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  • CLASSES

    Erectile Dysfunction Products
    Pulmonary Hypertension Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Oral phosphodiesterase-5 (PDE5) inhibitor
    Used for erectile dysfunction (ED or impotence) and for pulmonary arterial hypertension
    Contraindicated for use in patients on nitrate therapy due to the risk of cardiovascular adverse events

    COMMON BRAND NAMES

    Revatio, Viagra

    HOW SUPPLIED

    Revatio Oral Pwd F/Recon: 1mL, 10mg
    Revatio/Sildenafil/Sildenafil Citrate Intravenous Inj Sol: 0.8mg, 1mL
    Revatio/Sildenafil/Sildenafil Citrate/Viagra Oral Tab: 20mg, 25mg, 50mg, 100mg

    DOSAGE & INDICATIONS

    For the treatment of erectile dysfunction (ED).
    For the treatment of erectile dysfunction and lower urinary tract symptoms (LUTS) in combination with alfuzosin.
    Oral dosage
    Adult Males

    In a pilot study, sildenafil (25 mg PO once daily at night) combined with alfuzosin (10 mg PO once daily after the same meal) proved to be more effective than monotherapy with either agent for improving both voiding and sexual function in men with ED and LUTS suggestive of benign prostatic hyperplasia (BPH). Marked improvements in International Prostate Symptom Scores (IPSS) were noted with the combination compared to each agent alone. As expected, alfuzosin monotherapy significantly improved urinary frequency, nocturia, maximum urinary flow rate (Qmax), and postvoid residual urine (PVRU) volume whereas sildenafil showed minimal or no significant impact. Monotherapy with sildenafil showed significant improvements in erectile function whereas alfuzosin showed only a trend for improvement. The combination of sildenafil and alfuzosin, however, showed the most improvement in LUTS and erectile function compared to monotherapy with each agent. Interestingly, another study reported that sildenafil monotherapy improved LUTS but had no effect on Qmax.

    Oral dosage
    Adult Males

    50 mg PO, approximately 1 hour prior to sexual activity, up to once daily. The dose may be taken from 0.5 to 4 hours before sexual activity. Increase up to 100 mg or decrease to 25 mg based on clinical response. Maximum dosing frequency is once daily. PDE5 inhibitors are first line agents for ED according to guidelines. Although associated with high rates of success, approximately 35% of ED patients fail to respond to PDE5 inhibitor therapy. A course of an alternate PDE5 inhibitor may be considered if a patient does not respond to a PDE5 inhibitor trial; a treatment failure may be deemed after at least 4 unsuccessful trials. Patients refractory to PDE5 inhibitors should be counseled on appropriate use, potentially modifiable factors (e.g., hormonal abnormalities, food or drug interactions, lack of adequate sexual stimulation, heavy alcohol use, and the patient's relationship with his partner), and the risks and benefits of other therapies. Second-line treatment options include intracavernous injection and intra-urethral therapy. Follow-up visits for ED patients, regardless of therapy, are necessary to determine whether therapy continues to be effective and whether cardiovascular health has significantly changed.

    Geriatric Males

    25 mg PO, approximately 1 hour prior to sexual activity, up to once daily.

    Adult or Geriatric males with hepatic cirrhosis or severe renal impairment, or receiving potent CYP3A4 inhibitors (e.g., erythromycin, ritonavir, ketoconazole, itraconazole, saquinavir) concomitantly

    25 mg PO, approximately 1 hour prior to sexual activity, up to once daily. In patients receiving sildenafil with ritonavir, the maximum dosing frequency is every 48 hours.

    For the treatment of pulmonary hypertension.
    To improve exercise ability and delay clinical worsening in patients with WHO Group I pulmonary hypertension.
    NOTE: Studies establishing effectiveness were short-term (12 to 16 weeks) and included predominately patients with NYHA Functional Class II-III symptoms and idiopathic etiology (71%) or pulmonary hypertension associated with connective tissue disease (25%).
    Oral dosage
    Adults

    5 mg or 20 mg PO 3 times per day. It is recommended that doses be taken approximately 4 to 6 hours apart. Doses greater than 20 mg PO 3 times per day are not recommended by the manufacturer. In clinical trials, sildenafil improved exercise capacity, WHO functional class, and hemodynamics; no greater efficacy was achieved with the use of higher doses. In addition to improved exercise capacity and hemodynamic parameters, sildenafil (initiated at 20 mg 3 times daily, titrated to 40 to 80 mg 3 times daily) plus long-term epoprostenol therapy also resulted in delayed time to clinical worsening during clinical studies. Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity.

    Intravenous dosage

    Sildenafil injection is intended for the continued treatment of patients with PAH who are currently prescribed oral sildenafil and are temporarily unable to tolerate oral medication.

    Adults

    2.5 mg or 10 mg IV bolus 3 times per day. The dose does not need to be adjusted for body weight.

    For childhood primary and secondary pulmonary hypertension†.
    Oral dosage
    Children and Adolescents weighing more than 20 kg

    20 mg PO 3 times daily. Monitor patients carefully. Avoid higher dosing due to a greater risk of mortality in pediatric patients (age 1 to 17 years) treated with high dose sildenafil monotherapy. A randomized, double-blind, placebo-controlled, dose-escalation study in 234 patients 1 to 17 years evaluated the effect of low (10 mg PO 3 times daily), medium (10 to 40 mg PO 3 times daily based on weight), and high (20 to 80 mg PO 3 times daily based on weight) doses of sildenafil on peak oxygen consumption (primary endpoint), functional class, and hemodynamics. After 16 weeks, the low dose did not result in improvement in these outcomes, and interim data from an extension study showed increased mortality risk after 3 years or more of treatment with high doses. The study protocol was altered at the point of the interim analysis of the extension study to the following weight-based dosage: 10 mg PO 3 times per day in patients weighing 8 to 20 kg, 10 to 20 mg PO 3 times per day in patients weighing 21 to 45 kg, and 20 mg PO 3 times per day in patients weighing more than 45 kg.

