Teva-Sildenafil R Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

TEVA-SILDENAFIL R (sildenafil citrate) is indicated for:

• treatment of primary pulmonary arterial hypertension (PPH) or pulmonary hypertension secondary to connective tissue disease (CTD) in adult patients with WHO functional class II or III who have not responded to conventional therapy.

Pediatrics (< 18 years of age)

TEVA-SILDENAFIL R is not indicated for use in children less than 18 years of age (see WARNINGS AND PRECAUTIONS, Pediatrics and ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Pediatric Clinical Trial Safety Data).

CONTRAINDICATIONS

• Sildenafil citrate 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 ACTION AND CLINICAL PHARMACOLOGY, DOSAGE AND ADMINISTRATION).

• TEVA-SILDENAFIL R is contraindicated in patients who are hypersensitive to this drug

  • listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
• TEVA-SILDENAFIL R is contraindicated in patients with previous episode of non-arteritic anterior ischaemic optic neuropathy (NAION) (see WARNINGS AND PRECAUTIONS).

TEVA-SILDENAFIL R is contraindicated in combination with the most potent of the CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir).

• Vaso-occlusive crises in patients with sickle cell anaemia

  Sildenafil should not be used in patients with pulmonary hypertension secondary to sickle cell anaemia. In a clinical study events of vaso-occlusive crises requiring hospitalisation were reported more commonly by patients receiving sildenafil than those receiving placebo leading to the premature termination of this study.

• The safety of sildenafil has not been studied in the following sub-groups of patients and its use is therefore contraindicated:

  • Severe hepatic impairment
  • Recent history of stroke or myocardial infarction, or life-threatening arrhythmia
  • Patients with coronary artery disease causing unstable angina;
  • Severe hypotension (blood pressure < 90/50 mmHg) at initiation.
  • The co-administration of PDE5 inhibitors, including TEVA-SILDENAFIL R, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may lead to potentially life-threatening episodes of symptomatic hypotension or syncope.

WARNINGS AND PRECAUTIONS

General

TEVA-SILDENAFIL R (sildenafil citrate) is not recommended in the following cases:

• Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease. Since there are no clinical data on administration of sildenafil citrate to patients with venous occlusive disease, administration of TEVA-

  • SILDENAFIL R to such patients is not recommended.
• The efficacy of sildenafil in patients already on bosentan therapy has not been conclusively demonstrated (6-minute walk distance (6MWD)). No benefit of sildenafil coadministered with bosentan was demonstrated over bosentan alone. The results of the 6MWD were different between primary PAH (PPH) and PAH associated with CTD. In PAH associated with CTD patients, on average, there was a reduction of 6MWD in sildenafil-bosentan group as compared to bosentan alone (-18.32m vs. 17.50m). The concomitant administration of sildenafil and bosentan is not an optimal choice in PPH patients stable on bosentan therapy and the use of sildenafil with bosentan is not recommended in patients with PAH associated with CTD (see DRUG INTERACTIONS, Drug-Drug Interactions and DETAILED PHARMACOLOGY, Human, Pharmacodynamic Studies).

Before prescribing TEVA-SILDENAFIL R (sildenafil citrate), it is important to note the following:

• In clinical trials, sildenafil has been shown to have systemic vasodilatory properties that result in transient decreases in blood pressure (see ACTION AND CLINICAL PHARMACOLOGY). Prior to prescribing TEVA-SILDENAFIL R, physicians should carefully consider whether their patients with certain underlying conditions could be adversely affected by such vasodilatory effects, for example patients with resting hypotension (BP <90/50), or with fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction.

• Sildenafil citrate is also marketed as VIAGRA for male erectile dysfunction.

  When used to treat male erectile dysfunction, non-arteritic anterior ischaemic optic neuropathy (NAION) has been reported rarely post-marketing in temporal association with the use of all phosphodiesterase type-5 inhibitors. NAION, a rare condition, can result in varying degrees of permanent loss of vision, for which there is no treatment. Most, but not all of these patients had underlying risk factors for the development of NAION, including but not necessarily limited to: low cup to optic disc ratio (the “crowded disc at risk”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidaemia and smoking. An observational study evaluated whether recent, episodic use of PDE5 inhibitors (as a class), typical of erectile dysfunction treatment, was associated with acute onset of NAION. The results suggest an approximately 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 males aged ≥ 50 per year in the general population. In case of sudden visual loss, patients should be advised to stop taking sildenafil and consult a physician immediately.

  Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore physicians should discuss this risk with these patients and whether they could be adversely affected by use of PDE5 inhibitors. PDE5 inhibitors, including sildenafil should be used with caution in these patients and only when the anticipated benefits outweigh the risks.

