasma levels. Larger effects were recorded among patients receiving concomitant nitrates (see 2 CONTRAINDICATIONS).

Effects of Sildenafil on Cardiac Parameters:

Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG.

Effects of Sildenafil on Erectile Response:

Sildenafil was studied in clinical trials of various designs. In fixed-dose clinical trials, 62%, 74%, and 82% of patients on 25 mg, 50 mg and 100 mg of sildenafil, respectively, reported an improvement in their erections, compared to 25% on placebo (p <0.0001, see 14 CLINICAL TRIALS).

In eight double-blind, placebo-controlled, cross-over studies using RigiScan® (a device used to objectively measure penile rigidity and duration of erections), erections during sexual stimulation improved significantly on sildenafil compared to placebo. These studies included patients with organic etiologies (such as spinal cord injury and diabetes mellitus), and patients without an established organic cause. Most studies assessed the efficacy of sildenafil approximately 60 minutes post-dose.

All eight studies investigating the effects of sildenafil on penile plethysmography (RigiScan®) after visual sexual stimulation (VSS) under laboratory conditions, consistently showed that doses of up to 100 mg resulted in statistically significant improvements in duration of erections of 60% rigidity (considered hard enough for penetrative sexual intercourse), compared with placebo. In patients who respond, the median time to onset of erections (60% rigidity) in response to VSS, was 25 minutes after an oral dose of 50 mg sildenafil. The mean total duration of erections 60% rigidity at the base of the penis was 3, 24 and 32 minutes for subjects receiving placebo, 25 mg and 50 mg doses, respectively, when exposed to VSS for 2 hours.

SILDENAFIL increases couples’ ability to have sexual intercourse (see 14 CLINICAL TRIALS).

10.3 Pharmacokinetics

Absorption:

Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute bioavailability is 41% (range 25%-63%). The oral pharmacokinetics of sildenafil is proportional over the recommended dose range studied (25 mg to 100 mg).

Sildenafil inhibits the human PDE5 enzyme in vitro by 50% at a concentration of 3.5 nM. In man, the mean maximum free plasma concentration of sildenafil following a single oral dose of 100 mg is approximately 18 ng/mL, or 38 nM.

When sildenafil was administered with a high-fat meal, the rate of absorption was significantly decreased, with a 29% reduction in C_max and a 60-minute delay in T_max. The patient may find that it takes longer to work if taken with a high-fat meal. However, although it was statistically significant (AUC decreased by 11%), the decrease in the extent of absorption was not clinically relevant. The relative bioavailability fed/fasted was 89% (90% CI; 84-94%) (see 9 DRUG INTERACTIONS).

Distribution:

The mean steady state volume of distribution (V_ss) for sildenafil is 105 litres, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.

Based upon measurements of sildenafil in the semen of healthy volunteers, less than 0.001% of the ingested dose may appear in the semen of patients 90 minutes after drug intake.

Metabolism:

Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N- demethylation of sildenafil at the N-methyl piperazine moiety. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency against PDE5 approximately 50% that of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil. The N-desmethyl metabolite is further metabolised, with a terminal half-life of approximately 4 hours.

Elimination:

The total body clearance of sildenafil is 41 L/h with a resultant terminal phase half-life of 3-5 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered dose) and to a lesser extent in the urine (approximately 13% of the administered dose).

Special Populations and Conditions

• Geriatrics: Healthy elderly subjects (65 years or older) had a reduced clearance of sildenafil, resulting in approximately 90 % higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40 %.

• Hepatic Insufficiency: In volunteers with hepatic cirrhosis (Child-Pugh A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and C_max (47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

  Since sildenafil clearance is reduced in geriatric patients (65 years or older), patients with renal impairment or patients with hepatic impairment, a starting dose of 25 mg should be considered. Based on efficacy and toleration, the dose may be increased to 50 mg or 100 mg (see 7 WARNINGS AND PRECAUTIONS, 4 DOSAGE AND ADMINISTRATION).

• Renal Insufficiency: In volunteers with mild (CL_cr = 50-80 mL/min) and moderate (CL_cr = 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of SILDENAFIL (50 mg) were not altered. In volunteers with severe (CL_cr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in increases in AUC (100%) and C_max (88%) compared to age-matched volunteers with no renal impairment.
• In addition, N-desmethyl metabolite AUC and C_max values were significantly increased by 200 % and 79 % respectively in subjects with severe renal impairment compared to subjects with normal renal function.