    Children weighing 20 kg or less

    10 mg PO 3 times daily. Monitor patients carefully. Avoid higher dosing due to a greater risk of mortality in pediatric patients (age 1 to 17 years) treated with high dose sildenafil monotherapy. A randomized, double-blind, placebo-controlled, dose-escalation study in 234 patients 1 to 17 years evaluated the effect of low (10 mg PO 3 times daily), medium (10 to 40 mg PO 3 times daily based on weight), and high (20 to 80 mg PO 3 times daily based on weight) doses of sildenafil on peak oxygen consumption (primary endpoint), functional class, and hemodynamics. After 16 weeks, the low dose did not result in improvement in these outcomes, and interim data from an extension study showed increased mortality risk after 3 years or more of treatment with high doses. The study protocol was altered at the point of the interim analysis of the extension study to the following weight-based dosage: 10 mg PO 3 times per day in patients weighing 8 to 20 kg, 10 to 20 mg PO 3 times per day in patients weighing 21 to 45 kg, and 20 mg PO 3 times per day in patients weighing more than 45 kg.

    Infants

    0.5 to 1 mg/kg/dose PO every 8 hours. Prior to the release of pediatric pulmonary hypertension guidelines, the generally accepted dose of sildenafil was 0.5 to 2 mg/kg/dose every 6 to 8 hours, with some regimens, particularly those described in earlier reports, administering doses every 4 hours ; however, guidelines recommend more conservative dosing based on a greater risk of mortality in pediatric patients (age 1 to 17 years) treated with high dose sildenafil monotherapy, as seen in the STARTS-2 trial. Relevance of this data to the infant population is unclear.

    For the treatment of severe pulmonary hypertension†.
    Oral dosage
    Adults

    Doses of 50 mg PO twice daily and 25 mg PO every 8 hours have been used in clinical studies. One study used a step-up protocol using 50 mg PO twice daily for 4 weeks then 100 mg PO twice daily for 4 more weeks, however, no further benefit was seen at the higher dose. Sildenafil decreased pulmonary artery pressures and improved exercise capacity and symptoms in patients with moderate to severe pulmonary hypertension (PH). Additional studies reported sildenafil to be effective in treating pulmonary hypertension in patients with hemoglobinopathies and in those who were refractory to epoprostenol. The effect of sildenafil treatment on mortality in patients with PH has not been studied.

    For use as a pulmonary vasodilator to predict treatment response in patients with pulmonary hypertension†.
    Oral dosage
    Adults

    The effects of inhaled nitric oxide (NO), a single oral sildenafil dose, and the combination of oral sildenafil and inhaled NO were compared consecutively in 13 patients with severe pulmonary hypertension. Patients first received inhaled NO (10, 20, 40, and 80 ppm, each for 10 minutes); complete hemodynamics were taken at the most effective dose (80 ppm) in most patients. Nitric oxide was then stopped and, after 10 minutes, a single dose of sildenafil 75 mg PO was given. Monitoring occurred for 50 minutes with continuos ECG and arterial and pulmonary artery pressures; complete hemodynamics were recorded at 50 minutes (peak hemodynamic effects of sildenafil occur at about 50 minutes). One hour after sildenafil, inhaled NO was readministered. The results showed sildenafil was superior to NO in decreasing the mean pulmonary artery pressure and was equally effective and selective in reducing pulmonary vascular resistance. Sildenafil also caused a significant increase in the cardiac index whereas NO had no effect. Further, sildenafil decreased pulmonary artery wedge pressure (PAWP), while NO increased PAWP. The combination had additive vasodilatory effects in pulmonary circulation but not the systemic circulation. Additional studies are required to determine the maximal duration of effect, the pharmacokinetics, and the safety of sildenafil in patients with pulmonary hypertension.

    For severe pulmonary hypertension† in combination with iloprost.
    Oral dosage
    Adults

    The safety and efficacy of the combination of sildenafil and iloprost was evaluated in 30 patients with severe pulmonary hypertension (n = 16), chronic thromboembolic pulmonary hypertension (n = 13), or pulmonary hypertension due to aplasia of the left pulmonary artery (n = 1). Following administration of nitric oxide and aerosolized iloprost and a 2-hour observation period, patients were randomized to receive either 12.5 mg sildenafil, 50 mg sildenafil, 12.5 mg sildenafil plus inhaled iloprost, or 50 mg sildenafil plus inhaled iloprost. The study results indicated that the regimen containing 50 mg PO of sildenafil plus inhaled iloprost was the most effective at reducing pulmonary vascular resistance. This regimen also was synergistic, meaning the effect on pulmonary resistance was greater than either 50 mg sildenafil alone or iloprost alone. The 12.5 mg sildenafil dose regimen was the least potent of the regimens. Overall, the combination of sildenafil and inhaled iloprost appears to be an effective regimen with vasodilatory effects lasting over 3 hours and with no serious adverse events.

    For weaning of inhaled nitric oxide (iNO) in patients with pulmonary hypertension†.
    Oral dosage
    Neonates, Infants, and Children

    0.22 to 0.5 mg/kg/dose PO administered as a one time dose 1 hour prior to discontinuing iNO or given 4 times daily has been studied. None of the 15 patients receiving a one time sildenafil dose of 0.3 to 0.5 mg/kg/dose PO 1 hour prior to discontinuation of iNO experienced rebound pulmonary hypertension compared to 10 of 14 patients receiving placebo. In 7 patients receiving sildenafil 0.22 to 0.47 mg/kg/dose PO 4 times daily, mean iNO dose was significantly reduced compared to baseline within 24 hours of sildenafil initiation (12.2 vs. 29.8 ppm, p = 0.024). Guidelines recommend sildenafil use to prevent rebound pulmonary hypertension and facilitate iNO weaning in patients with evidence of increased pulmonary artery pressure upon iNO withdrawal; however, they do not provide specific dosing. Recommended maintenance dosing for pulmonary hypertension is 0.5 to 1 mg/kg/dose PO 3 times daily in patients younger than 1 year, 10 mg PO 3 times daily in patients weighing 20 kg or less, and 20 mg PO 3 times daily in patients weighing more than 20 kg.

    For the treatment of anorgasmy† or sexual dysfunction† in patients receiving antidepressant therapy.
    For the treatment of sexual dysfunction† in females receiving antidepressant therapy.
    Oral dosage
    Adult females

    In open-label studies of women with sexual dysfunction due to antidepressant therapy, improvements were reported following 50 mg PO given 60 to 90 minutes before sexual activity. If a partial response was noted with the initial dose, some patients were instructed to increase the dose to 100 mg PO.