• There is evidence that patients at risk for NAION may have abnormal optic discs (e.g. crowded disc) prior to development of the condition. If physicians are concerned about the overall risk of NAION, they should consider discussing these concerns with an ophthalmologist. Physicians should advise patients to stop use of TEVA-SILDENAFIL R and seek medical attention in the event of a sudden loss of vision in one or both eyes.

  Administration of TEVA-SILDENAFIL R (a PDE5 inhibitor) to patients with previously diagnosed NAION is contraindicated (see CONTRAINDICATIONS).

• There are no controlled clinical data on the safety or efficacy of sildenafil citrate in patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases) (see ACTION AND CLINICAL PHARMACOLOGY). If prescribed, this should be done with caution.
• Rare cases of central serous chorioretinopathy have been reported post-marketing 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 possibly underlying risk factors, a combination of these factors, or to other factors (see POST-MARKET ADVERSE DRUG REACTIONS).
• Alpha-blockers: Caution is advised when Phosphodiesterase Type 5 (PDE5) inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including sildenafil, and alpha-adrenergic blocking agents are both vasodilators with blood pressure lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly, leading to symptomatic hypotension. In the sildenafil interaction studies with alpha-blockers (see DRUG INTERACTIONS), cases of symptomatic hypotension consisting of dizziness and lightheadedness were reported. In order to minimize the potential for developing postural hypotension, patients should be hemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Physicians should advise patients what to do in the event of postural hypotensive symptoms. No cases of syncope or fainting were reported during these interaction studies. Consideration should be given to the fact that safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and concomitant use of anti-hypertensive drugs.

• TEVA-SILDENAFIL R 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).

  Prolonged erections and priapism have been reported with sildenafil in post-marketing experience. 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 ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).

• In humans, sildenafil has no effect on bleeding time when taken alone or with acetylsalicyclic acid. In vitro studies with human platelets indicate that sildenafil potentiates the anti-aggregatory 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 DRUG INTERACTIONS, ACTION AND CLINICAL PHARMACOLOGY, DETAILED PHARMACOLOGY).
• The incidence of epistaxis was higher in patients with PAH secondary to CTD (sildenafil 12.9%, placebo 0%) than in PPH patients (sildenafil 2.3%, placebo 2.4%). Incidence was also higher in sildenafil-treated patients with concomitant oral Vitamin K antagonist (8.8% versus 1.7% not treated with concomitant Vitamin K antagonist).
• There is no safety information on the administration of sildenafil citrate to patients with bleeding disorders or active peptic ulceration. Therefore, TEVA-SILDENAFIL R should be administered with caution to these patients.
• The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitor products, including VIAGRA, has not been studied in PAH patients and such concomitant use is not recommended (see DRUG INTERACTIONS, Serious Drug Interactions).

Cardiovascular

There is no controlled clinical data on the safety or efficacy of sildenafil citrate in the following groups, if prescribed, this should be done with caution:

• Patients with hypertension (BP >170/110);

Cardiovascular risk factors

In post-marketing experience with sildenafil for male erectile dysfunction, serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have been reported in temporal association with the use of sildenafil. Most, but not all, of these patients had pre-existing cardiovascular risk factors. Many events were reported to occur during or shortly after sexual intercourse and a few were reported to occur shortly after the use of sildenafil without sexual activity. It is not possible to determine whether these events are related directly to these factors or to other factors (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).

Otologic

Sudden decrease or loss of hearing has been reported in a few numbers of postmarketing cases with the use of PDE5 inhibitors, including TEVA-SILDENAFIL R. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including sildenafil citrate. 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 POST-MARKET ADVERSE DRUG REACTIONS). Physicians should advise patients to seek prompt medical attention in case of sudden decrease or loss of hearing.

Skin / Appendages

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

Special Populations

Pregnant Women: No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits, which received up to 200 mg/kg/day during organogenesis. There are no data from the use of sildenafil in pregnant women. Studies in animals have shown toxicity with respect to postnatal development (see TOXICOLOGY).

Due to lack of data, TEVA-SILDENAFIL R should not be used in pregnant women unless strictly necessary.

Nursing Women: There are no adequate and well-controlled studies in lactating women. Limited data indicate that sildenafil and its active metabolite are excreted into breast milk at very low levels. Prescribers should carefully assess the mother’s clinical need for TEVA-SILDENAFIL R and any potential adverse effects on the breastfed child.

Fertility:

Non-clinical data revealed no special hazard for humans based on conventional studies of fertility.

Pediatrics (< 18 years old): TEVA-SILDENAFIL R is not indicated for use in children less than 18 years of age.

In a long-term trial in pediatric patients with PAH, an increase in mortality with increasing sildenafil dose was observed. Deaths were first observed after about 1 year of treatment, and causes of death were typical of patients with PAH (See INDICATIONS AND CLINICAL USE and ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Pediatric Clinical Trial Safety Data).