11 STORAGE, STABILITY AND DISPOSAL

Store at controlled room temperature (15°C – 30°C).

12 SPECIAL HANDLING INSTRUCTIONS

Not Applicable.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: sildenafil citrate

Chemical name: Piperazine,1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4-methyl-,2-hydroxy-1,2,3-propanetricarboxylate

Molecular formula: C₂₂H₃₀N₆O₄S·C₆H₈O₇

molecular mass: 666.71 g/mol

Structural formula:

Physicochemical

properties: Sildenafil citrate is a white to off-white crystalline powder.

14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

Study demographics and trial design

Sildenafil was evaluated at doses including 25 mg, 50 mg and 100 mg in 21 randomized, double-blind, placebo-controlled trials of up to 6 months duration. In these studies, sildenafil was administered to more than 3000 patients aged 19 to 87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years.

This patient population included men with the following concomitant conditions: angina, benign prostatic hyperplasia (BPH), depression, type I and type II diabetes mellitus, hypertension, previous myocardial infarction, radical prostatectomy, spinal cord injury, transurethral resection of the prostate (TURP), and vasculogenic disease.

Efficacy was demonstrated in all 21 studies and results were consistent regardless of baseline severity, etiology and age. Efficacy was maintained over the long-term (1 year). Sildenafil was effective in a broad range of ED patients, including those with a history of coronary artery disease (myocardial infarction, angina), hypertension, other cardiac disease (arrhythmias, congestive heart failure), peripheral vascular disease, diabetes mellitus, depression, coronary artery bypass graft (CABG), radical prostatectomy and TURP, and in patients taking antidepressants, antihypertensives, antipsychotics, and diuretics.

14.2 Study Results

Sildenafil was studied in clinical trials of various designs. In fixed-dose clinical trials, 62%, 74%, and 82% of patients on 25 mg, 50 mg and 100 mg of sildenafil, respectively, reported an improvement in their erections, compared to 25% on placebo (see Figure 1).

Figure 1 - Percentage of Patients reporting an Improvement in Erections

The primary efficacy endpoints were the ability to both achieve and maintain an erection sufficient for sexual intercourse, as measured by patient responses to the International Index of Erectile Function (IIEF), a sexual function questionnaire. The results from the partner questionnaire corroborated the data from the study subjects, with analyses showing clear treatment related improvements in the ability to achieve and maintain erections.

Responses to the IIEF are scored on a five-point scale ranging from ‘almost never/never’ (1) to ‘almost always/always’ (5), with a score of (0) assigned for no attempts at sexual intercourse. During IIEF validation, scores for the primary efficacy endpoints for men without erectile dysfunction were 4.38 and 4.34, respectively. Compared to baseline treatment over 12 weeks, sildenafil patients reported the following statistically significant changes (see Figure 2).

Figure 2 - Effect of Sildenafil on Ability to Achieve and Maintain an Erection Sufficient for Sexual Intercourse

Men with untreated ED have lower scores (Figure 3, Bar 1) for all sexual function domains of the IIEF (erection, orgasm, desire, overall satisfaction, intercourse satisfaction). In these men, sildenafil restores the values of the domains (Figure 3, Bar 2) towards the values of age matched controls without ED (Figure 3, Bar 3).

Figure 3 - Effect of Sildenafil on Male Sexual Function Domains of the IIEF

Sildenafil increases couples’ ability to have sexual intercourse. With sildenafil, 64%, 67% and 72% of attempts resulted in successful sexual intercourse on doses of 25 mg, 50 mg, and 100 mg, respectively, compared to 23% on placebo. Of sildenafil patients with one or more successful attempt at intercourse, 81% of attempts were successful.

The efficacy of sildenafil was maintained over time. In a long-term, open-label trial of 12-month duration, 88% (256/292) of patients reported that sildenafil treatment improved their erections. Eighty-seven percent (87%) of patients completed the one-year study. When these patients were followed for an additional year (total exposure of 24-months), oral sildenafil was an effective, well tolerated treatment for erectile dysfunction of organic, pyschogenic or mixed aetiology.

