17 PATIENT COUNSELING INFORMATION

There are no adequate and well-controlled studies of sildenafil in pregnant women.

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Coadministration of sildenafil, tadalafil or vardenafil and other organic nitrates has been shown to potentiate the hypotensive effects of nitrates; concomitant administration of these drugs for erectile dysfunction with nitrates is contraindicated. [20][22][23] Many sildenafil citrate tablets 50mg methscopolamine-containing products list methscopolamine nitrate as the ingredient. Therefore, the concomitant use of sildenafil, tadalafil or vardenafil and products which contain methscopolamine nitrate is not recommended. Sildenafil is metabolized principally by cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Cimetidine is a known inhibitor of hepatic CYP enzymes and reduces the metabolism of sildenafil.

5.2 Worsening Pulmonary Vascular Occlusive Disease

Cimetidine (800 mg) caused a 56% increase in plasma sildenafil concentrations when coadministered with sildenafil 50 mg to healthy volunteers. Population data from patients in clinical trials also indicate a reduction in sildenafil clearance when it was coadministered with cimetidine. If possible, cimetidine use should be avoided in patients who take sildenafil. Etravirine is an inducer of CYP3A4; coadministration may result in decreased sildenafil concentrations. Dosage adjustments may be needed based on clinical efficacy.

5.5 Hearing Loss

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving ritonavir. Coadministration of ritonavir with sildenafil results in an 11-fold increase of sildenafil AUC; one death has been reported in a patient who received sildenafil in combination with ritonavir and Fortovase. [25] Substantially increased sildenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. If coadministered when sildenafil is used for erectile dysfunction, a reduced dose of sildenafil 25 mg every 48 hours with increased monitoring for adverse reactions is recommended. [26][27] When sildenafil is used for the treatment of pulmonary arterial hypertension (PAH), the use of ritonavir is contraindicated because a safe and effective dose has not been established. According to the manufacturers, Revatio should be used during pregnancy only if clearly needed; Sildenafil is not indicated for use in women. It is not known if sildenafil or its metabolites are excreted in human breast milk. The prescribing information for Revatio recommends caution when the drug is administered to a nursing mother; Sildenafil is not indicated for use in women.

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[12][15] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.

• Sildenafil is sometimes used off-label for other health issues.
• Its interaction with blood thinners should be monitored.
• Men with retinitis pigmentosa should avoid sildenafil.
• Always inform healthcare providers about all treatments.
• Use sildenafil in conjunction with a healthy lifestyle.
• Avoid unnecessary medication to prevent side effects.
• Be aware of potential drug interactions with sildenafil.
• Proper storage maintains medication efficacy over time.

If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA. In 2012, the FDA recommended against the use of sildenafil for the treatment of pulmonary hypertension in neonates, infants, children, or adolescents based on the results of a long-term pediatric clinical trial showing an increased risk of death in pediatric patients receiving a high dose of sildenafil compared to those receiving a low dose (HR 3.9, p = 0.007).

7. Drug Interactions

Also, when using for erectile dysfunction, use sildenafil with caution in patients with sickle cell disease because the risk of priapism may be increased. This list may not include all contraindications. Possible interactions include: certain drugs for high blood pressure; certain drugs for the treatment of HIV infection or AIDS; certain drugs used for fungal or yeast infections, like fluconazole, ketoconazole, and voriconazole; cimetidine; erythromycin; rifampin. This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use.

Binding Characteristics

Some items may interact with your medicine. NOTE: Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. [19] Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects. The manufacturer recommends dosage reduction in patients receiving potent cytochrome CYP3A4 inhibitors.

Full Text Sources

Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina. Sildenafil administration to patients who are concurrently using organic nitrates or nitrites in any form is contraindicated. The safety and efficacy of tadalafil administered concurrently with any other phosphodiesterase (PDE5) inhibitors, such as sildenafil, has not been studied. The manufacturer of tadalafil recommends to avoid the use of tadalafil with any other PDE5 inhibitors. [15][16] The FDA has since clarified its recommendation stating that there may be patients in which the benefits of sildenafil therapy outweigh the risks, such as when other treatment options are limited and when close monitoring is available, and advises health care providers to weigh the risk-benefit profile for individual patients when deciding whether to initiate sildenafil.

• Sildenafil use should be disclosed to your healthcare provider.
• Not suitable for men with severe cardiovascular conditions.
• Ask about possible drug interactions before starting.
• Adjustments may be needed for older adults.
• Timing of medication is important for maximum effect.
• Monitoring for side effects helps prevent complications.
• Stop using sildenafil if health issues arise.
• Always follow professional medical advice.

[17] Despite the FDA’s caution against use, The Pediatric Pulmonary Hypertension Network (PPHNet) recommends cautious initiation and titration of sildenafil, avoidance of high doses (> 20 mg PO 3 times daily), and consultation and/or referral to providers experienced in the treatment of pulmonary hypertension in pediatric patients.