Geriatrics (≥ 65 years): Healthy elderly volunteers had a reduced clearance of sildenafil, but studies did not include sufficient numbers of subjects to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger pulmonary arterial hypertension 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 and DOSAGE AND ADMINISTRATION).

Combination Sildenafil Citrate + Epoprostenol: (see ADVERSE REACTIONS and Drug- Drug Interactions)

Information for Patients

Physicians should discuss with patients the contraindication of TEVA-SILDENAFIL R with regular and/or intermittent use of organic nitrates.

Physicians should advise patients to stop use of TEVA-SILDENAFIL R and seek immediate medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors when used in the treatment of male erectile dysfunction. Should the vision loss be diagnosed as NAION, continued use of TEVA-SILDENAFIL R is not recommended (see WARNINGS AND PRECAUTIONS, General).

Effects on ability to drive and use machines:

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

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Sildenafil Oral Administration:

Safety data on sildenafil citrate were obtained from a single pivotal study, consisting of 68 (25%) men and 209 (75%) women, and an open-label extension study in 277 treated patients with pulmonary arterial hypertension. The 259 subjects who completed the pivotal study entered a long-term extension study. Doses up to 80 mg three times a day were studied and after 3 years 87% of 183 patients on treatment were receiving sildenafil citrate 80 mg t.i.d.

The overall frequency of discontinuation in sildenafil-treated patients at the recommended daily dose of 20 mg t.i.d. was low (2.9%) and the same as placebo (2.9%).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Sildenafil Oral Administration:

In the pivotal placebo-controlled trial in pulmonary arterial hypertension, the adverse drug reactions that occurred in at least 3% of sildenafil-treated patients at any of the 20, 40, or 80 mg t.i.d. doses, and more commonly on sildenafil than on placebo, are shown in Table 1.

Table 1. Sildenafil Adverse Events More Frequent than Placebo in ≥ 3% of Patients (N ≥ 2

Patients) Reported in Percentage

In a placebo-controlled fixed dose titration study of sildenafil citrate (starting with recommended dose of 20 mg t.i.d. and increased to 40 mg t.i.d. and then 80 mg t.i.d.) as an adjunct to intravenous epoprostenol in pulmonary arterial hypertension, the clinically meaningful adverse drug reactions that were reported by at least 2% of patients in the sildenafil citrate arm are shown in Table 2. The duration of treatment was 16 weeks. The overall frequency of discontinuations in sildenafil/epoprostenol treated patients due to adverse events was 5.2% compared to 10.7% in the placebo/epoprostenol treated patients. There were 242 subjects who completed the initial study and entered a long-term extension study. Doses up to 80 mg three times a day were studied and after 3 years 68% of 133 patients on treatment were receiving sildenafil citrate 80 mg t.i.d.

Table 2. Sildenafil-Epoprostenol all causality adverse events reported by ≥ 2% of sildenafil treated patients and more frequent than placebo.

A total of 10 PAH subjects enrolled and completed the study. The mean postural changes in systolic and diastolic blood pressure over time were small (< 10 mmHg) and returned towards baseline beyond 2 hours. No symptoms of hypotension were associated with these changes. The mean changes in heart rate were clinically insignificant. Two subjects experienced a total of 3 adverse reactions (flushing, flatulence and hot flush). There was one serious adverse event in a subject with severe ischaemic cardiomyopathy who experienced ventricular fibrillation and death 6 days post study drug; the event was judged to be unrelated to study drug.

Post-Market Adverse Drug Reactions

Cardio-vascular system

In post-marketing experience with sildenafil citrate at doses indicated for male erectile dysfunction (MED), 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 citrate, to sexual activity, to the patient’s underlying cardiovascular disease, or to a combination of these or other factors.

Nervous System: seizure, seizure recurrence, transient global amnesia

Otologic system: Cases of sudden decrease or loss of hearing have been reported post-marketing in temporal association with the use of PDE5 inhibitors, including sildenafil citrate. 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 citrate, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors (see WARNINGS AND PRECAUTIONS).

Rare cases of central serous chorioretinopathy have been reported post-marketing in temporal association with the use of sildenafil citrate. It is not known if medical and other factors 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 possibly underlying risk factors, a combination of these factors, or to other factors (See WARNINGS AND PRECAUTIONS).

Skin / Appendages: Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Erythema Multiforme (EM).

Reproductive system and breast disorders: priapism, erection increased and prolonged.