In a controlled clinical study which reflects the recommended dosage regimen, 74% of patients were taking sildenafil 100 mg after 12 weeks of treatment, compared to 23% and 3% taking sildenafil 50 mg and 25 mg, respectively.

Other Patient Populations:

Across all trials, sildenafil improved the erections of 59% of diabetic patients, and 43% of radical prostatectomy patients (versus 16% and 15% on placebo, respectively). This was assessed using the GAQ.

In a study of patients with spinal cord injury, sildenafil improved the ability to have sexual intercourse in 80% of patients versus 10% on placebo.

Subgroup analyses of responses to a global improvement question in patients with psychogenic etiology in two fixed-dose studies and two titrations studies showed 84% of sildenafil patients reported improvement in erections compared with 26% of placebo patients.

These studies confirm that sildenafil enhances the erectile response to sexual stimulation in subjects with erectile dysfunction (ED) of psychogenic and broad-spectrum etiology, including patients with diabetes mellitus and with spinal cord injury.

Use with Other Concomitant Therapies:

Antihypertensives

A large (n=568) randomized, double-blind, placebo-controlled, parallel group, multicenter, flexible-dose study (sildenafil up to 100 mg) in males with erectile dysfunction and arterial hypertension taking 2 or more antihypertensive agents was conducted (the majority of these were diuretics, beta blockers, ACE inhibitors and calcium channel blockers). Fifty-eight percent of the patients were taking 2 antihypertensive agents and 42% were taking 3 or more antihypertensive agents composed of similar groups of drugs for blood pressure control.

Sildenafil improved the erections in 71% of men compared to 18% in the placebo group, and 62% of attempts at sexual intercourse were successful with sildenafil compared to 26% on placebo. The incidence rate of all adverse events, including those possibly related to hypotensive episodes, was consistent with observations in other patient populations. Also, there was no evidence of an increased incidence rate of any adverse event in the subgroups taking 2 antihypertensive agents and 3 or more antihypertensive agents. There was no indication of additional safety risk of sildenafil use in this subject population (see 7 WARNINGS AND PRECAUTIONS).

14.3 Comparative Bioavailability Studies

A blind, randomized, two-way, single dose, crossover bioequivalence study of SILDENAFIL 100 mg tablets (Pharmascience Inc.) and VIAGRA® 100 mg tablets (Pfizer Canada Inc.) was conducted in 26 healthy male subjects under fasting conditions. The pharmacokinetic data calculated for the SILDENAFIL 100 mg tablets and VIAGRA® 100 mg tablets formulations are tabulated below:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ SILDENAFIL (sildenafil citrate) tablets, 100 mg (Pharmascience Inc.)

² VIAGRA® (sildenafil citrate) tablets, 100 mg (Pfizer Canada Inc.) Canada.

³ Expressed as the median (range) only

⁴ Expressed as the arithmetic mean (CV %) only

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

Long-Term Toxicity - Mice:

Long-Term Toxicity - Rats:

Long-Term Toxicity - Dogs:

Carcinogenesis and Mutagenesis:

Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in systemic drug exposure (AUC) of 110- and 146-times, respectively, for male (unbound sildenafil and its major metabolite) and female (unbound sildenafil) rats. The exposures observed in humans given the Recommended Human Dose (RHD) of 20 mg t.i.d. sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 1.1 times the RHD on a mg/m² basis.

Sildenafil has been studied in a comprehensive battery of tests designed to detect genotoxic activity. Sildenafil did not display mutagenic activity in bacterial or mammalian cells in vitro, or clastogenic activity in vitro or in vivo.

As the clinical dose is administered three times daily, the clinical free AUC used to calculate exposure multiples was 19 ng-h/mx³, and compared with the AUC 0-24 hours in the preclinical species.

Reproductive and Developmental Toxicology:

No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 32 and 68 times the RHD 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. In the non-pregnant rat the AUC at this dose was about 24 times unbound human AUC.

Rabbits:

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. VIAGRA® Tablets, 25 mg, 50 mg and 100 mg, Orodispersible Films, 50 mg, submission control 274068, Product Monograph, BGP Pharma ULC. DEC 27, 2023.