5.2 Worsening Pulmonary Vascular Occlusive Disease

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving saquinavir. Sildenafil is contraindicated for use with the anti-retroviral protease inhibitors when used for pulmonary arterial hypertension (PAH). [28] If sildenafil is coadministered with saquinavir and used for erectile dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions. [27][28] Coadministration of saquinavir, especially when ‘boosted’ with ritonavir, with PDE5 inhibitors is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. One death has been reported in a patient who received sildenafil in combination with ritonavir and saquinavir (Fortovase).

Figure 3.5.1

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving amprenavir. Coadministration with sildenafil results in a 210% increase in sildenafil AUC. [29] If sildenafil is coadministered with amprenavir and used for erectile dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions. [27][30] Substantially increased sildenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving fosamprenavir.

Study 2: Sildenafil citrate with Doxazosin

[29] If sildenafil is coadministered with fosamprenavir and used for erectile dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions. [27][29] Coadministration with sildenafil results in a 210% increase in sildenafil AUC. Substantially increased sildenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving atazanavir. [31] If sildenafil is coadministered with atazanavir and used for erectile dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions. PPHNet also recommends against the abrupt discontinuation of sildenafil in pediatric patients currently receiving it as this could lead to clinical worsening or death. The FDA warning is based on chronic use of sildenafil as monotherapy and, therefore, does not apply to short-term use in critically ill patients.

Warnings & Precautions

Sildenafil should be used cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Sildenafil can decrease the tone of the lower esophageal sphincter and inhibit esophageal motility. Safety and efficacy of sildenafil has not been established in the treatment of pulmonary hypertension secondary to sickle cell disease. Vaso-occlusive crisis (sickle-cell crisis) requiring hospitalization has been reported more frequently in patients with pulmonary hypertension secondary to sickle cell disease who received sildenafil than by those who received placebo. Also, when using for erectile dysfunction, use sildenafil with caution in patients with sickle cell disease because the risk of priapism may be increased. This list may not include all contraindications. Possible interactions include: certain drugs for high blood pressure; certain drugs for the treatment of HIV infection or AIDS; certain drugs used for fungal or yeast infections, like fluconazole, ketoconazole, and voriconazole; cimetidine; erythromycin; rifampin.

• Sildenafil tablets 125 mg can be part of a broader ED treatment plan.
• Psychological counseling may enhance effectiveness.
• Combining therapies can improve outcomes.
• Lifestyle modifications include weight management and exercise.
• Quitting smoking can improve erectile health.
• Vasodilator drugs should be avoided when using sildenafil.
• Maintain a balanced diet alongside medication.
• Support groups can offer additional assistance.

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use.

Brand Name	Manufacturer	Country of Origin	Description
Viagra	Pfizer	USA	Most well-known brand
Revatio	Pfizer	USA	Used for pulmonary hypertension
Sildenafil ZYDUS	Zydus Cadila	India	Generic alternative
Sildenafil Mylan	Mylan Pharmaceuticals	USA	Generic options

Some items may interact with your medicine. NOTE: Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. [19] Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects. The manufacturer recommends dosage reduction in patients receiving potent cytochrome CYP3A4 inhibitors. Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina. Sildenafil administration to patients who are concurrently using organic nitrates or nitrites in any form is contraindicated.

Side Effects

[27][31] Coadministration of atazanavir with PDE5 inhibitors is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving darunavir. [32] When sildenafil is coadministered with darunavir and used for erectile dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions. [27][32] Coadministration of darunavir with PDE5 inhibitors is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is contraindicated for use with cobicistat when used for pulmonary arterial hypertension (PAH). The safety and efficacy of tadalafil administered concurrently with any other phosphodiesterase (PDE5) inhibitors, such as sildenafil, has not been studied. The manufacturer of tadalafil recommends to avoid the use of tadalafil with any other PDE5 inhibitors. Coadministration of sildenafil, tadalafil or vardenafil and other organic nitrates has been shown to potentiate the hypotensive effects of nitrates; concomitant administration of these drugs for erectile dysfunction with nitrates is contraindicated. [20][22][23] Many sildenafil citrate tablets 50mg methscopolamine-containing products list methscopolamine nitrate as the ingredient. Therefore, the concomitant use of sildenafil, tadalafil or vardenafil and products which contain methscopolamine nitrate is not recommended. Sildenafil is metabolized principally by cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes.

• Sildenafil tablets 125 mg should not be used by women.
• Always read the medication guide thoroughly.
• Overdose can cause serious health issues.
• Sildenafil can cause a sudden decrease in blood pressure.
• Inform your doctor of all medications you take.
• Sildenafil may improve erectile function in men with ED.
• Do not use sildenafil more than once per day.
• Effects can vary based on individual health.