Pediatric Clinical Trial Safety Data

Pulmonary arterial hypertension

Adverse reactions reported in ≥ 3% of 229 subjects treated with sildenafil (combined dose group) were:

From a data-cut > 7 years after the start of a placebo-controlled safety study in patients 1 to 17 years of age with PAH, there were a total of 42 deaths reported which were dose-dependent. The following AEs occurred in the trial:

Eye Disorders: visual impairment (3%)

Gastrointestinal disorders: vomiting (22%), diarrhea (15%), nausea (9%), dyspepsia (6%)

General disorders and administration site conditions: pyrexia (17%)

Investigations: blood pressure diastolic decreased

Musculoskeletal and connective tissue disorders: pain in extremity (4%);

Nervous system disorders: headache (26%)

Respiratory, thoracic, and mediastinal disorders: epistaxis (12%), rhinorrhea (3%) Respiratory Infection and infestations: upper respiratory tract infection (31%), bronchitis (20%), pharyngitis (18%), influenza (12%), pneumonia (10%)

Most of these adverse reactions were considered mild to moderate in severity.

Persistent pulmonary hypertension of the newborn

A randomized, double-blind, two-arm, parallel-group, placebo-controlled study was conducted in 59 neonates with persistent pulmonary hypertension of the newborn (PPHN), or hypoxic respiratory failure (HRF) and at risk for PPHN with oxygenation index (OI) >15 and <60. The primary objective was to evaluate the efficacy and safety of IV sildenafil when added to inhaled nitric oxide (iNO) compared with iNO alone. Administration of IV sildenafil when added to iNO did not result in a statistically significant difference in treatment failure rates. IV sildenafil should not be used in neonates with PPHN as benefits do not outweigh the risks.

Treatment-emergent adverse events of all causalities and serious adverse events were reported in 22 (75.9%) and 7 (24.1%) subjects in the iNO + IV sildenafil treatment group, respectively, and in 19 (63.3%) and 2 (6.7%) subjects in the iNO + placebo group, respectively. The most commonly reported treatment-emergent adverse events of all causalities were hypotension (8 [27.6%] subjects), hypokalemia (7 [24.1%] subjects), anemia and drug withdrawal syndrome (4 [13.8%] subjects each) and bradycardia (3 [10.3%] subjects) in the iNO + IV sildenafil treatment group and pneumothorax (4 [13.3%] subjects), anemia, edema, hyperbilirubinemia, C-reactive protein increased, and hypotension (3 [10.0%] subjects each) in the iNO + placebo treatment group. Most events in both treatment groups were mild in intensity.

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 ACTION AND 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 P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC₅₀>150 mM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations.

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%.

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

Drug-Drug Interactions

Unless otherwise specified, drug interaction studies have been performed in healthy adult male subjects using oral sildenafil. These results are relevant to other populations and routes of administration.

Table 3 – Established or Potential Drug-Drug Interactions

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

Drug-Food Interactions

Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and co-administration results in 1.23-fold higher sildenafil exposure (AUC) with no change in peak plasma concentrations.

Alcohol has the potential for interaction with sildenafil. Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08% (80 mg/dL). However, patients taking PDE5 inhibitors, including sildenafil, should avoid consuming alcohol, which may increase the potential for orthostatic signs and symptoms including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.

Drug-Herb Interactions

Efficacy of sildenafil should be closely monitored in patients using concomitant St-Johns’s wort, a CYP3A4 inducer.

Drug-Laboratory Interactions

Interaction with laboratory tests has not been established. (See DOSAGE AND ADMINISTRATION)

DOSAGE AND ADMINISTRATION

Dosing Considerations

Dosing of TEVA-SILDENAFIL R (sildenafil citrate) may be affected by the following:

• concomitant administration of alpha-blockers
• concomitant administration of potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir) and weak CYP3A4 inhibitors (e.g. grapefruit juice)
• co-administration with CYP3A4 inducers (e.g. rifampin) (see PRECAUTIONS, DRUG INTERACTIONS)

Recommended Dose and Dosage Adjustment

Adult Oral Dose:

The recommended dose of TEVA-SILDENAFIL R (sildenafil citrate) is 20 mg three times a day (t.i.d.).

Use in patients with renal and hepatic impairment:

No dose adjustments are required for renal impaired patients (including severe renal impairment, creatinine clearance <30 mL/min), and hepatic impaired patients (Child Pugh class A and B).

Patients using other medicinal products:

Co-administration of TEVA-SILDENAFIL R with CYP3A4 inducers (e.g. potent inducers such as barbiturates, carbamazepine, phenytoin, efavirenz, nevirapine, rifampin, rifabutin) may alter plasma levels of either or both medications. Dosage adjustments may be necessary (see PRECAUTIONS).

Co-administration of most potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir) with TEVA-SILDENAFIL R substantially increases serum concentrations of sildenafil and is therefore not recommended (see WARNINGS, DRUG INTERACTIONS).

A downward dose adjustment to 20 mg twice daily should be considered when sildenafil is co-administered to patients already receiving CYP3A4 inhibitors like erythromycin or saquinavir. A downward dose adjustment to 20 mg once daily is recommended in case of co-administration with more potent CYP3A4 inhibitors like clarithromycin, telithromycin and nefazodone.