    For the treatment of sexual dysfunction† in males receiving antidepressant therapy.
    Oral dosage
    Adult males

    A prospective, parallel-group, double-blind study involving 90 men evaluated the efficacy of sildenafil in improving sexual dysfunction associated with antidepressant therapy (i.e., selective and non-selective serotonin reuptake inhibitors). During the 6-week study, patients were randomly assigned to receive sildenafil at a flexible dose starting at 50 mg and adjusted to 100 mg before sexual activity or placebo; 89 patients completed the study. Sildenafil significantly improved erectile function, arousal, ejaculation, orgasm, and overall sexual satisfaction compared to patients receiving placebo.

    For the treatment of Raynaud's phenomenon† resistant to vasodilator therapy.
    Oral dosage
    Adults

    A double-blind, placebo-controlled, crossover study evaluated sildenafil for symptomatic secondary Raynaud's phenomenon resistant to vasodilatory therapy. Patients (n = 18, 15 were female) were randomly assigned to receive placebo or sildenafil 50 mg PO twice daily for 4 weeks; a washout period of 1 week was used before crossover. The results showed that sildenafil significantly improved microcirculation and symptoms associated with Raynaud's. In patients with chronic digital ulcerations, sildenafil treatment resulted in healing of trophic lesions which reappeared or progressed when sildenafil was stopped. Ulcerations did not heal while receiving placebo. Sildenafil therapy may be an alternative therapy in patients with Raynaud's resistant to vasodilatory therapy.

    For altitude sickness prophylaxis, specifically prevention of high altitude pulmonary edema.
    Oral dosage
    Adults

    50 mg PO every 8 hours is recommended in clinical practice guidelines. Slow ascent is the primary recommended method for prevention of high altitude pulmonary edema (HAPE). Pharmacologic prophylaxis should only be considered for individuals with a prior history of HAPE, and nifedipine is preferred. Start prophylaxis the day prior to ascent. Continue prophylaxis for 5 days after reaching target altitude or until descent is initiated.

    For the treatment of persistent pulmonary hypertension of the newborn† (PPHN).
    For adjunctive therapy for PPHN using the oral route of administration.
    Oral dosage
    Neonates

    0.5 to 1 mg/kg/dose PO every 8 hours. Delay use in extremely premature infants until retinal vascularization is established. The pharmacokinetics of sildenafil are highly variable in neonates; careful dose titration and monitoring is recommended. Prior to the release of pediatric pulmonary hypertension guidelines, the generally accepted dose of sildenafil was 0.5 to 2 mg/kg/dose every 6 to 8 hours, with doses ranging up to 3 mg/kg/dose every 6 hours ; however, guidelines recommend more conservative dosing based on a greater risk of mortality in pediatric patients (age 1 to 17 years) treated with high dose sildenafil monotherapy, as seen in the STARTS-2 trial. Relevance of this data to the neonatal population is unclear.

    For adjunctive therapy for PPHN using the intravenous route of administration.
    Continuous intravenous infusion dosage
    Neonates

    0.4 mg/kg IV loading dose over 3 hours followed by a continuous infusion of 0.067 mg/kg/hour (1.6 mg/kg/day); this dose has been proposed based on the results of an open-label, dose-escalation study in 36 term neonates. Delay use in extremely premature infants until retinal vascularization is established.

    Intermittent intravenous dosage
    Neonates

    Very limited data are available; intermittent IV infusions have been used when oral intake was not possible in 3 neonates. An initial dosage of 0.4 to 0.5 mg/kg/dose IV every 6 hours (infused over 3 hours) was given to 2 term neonates with pulmonary hypertension secondary to congenital diaphragmatic hernia. The dose was gradually titrated up to 2 mg/kg/dose IV based on clinical response. For doses less than 1.5 mg/kg/dose IV, the infusion time was gradually decreased to over 1 hour (weaned by 1 hour every 36 to 48 hours). The third neonate (gestational age 25 weeks, postnatal age 18.6 weeks) was receiving oral sildenafil 1.67 mg/kg/dose PO every 6 hours and was converted to sildenafil 1.25 mg/kg/dose IV every 6 hours when she became "nothing-by-mouth" (NPO) status. All 3 neonates were also receiving inhaled nitric oxide at the time of sildenafil initiation. The duration of treatment ranged from 6 to 51 days, and respiratory support was able to be decreased over time in all patents.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    100 mg/day PO for erectile dysfunction; 60 mg/day PO or 30 mg/day IV for pulmonary arterial hypertension. Doses up to 240 mg/day PO were utilized during clinical trials for pulmonary arterial hypertension; however, no greater efficacy was observed and the manufacturer recommends not to exceed 60 mg/day.

    Geriatric

    100 mg/day PO for erectile dysfunction; 60 mg/day PO or 30 mg/day IV for pulmonary arterial hypertension. Doses up to 240 mg/day PO were utilized during clinical trials for pulmonary arterial hypertension; however, no greater efficacy was observed and the manufacturer recommends not to exceed 60 mg/day.

    Adolescents

    Safety and efficacy have not been established. Guidelines recommend 20 mg PO 3 times daily.

    Children

    Weight more than 20 kg: Safety and efficacy have not been established. Guidelines recommend 20 mg PO 3 times daily.
    Weight 20 kg or less: Safety and efficacy have not been established. Guidelines recommend 10 mg PO 3 times daily.

    Infants

    Safety and efficacy have not been established. Guidelines recommend 1 mg/kg/dose PO every 8 hours.

    Neonates

    Safety and efficacy have not been established. Guidelines recommend 1 mg/kg/dose PO every 8 hours and 0.4 mg/kg IV as a loading dose followed by a continuous infusion of 0.067 mg/kg/hour.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Hepatic cirrhosis (Child-Pugh Class A and B): reduce starting dose to 25 mg PO (see Contraindications for hepatic disease).

    Renal Impairment

    CrCl >= 30 ml/min: no dosage adjustment needed.
    CrCl < 30 ml/min: reduce starting dose to 25 mg PO.
     
