5 WARNINGS AND PRECAUTIONS

5.1 Cardiovascular

There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Therefore, treatments for erectile dysfunction, including sildenafil citrate, should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status. The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assessment.

Sildenafil citrate has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 8.4/5.5 mmHg), [ see Clinical Pharmacology (12.2)]. While this normally would be expected to be of little consequence in most patients, prior to prescribing sildenafil citrate, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity.

Use with caution in patients with the following underlying conditions which can be particularly sensitive to the actions of vasodilators including sildenafil citrate – those with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure.

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

5.2 Prolonged Erection and Priapism

Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of sildenafil tablets. 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.

Sildenafil citrate 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). However, there are no controlled clinical data on the safety or efficacy of sildenafil citrate in patients with sickle cell or related anemias.

5.3 Effects on the Eye

Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil citrate, and seek 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 rare condition and 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. Based on published literature, the annual incidence of NAION is 2.5 to 11.8 cases per 100,000 in males aged ≥ 50. An observational case-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies.

Neither the rare post-marketing reports, nor the association of PDE5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE5 inhibitor use and NAION [ see Adverse Reactions (6.2)].

Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including sildenafil citrate, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with “crowded” optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including sildenafil citrate, for this uncommon condition.

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); if prescribed, this should be done with caution.

5.4 Hearing Loss

Physicians should advise patients to stop taking PDE5 inhibitors, including sildenafil citrate, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including sildenafil citrate. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [ see Adverse Reactions ( 6.1, 6.2) ].

**5.5 Hypotension when Co-administered with Alpha-blockers or Anti-

hypertensives**

Alpha-blockers

Caution is advised when PDE5 inhibitors are co-administered with alpha- blockers. PDE5 inhibitors, including sildenafil citrate, 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 occur. In some patients, concomitant use of these two drug classes can lower blood pressure significantly [ see Drug Interactions (7.2) and Clinical Pharmacology (12.2)] leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting).

Consideration should be given to the following:

• Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors. Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor.
• In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose [ see Dosage and Administration (2.3)].
• In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor.
• Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.

Anti-hypertensives

Sildenafil citrate has systemic vasodilatory properties and may further lower blood pressure in patients taking anti-hypertensives medications.

In a separate drug interaction study, when amlodipine, 5 mg or 10 mg, and sildenafil citrate, 100 mg were orally administered concomitantly to hypertensive patients mean additional blood pressure reduction of 8 mmHg systolic and 7 mmHg diastolic were noted [ see Drug Interactions (7.3) and Clinical Pharmacology (12.2)].

5.6 Adverse Reactions with the Concomitant Use of Ritonavir

The concomitant administration of the protease inhibitor ritonavir substantially increases serum concentrations of sildenafil (11-fold increase in AUC). If sildenafil citrate is prescribed to patients taking ritonavir, caution should be used. Data from subjects exposed to high systemic levels of sildenafil are limited. Decreased blood pressure, syncope, and prolonged erection were reported in some healthy volunteers exposed to high doses of sildenafil (200 to 800 mg). To decrease the chance of adverse reactions in patients taking ritonavir, a decrease in sildenafil dosage is recommended [ see Dosage and Administration (2.4), Drug Interactions (7.4), and Clinical Pharmacology (12.3)].

**5.7 Combination with other PDE5 Inhibitors or Other Erectile Dysfunction

Therapies**

The safety and efficacy of combinations of sildenafil tablets, 25 mg, 50 mg and 100 mg with other PDE5 Inhibitors, including sildenafil tablets, 20 mg or other pulmonary arterial hypertension (PAH) treatments containing sildenafil, or other treatments for erectile dysfunction have not been studied. Such combinations may further lower blood pressure. Therefore, the use of such combinations is not recommended.

5.8 Effects on Bleeding

There have been postmarketing reports of bleeding events in patients who have taken sildenafil citrate. A causal relationship between sildenafil citrate and these events has not been established. In humans, sildenafil citrate has no effect on bleeding time when taken alone or with aspirin. However, in vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor). In addition, the combination of heparin and sildenafil citrate had an additive effect on bleeding time in the anesthetized rabbit, but this interaction has not been studied in humans.

The safety of sildenafil citrate is unknown in patients with bleeding disorders and patients with active peptic ulceration.

5.9 Counseling Patients About Sexually Transmitted Diseases

The use of sildenafil citrate offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 20- and 38- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18 to 21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.4 times the MRHD on a mg/m2 basis in a 50 kg subject.

Mutagenesis

Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity.

Impairment of Fertility

There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Nitrates

Physicians should discuss with patients the contraindication of sildenafil citrate with regular and/or intermittent use of nitric oxide donors, such as organic nitrates or organic nitrites in any form [ see Contraindications (4.1)].

Guanylate Cyclase (GC) Stimulators

Physicians should discuss with patients the contraindication of sildenafil citrate with use of guanylate cyclase stimulators such as riociguat [ see Contraindications (4.3)].

Concomitant Use with Drugs Which Lower Blood Pressure

Physicians should advise patients of the potential for sildenafil citrate to augment the blood pressure lowering effect of alpha-blockers and anti- hypertensive medications. Concomitant administration of sildenafil citrate and an alpha-blocker may lead to symptomatic hypotension in some patients. Therefore, when sildenafil citrate is co-administered with alpha-blockers, patients should be stable on alpha-blocker therapy prior to initiating sildenafil citrate treatment and sildenafil citrate should be initiated at the lowest dose [ see Warnings and Precautions (5.5)].

Cardiovascular Considerations

Physicians should discuss with patients the potential cardiac risk of sexual activity in patients with preexisting cardiovascular risk factors. Patients who experience symptoms (e.g., angina pectoris, dizziness, nausea) upon initiation of sexual activity should be advised to refrain from further activity and should discuss the episode with their physician [ see Warnings and Precautions (5.1)].

Sudden Loss of Vision

Physicians should advise patients to stop use of all PDE5 inhibitors, including sildenafil citrate, and seek 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 possible permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. Physicians should discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye. Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a “crowded” optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitor, including sildenafil citrate, for this uncommon condition [ see Warnings and Precautions (5.3) and Adverse Reactions (6.2)].

Sudden Hearing Loss

Physicians should advise patients to stop taking PDE5 inhibitors, including sildenafil citrate, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including sildenafil citrate. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [ see Warnings and Precautions (5.4) and Adverse Reactions (6.2)].

Priapism

Physicians should warn patients that prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of sildenafil citrate. 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 may result [ see Warnings and Precautions (5.2)].

Avoid Use with other PDE5 Inhibitors

Physicians should inform patients not to take sildenafil tablets, 25 mg, 50 mg and 100 mg with other PDE5 inhibitors including sildenafil tablets, 20 mg or other pulmonary arterial hypertension (PAH) treatments containing sildenafil. Sildenafil is also marketed as sildenafil tablets, 20 mg for the treatment of PAH. The safety and efficacy of sildenafil tablets, 25 mg, 50 mg and 100 mg with other PDE5 inhibitors, including sildenafil tablets, 20 mg, have not been studied [ see Warnings and Precautions (5.7)].

Sexually Transmitted Disease

The use of sildenafil citrate offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered [ see Warnings and Precautions (5.9)].

This product’s label may have been updated. For current full prescribing information, please visit www.torrentpharma.com

Trademarks are the property of their respective owners.

Manufactured by:

TORRENT PHARMACEUTICALS LTD., INDIA.

Manufactured for:

TORRENT PHARMA INC., Basking Ridge, NJ 07920.

8088768 Revised August 2022