Sildenafil was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors, or nitrates in any form, is therefore contraindicated.

TEVA-SILDENAFIL R may be used concomitantly in patients stabilized on epoprostenol (see ADVERSE REACTIONS and Drug-Drug Interactions).

Geriatric Use (≥ 65 years):

No dose adjustment is required. However, in general, dose selection for elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see ACTION AND CLINICAL PHARMACOLOGY).

Use in children:

TEVA-SILDENAFIL R is not indicated for use in children less than 18 years of age.

Administration

Oral Dose Administration

TEVA-SILDENAFIL R (sildenafil citrate) should be taken approximately 6-8 hours apart, with or without food.

OVERDOSAGE

In studies with healthy volunteers of single oral doses 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 it is not eliminated in the urine (see DETAILED PHARMACOLOGY).

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type-5 (PDE5) in the smooth muscle of the pulmonary vasculature, where PDE5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary hypertension, this can lead to selective vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.

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 WARNINGS AND PRECAUTIONS, DETAILED PHARMACOLOGY).

In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity observed in vitro, and the mild peripheral arterial-venous dilatation in vivo.

Pharmacodynamics

Effects of TEVA-SILDENAFIL R on Blood Pressure- Oral Administration

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 8.3/5.3 mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing, and was not different than 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, DETAILED PHARMACOLOGY).

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 t.i.d. to patients with pulmonary arterial hypertension, no clinically relevant effects on ECG were reported.

After chronic dosing of 80 mg t.i.d. sildenafil to healthy patients, the largest mean change from baseline in supine systolic and supine diastolic blood pressure was a decrease of 9.0 mmHg and 8.4 mmHg respectively.

After chronic oral dosing of 80 mg t.i.d. sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9.4 mmHg and 9.1 mmHg respectively.

After chronic oral dosing of 80 mg t.i.d. sildenafil to patients with pulmonary arterial hypertension, lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mmHg). This may be due to improvements in cardiac output secondary to the beneficial effects of sildenafil on pulmonary vascular resistance.

In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (>70% stenosis of at least one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7% and 6% respectively compared to baseline. Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil showed no effect on cardiac output, and did not impair blood flow through the stenosed coronary arteries.

Pharmacokinetics

Sildenafil citrate tablets are rapidly absorbed after oral administration, with mean absolute bioavailability of about 41%. After oral three-times-daily (t.i.d.) dosing of sildenafil, AUC and C_max increase in proportion with dose over the dose range of 20-40 mg t.i.d. After 80 mg t.i.d., a slightly more than dose-proportional increase of sildenafil plasma levels has been observed. It is eliminated predominantly by hepatic metabolism (mainly cytochrome P450 3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil. The concomitant use of potent cytochrome P450 3A4 (CYP3A4) inhibitors (e.g. ritonavir ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil (see DRUG INTERACTIONS, DOSAGE AND ADMINISTRATION, DETAILED PHARMACOLOGY). Both sildenafil and the metabolite have terminal half-lives of about 4 hours.

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. When sildenafil was administered with a high-fat meal, the rate of absorption was significantly decreased, with a 29% mean reduction in C_max and a 60-minute mean delay in T_max, however, the extent of absorption was not significantly affected (AUC decreased by 11%). This is not clinically relevant for chronic dosing in this patient population.

Distribution: The mean steady state volume of distribution (Vss) for sildenafil is 105 L, 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 semen of healthy volunteers 90 minutes after dosing, less than 0.0002% (average 188 ng) of the administered dose may appear in the semen of patients.

Metabolism: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite (UK-103,320) results from N-desmethylation of sildenafil at the N-methyl piperazine moiety. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil’s pharmacologic effects. In patients with pulmonary arterial hypertension, however, the ratio of UK-103,320 to sildenafil is higher. Plasma concentrations of UK-103,320 are approximately 72% those of sildenafil after 20 mg t.i.d. oral dosing (translating into a 36% contribution to sildenafil’s pharmacological effects). The subsequent effect on efficacy is unknown.

Excretion: 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

Pediatrics: TEVA-SILDENAFIL R is not indicated for use in children less than 18 years of age.

Geriatrics: Healthy elderly volunteers (65 years or over) 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%.

Gender: Comparison of the female PK data with historic control of male data resulted in ratios

(90%CI) for Cmax and AUCt of 80% (65%;99%) and 103% (85%; 124%) respectively with a difference (90%CI) in T_max of 0.5h (0.2h;0.8h). The average estimates for apparent oral clearance (CL/F) and volume of distribution (V/F) were similar for males (n=1335) and females

(n=433). Therefore, there are no clinically significant gender differences in sildenafil pharmacokinetics.