    Intermittent hemodialysis
    Follow dosage adjustment for patients with CrCl < 30 ml/min. Further dosage adjustment for hemodialysis is not needed since sildenafil is highly bound to plasma proteins and is unlikely to be significantly removed by hemodialysis.

    ADMINISTRATION

    Oral Administration

    May be administered without regard to meals.

    Oral Liquid Formulations

    Shake well for at least 10 seconds prior to each administration.
    Measure dose with the provided oral dosing syringe.
    Final concentration after reconstitution is 10 mg/mL.
     
    Reconstitution:
    Do not mix with any other medication or additional flavoring agent.
    Prior to reconstitution, tap the bottle to loosen the powder.
    Reconstitute with a total of 90 mL of water added in 2 portions. Initially, add 60 mL of water to the bottle and shake vigorously for at least 30 seconds. Add the remaining 30 mL of water and shake vigorously for at least 30 seconds.
    Remove the cap and press the adaptor for the oral syringe into the neck of the bottle; replace cap.
    Write an expiration date of 60 days from the date of constitution on the bottle label.
    Storage: Store below 30 degrees C (86 degrees F) or in refrigerator at 2 to 8 degrees C (36 to 46 degrees F). Do not freeze. Discard any unused portion after 60 days.

    Extemporaneous Compounding-Oral

    Extemporaneous 2.5 mg/mL sildenafil oral suspension:
    NOTE: Extemporaneously prepared sildenafil oral suspension is not approved by the FDA; an FDA-approved powder for oral suspension is now commercially available.
    With a mortar and pestle, grind thirty 25-mg sildenafil citrate tablets to a fine powder.
    In a separate container, mix 1 of the following: 1) 150 mL of Ora-Sweet with 150 mL of Ora-Plus; or 2) 150 mL of Simple Syrup, NF with 150 mL of methylcellulose 1%.
    Add a small amount of the mixture to the fine powder and mix into a uniform paste. Add geometric amounts of the vehicle to the almost desired volume while mixing. Transfer to a graduated cylinder and adjust to volume while mixing.
    Place in amber plastic bottles. Shake well before each use.
    Storage: This suspension is stable for 91 days when stored at 4 and 25 degrees C.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Sildenafil injection is available as a ready to use solution; further dilution is not required.
    Administer as an IV bolus injection.

    STORAGE

    Revatio:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Viagra:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Sildenafil is contraindicated in patients with a known hypersensitivity to any component of the tablet or injection. The safety and efficacy of combinations of sildenafil with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
     
    The use of sildenafil is not recommended in patients with pulmonary veno-occlusive disease (PVOD). Administration of sildenafil in this population may significantly worsen cardiovascular status. In addition, if signs of pulmonary edema occur during sildenafil administration, the possibility of associated PVOD should be considered.

    Nitrate/nitrite therapy

    Sildenafil is contraindicated in patients who are currently on nitrate/nitrite therapy (see Drug Interactions). Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil was shown to potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form are not to receive sildenafil. This includes any patient who receives intermittent nitrate therapies. It is unknown if it is safe for patients to receive nitrates once sildenafil has been administered.

    Geriatric, hepatic disease, renal impairment

    The following factors are associated with up to an eight time increase in plasma concentrations of sildenafil compared with healthy subjects: geriatric patients (40% increase in sildenafil AUC), hepatic disease (e.g., cirrhosis, 80% increase), severe renal impairment (i.e., CrCl < 30 ml/min, 100% increase), concomitant use of potent cytochrome P450 3A4 inhibitors (erythromycin (182% increase), itraconazole, ketoconazole, saquinavir (210% increase)). Because higher plasma concentrations may increase the incidence of adverse reactions, the sildenafil starting dose should be 25 mg in these patients. Additionally, ritonavir greatly increased the systemic concentrations of sildenafil in a study of healthy, non-HIV infected volunteers (11-fold increase in AUC). Based on these pharmacokinetic data, it is recommended not to exceed a maximum single dose of 25 mg sildenafil in a 48 hour period.

    Angina, aortic stenosis, cardiac arrhythmias, cardiac disease, coronary artery disease, heart failure, hypertension, hypotension, idiopathic hypertrophic subaortic stenosis, myocardial infarction, stroke

    There is a degree of cardiac risk associated with sexual activity; therefore, prescribers should evaluate the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction. Over 75 deaths due to cardiovascular events have been reported in association with sildenafil use. In a study conducted at the Mayo Clinic, sildenafil was shown to have limited cardiovascular effects during exercise in men with known or probable coronary artery disease. The study reported that sildenafil had no effect on exercise capacity or the hemodynamic response to exercise. Systolic blood pressure was reduced an average of 7 mmHg compared to baseline. Another study showed that sildenafil inhibited beta-adrenergic-stimulated systolic function. Using dobutamine in healthy volunteers, investigators reported that sildenafil suppressed the cardiac response to dobutamine but had minimal effect under resting conditions. It was also reported that the effects of sildenafil were independent of cardiac afterload or preload changes. Health care professionals should consider whether the individual would be adversely affected by vasodilatory events. In particular, caution should be used if sildenafil is prescribed in the following patient groups: patients who have suffered a myocardial infarction, stroke, or life-threatening cardiac arrhythmias in the last 6 months; patients with resting hypotension (BP < 90/50) or resting hypertension (BP > 170/100); patients with fluid depletion; patients with cardiac disease, heart failure or coronary artery disease which causes unstable angina. The American College of Cardiology recommends that sildenafil be used with caution in the following: patients with active coronary ischemia who are not taking nitrates (e.g., positive exercise test for ischemia); patients with congestive heart failure and borderline low blood pressure and borderline low volume status; patients on a complicated, multidrug, antihypertensive program; and patients taking drugs that can prolong the half-life of sildenafil (see Drug Interactions). However, one study reported that sildenafil was effective and well tolerated in patients on multidrug antihypertensive regimens and was not associated with additional safety risks in these patients. Patients with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure can be particularly sensitive to the actions of sildenafil and other vasodilators. Doses of sildenafil above 25 mg should not be given within 4 hours of an alpha-blocker (e.g., doxazosin, see Drug Interactions).