Cimetidine is a known inhibitor of hepatic CYP enzymes and reduces the metabolism of sildenafil. Cimetidine (800 mg) caused a 56% increase in plasma sildenafil concentrations when coadministered with sildenafil 50 mg to healthy volunteers.

Country	Legal Status	Prescription Required	Notes
USA	Prescription required	Yes	Approved for ED, PH
UK	Prescription required	Yes	Prescription necessary
India	Over-the-counter in some states	Varies	Varies by region
Canada	Prescription required	Yes	Approved for ED and PH

Population data from patients in clinical trials also indicate a reduction in sildenafil clearance when it was coadministered with cimetidine. If possible, cimetidine use should be avoided in patients who take sildenafil. Etravirine is an inducer of CYP3A4; coadministration may result in decreased sildenafil concentrations. Dosage adjustments may be needed based on clinical efficacy. Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving ritonavir. Coadministration of ritonavir with sildenafil results in an 11-fold increase of sildenafil AUC; one death has been reported in a patient who received sildenafil in combination with ritonavir and Fortovase. [25] Substantially increased sildenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. If coadministered when sildenafil is used for erectile dysfunction, a reduced dose of sildenafil 25 mg every 48 hours with increased monitoring for adverse reactions is recommended. [26][27] When sildenafil is used for the treatment of pulmonary arterial hypertension (PAH), the use of ritonavir is contraindicated because a safe and effective dose has not been established. Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving saquinavir. Sildenafil is contraindicated for use with the anti-retroviral protease inhibitors when used for pulmonary arterial hypertension (PAH).

2.1 Recommended Dosage in Adults

There are no adequate and well-controlled studies of sildenafil in pregnant women. According to the manufacturers, Revatio should be used during pregnancy only if clearly needed; Sildenafil is not indicated for use in women. It is not known if sildenafil or its metabolites are excreted in human breast milk. The prescribing information for Revatio recommends caution when the drug is administered to a nursing mother; Sildenafil is not indicated for use in women. [12][15] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.

Clinical monitoring

If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA. In 2012, the FDA recommended against the use of sildenafil for the treatment of pulmonary hypertension in neonates, infants, children, or adolescents based on the results of a long-term pediatric clinical trial showing an increased risk of death in pediatric patients receiving a high dose of sildenafil compared to those receiving a low dose (HR 3.9, p = 0.007). [15][16] The FDA has since clarified its recommendation stating that there may be patients in which the benefits of sildenafil therapy outweigh the risks, such as when other treatment options are limited and when close monitoring is available, and advises health care providers to weigh the risk-benefit profile for individual patients when deciding whether to initiate sildenafil. [17] Despite the FDA’s caution against use, The Pediatric Pulmonary Hypertension Network (PPHNet) recommends cautious initiation and titration of sildenafil, avoidance of high doses (> 20 mg PO 3 times daily), and consultation and/or referral to providers experienced in the treatment of pulmonary hypertension in pediatric patients. PPHNet also recommends against the abrupt discontinuation of sildenafil in pediatric patients currently receiving it as this could lead to clinical worsening or death.

2.1 Recommended Dosage in Adults

The FDA warning is based on chronic use of sildenafil as monotherapy and, therefore, does not apply to short-term use in critically ill patients. Sildenafil should be used cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Sildenafil can decrease the tone of the lower esophageal sphincter and inhibit esophageal motility. Safety and efficacy of sildenafil has not been established in the treatment of pulmonary hypertension secondary to sickle cell disease. Vaso-occlusive crisis (sickle-cell crisis) requiring hospitalization has been reported more frequently in patients with pulmonary hypertension secondary to sickle cell disease who received sildenafil than by those who received placebo. [28] If sildenafil is coadministered with saquinavir and used for erectile dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions. [27][28] Coadministration of saquinavir, especially when ‘boosted’ with ritonavir, with PDE5 inhibitors is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. One death has been reported in a patient who received sildenafil in combination with ritonavir and saquinavir (Fortovase). Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving amprenavir. Coadministration with sildenafil results in a 210% increase in sildenafil AUC. [29] If sildenafil is coadministered with amprenavir and used for erectile dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions.

6. Adverse Reactions/Side Effects

If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg every 48 hours with increased monitoring for adverse reactions during times of coadministration. [27][30] Substantially increased sildenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving fosamprenavir. [29] If sildenafil is coadministered with fosamprenavir and used for erectile dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions. [27][29] Coadministration with sildenafil results in a 210% increase in sildenafil AUC. Substantially increased sildenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving atazanavir. [31] If sildenafil is coadministered with atazanavir and used for erectile dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions. [27][31] Coadministration of atazanavir with PDE5 inhibitors is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving darunavir. [32] When sildenafil is coadministered with darunavir and used for erectile dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions. [27][32] Coadministration of darunavir with PDE5 inhibitors is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is contraindicated for use with cobicistat when used for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg every 48 hours with increased monitoring for adverse reactions during times of coadministration.