Hepatic Impairment: 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. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

Renal Impairment: In volunteers with mild (CLcr = 50-80 mL/min) and moderate (CLcr = 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg)

were not altered. In volunteers with severe (CLcr < 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting 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 200% and 79% respectively in subjects with severe renal impairment compared to subjects with normal renal function.

Population Pharmacokinetics:

Age, gender, race, and renal and hepatic function were included as covariates in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in pulmonary arterial hypertension patients. The data set available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a statistically significant impact on sildenafil pharmacokinetics in patients with pulmonary hypertension. However, CYP3A4 substrates reduced the apparent clearance of sildenafil, alone and in combination, with beta-blockers (by 22.3% and 37.4%, respectively). No other factor had a statistically significant influence on sildenafil pharmacokinetics.

In patients with pulmonary hypertension, the average steady state concentrations were 20-50% higher over the investigated dose range of 20-80 mg t.i.d., when compared to those of healthy volunteers. There was a doubling of C_min levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with pulmonary hypertension compared to healthy volunteers.

STORAGE AND STABILITY

Store at controlled room temperature (15-30 ºC).

SPECIAL HANDLING INSTRUCTIONS

Not Applicable.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Each tablet contains sildenafil citrate equivalent to 20 mg of sildenafil. It is supplied as

White to off white, biconvex circular film-coated tablets debossed with "20" on one side and plain on the other side.. The tablets are provided in bottles of 100’s.

The tablet core contains: calcium hydrogen phosphate, crosscarmellose sodium, magnesium stearate and microcrystalline cellulose. The film coating contains: hydroxy propyl methylcellulose, polyethylene glycol, talcum and titanium dioxide.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Common 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 and molecular mass: C₂₂H₃₀N₆O₄S·C₆H₈O₇; 666.7

Structural formula:

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

CLINICAL TRIALS

Comparative Bioavailability Studies

A randomized, two-way, single-dose, crossover comparative bioavailability study of TEVA-SILDENAFIL R 20 mg tablets (Teva Canada Limited) with ^PrREVATIO^® 20 mg tablets (Pfizer Canada Inc.) was conducted in healthy, adult, male subjects under fasting conditions. Comparative bioavailability data from 29 subjects that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ TEVA-SILDENAFIL R (sildenafil citrate) tablets, 20 mg (Teva Canada Limited)

^{2 Pr}REVATIO^® (sildenafil citrate) tablets, 20 mg (Pfizer Canada Inc.)

³ Expressed as the median (range) only

⁴ Expressed as the arithmetic mean (CV %) only

Study Demographics and Trial Design

Table 4: Study of patient demographics for Study A1481140

Study Results

Study A1481140

A randomized, double-blind, placebo-controlled study was conducted in 278 patients with PAH. Of the 278 patients randomized, 277 patients received at least one dose of study drug. Patients were randomized to receive placebo (n=70) or sildenafil citrate 20 mg (n=69), 40 mg (n=67) or 80 mg (n=71) t.i.d. for a period of 12 weeks. A total of 175 (63%) patients had PPH, 84 (30%) had PAH associated with CTD, and 18 (7%) had PAH following surgical repair of left-to-right congenital heart lesions. The study population consisted of 68 (25%) men and 209 (75%) women with a mean age of 49 years (range: 18-81 years) and baseline 6-minute walk test distance between 100 and 450 meters (inclusive). Patients across WHO functional classes I-IV participated in the study.

In this study, sildenafil (or placebo) was added to patients’ background therapy, which could have included a combination of anticoagulant, digoxin, calcium channel blockers, diuretics and / or oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation was not permitted. Patients with left ventricular ejection fraction <45% or left ventricular shortening fraction <0.2 were not studied.

The primary efficacy endpoint was the change from baseline at Week 12 in 6-minute walk distance. Supportive endpoints included changes in hemodynamic parameters, functional class, background therapy, dyspnea score, Quality of Life (SF36 & EQ5D) and clinical worsening. At the recommended dose of 20 mg t.i.d., a placebo-corrected increase in walk distance of 45 meters was observed (p<0.0001). Placebo-corrected increases of 46 meters (p<0.0001) and 50 meters (P<0.0001) were observed on sildenafil 40 mg and 80 mg t.i.d., respectively, indicating no significant difference in effect between sildenafil doses.

The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at Week 8 and Week 12. Mean treatment effects consistently showed improvement in 6-minute walk distance in all sildenafil groups compared to placebo in all pre-defined subpopulations based on demographics, geographical regions, disease characteristics and baseline parameters (walk test and hemodynamics).