    Leukemia, multiple myeloma, penile structural abnormality, polycythemia, priapism

    Prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been associated with PDE5 inhibitor administration. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. Sildenafil and other agents for the treatment of erectile dysfunction should be used with caution in patients with penile structural abnormality (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as such as sickle cell anemia, leukemia, multiple myeloma, polycythemia, or a history of priapism). However, in one retrospective study, treatment with sildenafil did not cause any worsening deformity or progression of Peyronie's disease.

    Human immunodeficiency virus (HIV) infection

    Patients should be reminded that sildenafil, when used for erectile dysfunction, offers no protection against sexually transmitted disease. Counseling of patients about protective measures, including the prevention of transmission of human immunodeficiency virus (HIV) infection, should be considered.

    Coagulopathy, peptic ulcer disease

    Sildenafil has no effect on bleeding time when taken alone or with aspirin. In vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor). There is no safety information on the administration of sildenafil to patients with a coagulopathy or active peptic ulcer disease. Therefore, sildenafil should be administered with caution to these patients.

    Non-arteritic anterior ischemic optic neuropathy, retinitis pigmentosa, visual disturbance

    Use sildenafil cautiously in patients with preexisting visual disturbance. Post-marketing reports of sudden vision loss have occurred with phosphodiesterase inhibitors. Vision loss is attributed to a condition known as non-arteritic anterior ischemic optic neuropathy (NAION), where blood flow is blocked to the optic nerve. Patients with a history of NAION are at increased risk for recurrence. Only use a PDE5 inhibitor in these individuals if the anticipated benefit outweighs the risk. Patients with low cup to disc ratio ('crowded disc') are also at increased risk; however, this condition is uncommon, and there is insufficient evidence to support screening of prospective users of a PDE5 inhibitor. There is no safety information on the administration of sildenafil to patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa. A minority of patients with the inherited condition retinitis pigmentosa have genetic disorders of retinal phosphodiesterases. Therefore, sildenafil should be used with caution in these patients.

    Pregnancy

    Limited data do not report a clear association with the use of sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. No evidence of teratogenicity or embryofetal toxicity was observed in animal reproduction studies using sildenafil at doses 32- and 65-times the recommended human dose. There are risks to the mother and fetus from untreated pulmonary arterial hypertension.

    Breast-feeding

    Limited clinical data preclude a clear determination of the risk of sildenafil to an infant during breast-feeding. Data from a case report describe the presence of sildenafil and its active metabolite in human milk. There is insufficient information on the effects of sildenafil on the breast-fed infant and no information on the effects of sildenafil on milk production.

    Neonates, premature neonates

    Delay sildenafil use in extremely premature neonates until retinal vascularization is established. Phosphodiesterase type 5 (PDE5) inhibitors cross the blood-retina barrier and can inhibit retina-specific phosphodiesterase type 6 (PDE6). Expression of PDE6 in rod and cone photoreceptors of retinal tissue, and the discovery of PDE5 on retinal and choroid vasculature have raised concerns about the potential adverse effects sildenafil may have on the developing eye of premature neonates. An increased risk in the development or severity of retinopathy of prematurity has not been observed in retrospective studies ; however, further study is warranted.

    Abrupt discontinuation, children, infants

    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). 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. Despite the FDA's caution against use, The Pediatric Pulmonary Hypertension Network (PPHNet) recommends cautious initiation and titration of sildenafil, avoidance of high doses (more than 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. 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.

    Gastroesophageal reflux disease (GERD), hiatal hernia

    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.

    Sickle cell disease

    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.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 3.0-11.0
    myocardial infarction / Delayed / 0-2.0
    AV block / Early / 0-2.0
    intracranial bleeding / Delayed / 0-2.0
    cardiomyopathy / Delayed / 0-2.0
    cardiac arrest / Early / 0-2.0
    heart failure / Delayed / 0-2.0
    ventricular tachycardia / Early / 0-2.0
    angioedema / Rapid / 0-2.0
    anaphylactoid reactions / Rapid / 0-2.0
    tendon rupture / Delayed / 0-2.0
    exfoliative dermatitis / Delayed / 0-2.0
    hearing loss / Delayed / 0-2.0
    ocular hemorrhage / Delayed / 0-2.0
    retinal hemorrhage / Delayed / 1.4-1.4
    stroke / Early / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    ocular hypertension / Delayed / Incidence not known
    non-arteritic anterior ischemic optic neuropathy / Delayed / Incidence not known
    sickle-cell crisis / Delayed / Incidence not known

    Moderate

    edema / Delayed / 0-25.0
    peripheral edema / Delayed / 0-25.0
    dyspnea / Early / 0-7.0
    erythema / Early / 6.0-6.0
    gastritis / Delayed / 0-3.0
    blurred vision / Early / 3.0-3.0
    orthostatic hypotension / Delayed / 0-2.0
    hypotension / Rapid / 0-2.0
    migraine / Early / 0-2.0
    chest pain (unspecified) / Early / 0-2.0
    palpitations / Early / 0-2.0
    angina / Early / 0-2.0
    gout / Delayed / 0-2.0
    anemia / Delayed / 0-2.0
    hyperuricemia / Delayed / 0-2.0
    diabetes mellitus / Delayed / 0-2.0
    hyperglycemia / Delayed / 0-2.0
    leukopenia / Delayed / 0-2.0
    hypernatremia / Delayed / 0-2.0
    hypoglycemia / Early / 0-2.0
    hyperesthesia / Delayed / 0-2.0
    ataxia / Delayed / 0-2.0
    depression / Delayed / 0-2.0
    hypertonia / Delayed / 0-2.0
    colitis / Delayed / 0-2.0
    glossitis / Early / 0-2.0
    ejaculation dysfunction / Delayed / 0-2.0
    esophagitis / Delayed / 0-2.0
    stomatitis / Delayed / 0-2.0
    cystitis / Delayed / 0-2.0
    urinary incontinence / Early / 0-2.0
    testicular swelling / Early / 0-2.0
    dysphagia / Delayed / 0-2.0
    bone pain / Delayed / 0-2.0
    synovitis / Delayed / 0-2.0
    myasthenia / Delayed / 0-2.0
    skin ulcer / Delayed / 0-2.0
    contact dermatitis / Delayed / 0-2.0
    conjunctivitis / Delayed / 0-2.0
    cataracts / Delayed / 0-2.0
    photophobia / Early / 0-2.0
    priapism / Early / Incidence not known
    hypertension / Early / Incidence not known
    delirium / Early / Incidence not known
    euphoria / Early / Incidence not known
    mania / Early / Incidence not known
    hostility / Early / Incidence not known
    hallucinations / Early / Incidence not known
    confusion / Early / Incidence not known
    amnesia / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known

    Mild

    headache / Early / 16.0-57.0
    diarrhea / Early / 3.0-25.0
    nausea / Early / 25.0-25.0
    dyspepsia / Early / 7.0-17.0
    epistaxis / Delayed / 9.0-13.0
    flushing / Rapid / 10.0-10.0
    nasal congestion / Early / 4.0-9.0
    insomnia / Early / 0-7.0
    myalgia / Early / 0-7.0
    fever / Early / 6.0-6.0
    rhinitis / Early / 4.0-4.0
    paresthesias / Delayed / 0-3.0
    sinusitis / Delayed / 1.0-3.0
    rash / Early / 2.0-2.0
    dizziness / Early / 2.0-2.0
    syncope / Early / 0-2.0
    abdominal pain / Early / 0-2.0
    chills / Rapid / 0-2.0
    asthenia / Delayed / 0-2.0
    photosensitivity / Delayed / 0-2.0
    vertigo / Early / 0-2.0
    pharyngitis / Delayed / 0-2.0
    laryngitis / Delayed / 0-2.0
    drowsiness / Early / 0-2.0
    cough / Delayed / 0-2.0
    hyporeflexia / Delayed / 0-2.0
    tremor / Early / 0-2.0
    gingivitis / Delayed / 0-2.0
    orgasm dysfunction / Delayed / 0-2.0
    vomiting / Early / 0-2.0
    breast enlargement / Delayed / 0-2.0
    increased urinary frequency / Early / 0-2.0
    nocturia / Early / 0-2.0
    xerostomia / Early / 0-2.0
    diaphoresis / Early / 0-2.0
    urticaria / Rapid / 0-2.0
    pruritus / Rapid / 0-2.0
    otalgia / Early / 0-2.0
    tinnitus / Delayed / 0-2.0
    ocular pain / Early / 0-2.0
    xerophthalmia / Early / 0-2.0
    mydriasis / Early / 0-2.0
    back pain / Delayed / 2.0
    arthralgia / Delayed / 2.0
    agitation / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    paranoia / Early / Incidence not known
    irritability / Delayed / Incidence not known
    emotional lability / Early / Incidence not known
    ocular irritation / Rapid / Incidence not known
    diplopia / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Alfuzosin: (Moderate) Thereis is a risk of enhanced hypotensive effects in individual patients when alfuzosin is co-administered with phosphodiesterase (PDE5) inhibitors such as sildenafil. Sildenafil doses greater than 25 mg should not be taken within 4 hours of taking an alpha-blocker. Patients should be stabilized on their alpha blocker therapy prior to starting sildenafil, or if already receiving an optimum dose of sildenafil, the alpha blocker therapy should be started at the lowest possible dose. Concurrent use of PDE5 inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. There have been infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-headedness, but not syncope. Despite the potential for interaction, with regimen modifications, patients can take these drugs together.
    Aliskiren: (Moderate) Aliskiren can enhance the effects of sildenafil on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren.
    Aliskiren; Amlodipine: (Moderate) Aliskiren can enhance the effects of sildenafil on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren. (Moderate) Monitor for additive hypotension if amlodipine is administered concurrently with sildenafil, as both agents act independently to reduce blood pressure. When sildenafil 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure (SBP) was 8 mmHg systolic and 7 mmHg diastolic
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Aliskiren can enhance the effects of sildenafil on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren. (Moderate) Monitor for additive hypotension if amlodipine is administered concurrently with sildenafil, as both agents act independently to reduce blood pressure. When sildenafil 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure (SBP) was 8 mmHg systolic and 7 mmHg diastolic
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Aliskiren can enhance the effects of sildenafil on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren.
    Aliskiren; Valsartan: (Moderate) Aliskiren can enhance the effects of sildenafil on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren.
    Alpha-blockers: (Moderate) Patients should be stable on alpha-blocker therapy before initiating therapy with sildenafil or other phosphodiesterase type 5 (PDE5) inhibitors; the lowest dose should be used to initiate therapy. Conversely, patients already receiving an optimized dose of a PDE5 inhibitor should be started on the lowest dose of an alpha-blocker; increases in the alpha-blocker dose should be done in a stepwise fashion. Using sildenafil and alpha-blockers together may reduce blood pressure significantly in some patients and may lead to symptomatic hypotension. PDE5 inhibitors and alpha blockers are both vasodilators with blood pressure lowering effects. Sildenafil doses greater than 25 mg should not be taken within 4 hours of taking alpha-blockers.The manufacturer reports on 3 studies assessing the interaction between sildenafil with doxazosin. In these studies, healthy patients with BPH were stabilized on doxazosin for at least 14 days before receiving sildenafil or placebo. Patients receiving the combination of sildenafil and doxazosin had greater decreases in blood pressure than those receiving doxazosin and placebo. No episodes of syncope were reported in these studies. In one published study, sildenafil and doxazosin were used together in patients with non-organic erectile dysfunction refractory to sildenafil monotherapy; blood pressure was not significantly altered in this study. The safety of using PDE5 inhibitors and alpha-blockers together may also be affected by other factors, such as intravascular volume depletion and coadministration of other antihypertensive medications.
    Ambrisentan: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
    Amiodarone: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with amiodarone is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor.
    Amlodipine: (Moderate) Monitor for additive hypotension if amlodipine is administered concurrently with sildenafil, as both agents act independently to reduce blood pressure. When sildenafil 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure (SBP) was 8 mmHg systolic and 7 mmHg diastolic
    Amlodipine; Atorvastatin: (Moderate) Monitor for additive hypotension if amlodipine is administered concurrently with sildenafil, as both agents act independently to reduce blood pressure. When sildenafil 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure (SBP) was 8 mmHg systolic and 7 mmHg diastolic
    Amlodipine; Benazepril: (Moderate) Monitor for additive hypotension if amlodipine is administered concurrently with sildenafil, as both agents act independently to reduce blood pressure. When sildenafil 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure (SBP) was 8 mmHg systolic and 7 mmHg diastolic
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Monitor for additive hypotension if amlodipine is administered concurrently with sildenafil, as both agents act independently to reduce blood pressure. When sildenafil 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure (SBP) was 8 mmHg systolic and 7 mmHg diastolic
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Monitor for additive hypotension if amlodipine is administered concurrently with sildenafil, as both agents act independently to reduce blood pressure. When sildenafil 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure (SBP) was 8 mmHg systolic and 7 mmHg diastolic
    Amlodipine; Olmesartan: (Moderate) Monitor for additive hypotension if amlodipine is administered concurrently with sildenafil, as both agents act independently to reduce blood pressure. When sildenafil 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure (SBP) was 8 mmHg systolic and 7 mmHg diastolic
    Amlodipine; Telmisartan: (Moderate) Monitor for additive hypotension if amlodipine is administered concurrently with sildenafil, as both agents act independently to reduce blood pressure. When sildenafil 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure (SBP) was 8 mmHg systolic and 7 mmHg diastolic
    Amlodipine; Valsartan: (Moderate) Monitor for additive hypotension if amlodipine is administered concurrently with sildenafil, as both agents act independently to reduce blood pressure. When sildenafil 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure (SBP) was 8 mmHg systolic and 7 mmHg diastolic