Patients on all sildenafil citrate doses achieved a statistically significant reduction in mean right arterial pressure (mPAP) compared to those on placebo. At the recommended dose of 20 mg t.i.d., a placebo-corrected decrease in mPAP of -2.7 mmHg was observed (p=0.04) (Table 4). Additionally, placebo-corrected reductions of -3.0 mmHg (p=0.01) and -5.1 mmHg (p<0.0001) were observed for sildenafil 40 mg and 80 mg t.i.d., respectively. There was no significant difference in effect between sildenafil doses. Improvements were also seen across all doses of sildenafil citrate in pulmonary vascular resistance (PVR), right arterial pressure (RAP) and cardiac output (CO). Changes in heart rate (HR) and systemic blood pressure were negligible. The reduction in PVR was proportionally greater than the reduction in systemic vascular resistance (SVR).

Table5: Changes from Baseline to Week 12 in Key Hemodynamic Parameters at the Recommended Daily Dose of 20 mg t.i.d.

* The number of patients per treatment group varied slightly for each parameter due to missing assessments.

^a(p=0.04)

In the pivotal trial, the incidence of clinical worsening (in particular hospitalizations due to pulmonary arterial hypertension) showed a favorable trend in the sildenafil treatment groups. A greater percentage of patients on sildenafil 20 mg t.i.d. (28%) showed an improvement of at least one WHO functional class over the 12-week period compared with placebo (7%). Similarly, fewer patients on sildenafil 20 mg t.i.d. (3%) deteriorated by one or more WHO functional class over the 12-week period compared with placebo (10%). Improvements were also seen in Quality of Life parameters and a favorable trend was seen in Borg dyspnea score in sildenafil-treated patients compared with placebo. Additionally, the proportion of patients requiring an added class of background medication during the trial was greater in the placebo group (20%) compared to the patients receiving sildenafil 20 mg (13%).

Long-Term Treatment Effect

Following the pivotal study, two hundred fifty nine of the 277 sildenafil-treated patients entered a separate long-term extension study. At the end of 1 year, 94% of these patients were still alive. Long-term effects on the subjects treated with sildenafil for at least 1 year (N=149) showed that change from baseline in 6-Minute Walk distance was 50 m (95% CI: 40, 60) at Week 12 and 54 m (95% CI: 42, 67) at 1 year. In addition, 54 (36%) and 61 (41%) of the patients improved by at least one WHO functional class at Week 12 and at 1 year, respectively. These estimates do not account patients who discontinued prior to reaching 1 year of treatment, or those ongoing in the study that had not reached 1 year of treatment. Results may be influenced by the presence of additional therapy for pulmonary arterial hypertension (prostacyclins or endothelin receptor antagonists) in 6 (4%) of the 149 patients. Without a control group, these data must be interpreted cautiously and cannot be interpreted as an improvement in survival, or as maintenance of effect.

Study A1481141

A randomized, double-blind, placebo controlled, study was conducted in 267 patients with PAH who were stabilized on intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) ≥ 25mmHg and a pulmonary capillary wedge pressure (PCWP) ≤ 15mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-Minute Walk test distance ≥ 100m and ≤ 450m. Patients were randomized to placebo or sildenafil (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) when used in combination with intravenous epoprostenol.

The majority of patients in both treatment groups had PPH (78.9% on placebo and 79.9% on sildenafil). The remaining patients had PAH secondary to CTD (21.1% on placebo and 20.1% on sildenafil). The study population consisted of 20% men and 80% women with a mean age of 48 years (range: 18-75).

Analysis of the primary endpoint showed that there was a statistically significant greater increase in 6-Minute Walk distance for the sildenafil group compared with the placebo group at Week 16. The mean change from baseline at Week 16 (LOCF) was 30.1 m for the sildenafil group compared with 4.1 m for the placebo group giving an adjusted treatment difference of 26.0 m (95% CI: 10.8, 41.2) (p = 0.0009).

Patients on sildenafil achieved a statistically significant reduction in mean Pulmonary Arterial

Pressure (mPAP) compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil (95% CI: -5.7, -2.1) (p = 0.00003).

Clinical Worsening

Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death or lung transplantation or initiation of bosentan therapy or clinical deterioration requiring a change in epoprostenol therapy). Patients with clinical worsening events are summarized in Table 5. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo patients were 3 times more likely to experience an event and that patients receiving sildenafil experienced a significant delay in time to clinical worsening versus placebo (p = 0.0074). In a post-hoc analysis this improvement is seen as early as Week 4 in which there is a statistically significant (p = 0.0256) difference between patients on sildenafil 20 mg TID compared to placebo (Figure 1).

Table 6. Clinical Worsening Events

Figure 1. Kaplan-Meier Plot of Time to Clinical Worsening (Days) ITT Population

Improvements in functional class were also demonstrated in subjects on sildenafil compared to placebo. More than twice as many sildenafil treated patients (35.6%) as the placebo group (14.4%) showed an improvement of at least one functional class.