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Coadministration of clarithromycin is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving clarithromycin. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Clarithromycin is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Coadministration of clarithromycin is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving clarithromycin. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Clarithromycin is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Amprenavir: (Major) 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. Sildenafil is contraindicated for use with the anti-retroviral protease inhibitors when used for pulmonary arterial hypertension (PAH). If sildenafil is coadministered with amprenavir and used for erectile dysfunction, use sildenafil at reduced adult doses of 25 mg every 48 hours with increased monitoring for adverse reactions. Substantially increased sildenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
    Amyl Nitrite: (Severe) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Apalutamide: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with apalutamide is necessary. Sildenafil is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant administration of strong CYP3A inducers is expected to substantially decrease plasma concentrations of sildenafil. Population pharmacokinetic analysis indicates an approximately 3-fold increase in sildenafil clearance with concomitant use of weak CYP3A inducers.
    Aprepitant, Fosaprepitant: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministered with multi-day regimens of oral aprepitant. A dose reduction of sildenafil may be required when using for erectile dysfunction. Sildenafil is a CYP3A4 substrate and aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate.
    Atazanavir: (Major) Sildenafil is contraindicated for use with atazanavir when used for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Atazanavir; Cobicistat: (Major) Sildenafil is contraindicated for use with atazanavir when used for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold. (Major) 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 in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Atropine; Difenoxin: (Moderate) Diphenoxylate/difenoxin is a synthetic opiate agonist with a chemical structure similar to that of meperidine. Prolonged erections have been reported in two patients taking sildenafil with dihydrocodeine. In both cases, patients reported erections subsided immediately after orgasm when taking sildenafil alone. Although more data are needed, use caution when prescribing opiate agonists and sildenafil concomitantly.
    Atropine; Diphenoxylate: (Moderate) Diphenoxylate/difenoxin is a synthetic opiate agonist with a chemical structure similar to that of meperidine. Prolonged erections have been reported in two patients taking sildenafil with dihydrocodeine. In both cases, patients reported erections subsided immediately after orgasm when taking sildenafil alone. Although more data are needed, use caution when prescribing opiate agonists and sildenafil concomitantly.
    Barbiturates: (Minor) Sildenafil is metabolized principally by the hepatic CYP3A4 and CYP2C9 isoenzymes. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of sildenafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates.
    Boceprevir: (Major) Sildenafil, when used for pulmonary arterial hypertension (PAH), is contraindicated with boceprevir. Coadministration of boceprevir with phosphodiesterase type 5 (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. Boceprevir can be used with sildenafil for erectile dysfunction; use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions.
    Brigatinib: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with brigatinib is necessary. Sildenafil is a CYP3A substrate and brigatinib induces CYP3A in vitro. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was coadministered with weak CYP3A inducers; brigatinib may also decrease sildenafil exposure.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Capecitabine: (Minor) Use caution if coadministration of capecitabine with sildenafil is necessary, and monitor for an increase in sildenafil-related adverse reactions. Sildenafil is metabolized principally CYP3A4 (major route) and 2C9 (minor route); capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
    Carbamazepine: (Minor) Sildenafil is metabolized principally by cytochrome P450 CYP3A4 and 2C9 enzymes. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, such as carbamazepine, will decrease plasma levels of sildenafil, however, no interaction studies have been performed.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbinoxamine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
    Ceritinib: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with ceritinib is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and ceritinib is a moderate CYP3A4 inhibitor.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chloramphenicol: (Major) Coadministration of chloramphenicol is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving chloramphenicol. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Chloramphenicol is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Cimetidine: (Major) Phosphodiesterase inhibitors are metabolized principally by cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Cimetidine is a known inhibitor of hepatic CYP enzymes. 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 phosphodiesterase inhibitors
    Ciprofloxacin: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministered with ciprofloxacin. A dose reduction of sildenafil may be required when using for erectile dysfunction. After concomitant administration of a single oral 50 mg dose of sildenafil with 500 mg of ciprofloxacin to healthy subjects, the mean Cmax and the mean AUC of sildenafil were both increased approximately two-fold. Sildenafil is a sensitive CYP3A4 substrate and ciprofloxacin is a moderate CYP3A4 inhibitor.
    Clarithromycin: (Major) Coadministration of clarithromycin is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving clarithromycin. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Clarithromycin is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Clopidogrel: (Moderate) At high concentrations in vitro, clopidogrel inhibits the activity of CYP2C9. Thus, clopidogrel could increase plasma concentrations of drugs metabolized by this isoenzyme, such as sildenafil. Although there are no in vivo data with which to predict the magnitude or clinical significance of this potential interaction, caution should be used when sildenafil is coadministered with clopidogrel.
    Cobicistat: (Major) 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 in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) 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 in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) 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 in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Codeine; Phenylephrine; Promethazine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Conivaptan: (Major) Coadministration of conivaptan is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving conivaptan. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Conivaptan is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Crizotinib: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with crizotinib is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Dabrafenib: (Major) The concomitant use of dabrafenib and sildenafil may lead to decreased sildenafil concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of sildenafil efficacy. Dabrafenib is a moderate CYP3A4 inducer and sildenafil is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 65%.