DETAILED PHARMACOLOGY

Human Pharmacodynamic Studies

Effects of Sildenafil on Blood Pressure (BP):

Oral doses of sildenafil of 50 mg, 100 mg and 200 mg produced statistically significant decreases in supine systolic and diastolic blood pressure (a mean maximum decrease of approximately 8.3 mm Hg and 5.3 mm Hg, respectively) compared with placebo, with no effect on pulse rate. The mean maximum fall in systolic and diastolic blood pressure occurred at peak plasma levels (approximately 1 hour post-dose), and there was a tendency for blood pressure to return to baseline values by 4 hours post-dose.

In healthy volunteers, there were no clinically significant changes in cardiac index (derived from bio-impedence measures of cardiac output) up to 12 hours post-dose for sildenafil administered orally (100 mg, 150 mg and 200 mg), nor intravenously (20-80 mg), compared with placebo. Sildenafil has both arteriodilator and venodilator effects on the peripheral vasculature.

Single oral doses of sildenafil above 15 mg were generally associated with a potentiation of the antiaggregatory effects of sodium nitroprusside (SNP) on ADP aggregation of ex vivo platelets. Sildenafil had no effect on other ex vivo tests (ADP-induced platelet aggregation of whole blood and ADP-induced aggregation of platelet-rich plasma in the absence of SNP). Sildenafil therefore has no direct effect on platelet function ex vivo, but potentiates the action of a nitric oxide (NO) donor, SNP. This confirms the need for an NO drive before sildenafil will produce its pharmacological effects. These modest effects on platelet activity, ex vivo, did not result in a clinically significant effect on bleeding time in healthy volunteers.

Effects of Sildenafil on Vision:

At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, contrast sensitivity, ERGs, intraocular pressure, or pupillometry. In a small size placebo-controlled study of patients with documented early age-related macular degeneration (n=9), sildenafil (single dose, 100 mg) demonstrated no significant changes in visual tests conducted (visual acuity, Amsler grid, color discrimination simulated traffic light, Humphrey perimeter and photostress).

Sildenafil added to bosentan therapy:

In a study of pulmonary arterial hypertension (PAH) patients (PPH and secondary PAH associated with CTD) on background bosentan therapy, no benefit (6-minute walk distance (6MWD)) of sildenafil (20mg three times a day) co-administered with bosentan (62.5-125mg twice a day) was demonstrated over bosentan alone. The PAH patients included those with primary PAH (PPH), and PAH associated with CTD. In this trial, the concomitant use of sildenafil and bosentan was associated with a neutral effect on 6MWD in PAH patients, with mean changes of 13.62 m (n=49, 95% CI: -3.89 to 31.12) and 14.08 m (n=53, 95% CI: -1.78 to 29.95) in sildenafil add-on and placebo add-on groups, respectively. The concomitant administration of sildenafil and bosentan is not an optimal choice in PPH patients stable on bosentan therapy. In a subgroup analysis for PPH (67 subjects), mean changes in 6MWD were 26.39 m (n=35, 95% CI: 10.70 to 42.08) in the sildenafil add-on group compared with 11.84 m (n=32, 95% CI: -8.83 to 32.52) in the bosentan alone group. In a subgroup analysis for pulmonary hypertension associated with CTD (36 subjects), there was a reduced 6MWD, 18.32 m (n=14, 95% CI: -65.66 to 29.02) in sildenafil add-on group compared with 17.50 m (n=21, 95% CI: -9.41 to 44.41) in the bosentan alone group. Therefore the use of sildenafil with bosentan is not recommended in patients with PAH associated with CTD.

Metabolism and Elimination

The major circulating metabolite of sildenafil, results from N-demethylation of sildenafil at the N-methyl piperazine moiety. It has a similar selectivity for PDE isozymes as sildenafil, but exhibits around 50% of the potency of sildenafil. The metabolism of sildenafil occurs in human hepatic microsomes and is mediated by two cytochrome P-450 isoforms [CYP2C9 (minor route) and CYP3A4 (major route)].

The concomitant use of potent cytochrome P-450 3A4 inhibitors (e.g. erythromycin, saquinavir, ritonavir, ketoconazole, itraconazole) as well as the non-specific CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil (see PRECAUTIONS, DRUG INTERACTIONS, DOSAGE AND ADMINISTRATION).

TOXICOLOGY

Acute Toxicity Mice and Rats:

Long-Term Toxicity – Mice

Long-Term Toxicity – Rats:

Long-Term Toxicity – Dogs:

Bioequivalence - 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.

Reproduction and Teratology

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.

In pups of rats which were pre- and postnatally treated with 60 mg/kg sildenafil, a decreased litter size, a lower pup weight on day 1 and a decreased 4-day survival were seen at exposures which were approximately fifty times the expected human exposure at 20 mg three times a day.

Effects in non-clinical studies were observed at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Rabbits:

Special Studies:

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