    Dalfopristin; Quinupristin: (Major) Coadministration of dalfopristin; quinupristin is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving dalfopristin; quinupristin. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Dalfopristin; quinupristin is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Danazol: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with danazol is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and danazol is a CYP3A4 inhibitor.
    Darunavir: (Major) Sildenafil is contraindicated for use with darunavir when used for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Darunavir; Cobicistat: (Major) 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 in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold. (Major) Sildenafil is contraindicated for use with darunavir when used for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration of ritonavir is contraindicated in patients receiving sildenafil for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use substantially increases the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Ritonavir, a strong CYP3A4 inhibitor, increased the AUC of sildenafil, a sensitive CYP3A4 substrate, by 11-fold in a drug interaction study.
    Delavirdine: (Major) Coadministration of delavirdine is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Delavirdine is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Dexamethasone: (Minor) Sildenafil is metabolized principally by CYP3A4. It can be expected that concomitant administration of sildenafil with CYP3A4 enzyme inducers like dexamethasone will decrease plasma concentrations of sildenafil.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Dextromethorphan; Quinidine: (Moderate) Sildenafil is metabolized principally by the hepatic isoenzymes CYP3A4 and CYP2C9. Inhibitors of these isoenzymes, such as quinidine, may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects.
    Dihydroergotamine: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Diltiazem: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with diltiazem is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Diphenhydramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Doxazosin: (Moderate) Patients should be stable on alpha-blocker therapy before initiating therapy with sildenafil or other phosphodiesterase type 5 (PDE5) inhibitors; the lowest dose should be used to initiate therapy. Conversely, patients already receiving an optimized dose of a PDE5 inhibitor should be started on the lowest dose of an alpha-blocker; increases in the alpha-blocker dose should be done in a stepwise fashion. Using sildenafil and alpha-blockers together may reduce blood pressure significantly in some patients and may lead to symptomatic hypotension. PDE5 inhibitors and alpha blockers are both vasodilators with blood pressure lowering effects. Sildenafil doses greater than 25 mg should not be taken within 4 hours of taking alpha-blockers.The manufacturer reports on 3 studies assessing the interaction between sildenafil with doxazosin. In these studies, healthy patients with BPH were stabilized on doxazosin for at least 14 days before receiving sildenafil or placebo. Patients receiving the combination of sildenafil and doxazosin had greater decreases in blood pressure than those receiving doxazosin and placebo. No episodes of syncope were reported in these studies. In one published study, sildenafil and doxazosin were used together in patients with non-organic erectile dysfunction refractory to sildenafil monotherapy; blood pressure was not significantly altered in this study. The safety of using PDE5 inhibitors and alpha-blockers together may also be affected by other factors, such as intravascular volume depletion and coadministration of other antihypertensive medications.
    Dronedarone: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with dronedarone is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor.
    Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
    Dutasteride; Tamsulosin: (Major) There is al risk of enhanced hypotensive effects in individual patients when tamsulosin is co-administered with phosphodiesterase (PDE5) inhibitors. Concurrent use of PDE5 inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Sildenafil doses greater than 25 mg should not be taken within 4 hours of taking an alpha-blocker. Patients should be stabilized on their alpha blocker therapy prior to starting either avanafil, tadalafil or vardenafil, or if already receiving an optimum dose of these PDE5 inhibitors, the alpha blocker therapy should be started at the lowest possible dose.
    Efavirenz: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as sildenafil.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as sildenafil.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as sildenafil.
    Elbasvir; Grazoprevir: (Moderate) Administering sildenafil with elbasvir; grazoprevir may result in elevated sildenafil plasma concentrations. Sildenafil is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Enzalutamide: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with enzalutamide is necessary. Sildenafil is a CYP3A4 (major) and CYP2C9 (minor) substrate. Enzalutamide is a strong CYP3A4 inducer and a moderate inducer of CYP2C9. Concomitant administration of strong CYP3A inducers is expected to substantially decrease plasma concentrations of sildenafil. Population pharmacokinetic analysis indicates an approximately 3-fold increase in sildenafil clearance with concomitant use of weak CYP3A inducers.
    Erythromycin: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with erythromycin is necessary; consider a starting dose of 25 mg of sildenafil when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and erythromycin is a moderate CYP3A4 inhibitor. In a drug interaction study, coadministration with erythromycin increased the Cmax and AUC of sildenafil by 160% and 182%, respectively. Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A inhibitors will be less for sildenafil injection than those observed after oral sildenafil administration.
    Erythromycin; Sulfisoxazole: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with erythromycin is necessary; consider a starting dose of 25 mg of sildenafil when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and erythromycin is a moderate CYP3A4 inhibitor. In a drug interaction study, coadministration with erythromycin increased the Cmax and AUC of sildenafil by 160% and 182%, respectively. Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A inhibitors will be less for sildenafil injection than those observed after oral sildenafil administration.
    Etravirine: (Moderate) Etravirine is an inducer of CYP3A4; coadministration may result in decreased sildenafil concentrations. Dosage adjustments may be needed based on clinical efficacy.
    Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as sildenafil , has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of sildenafil during coadministration with fenofibric acid.
    Fluconazole: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with fluconazole is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor.
    Fluoxetine: (Major) A starting dose of 25 mg of sildenafil for erectile dysfunction should be considered in patients taking fluoxetine. Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. The active metabolite of fluoxetine is a moderate CYP3A4 inhibitor. Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects.
    Fluoxetine; Olanzapine: (Major) A starting dose of 25 mg of sildenafil for erectile dysfunction should be considered in patients taking fluoxetine. Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. The active metabolite of fluoxetine is a moderate CYP3A4 inhibitor. Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects.
    Fluvoxamine: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with fluvoxamine is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor. In a drug interaction study, coadministration of fluvoxamine increased the sildenafil AUC by 40%.
    Fosamprenavir: (Major) Sildenafil is contraindicated for use with fosamprenavir when used for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Grapefruit juice: (Moderate) Sildenafil is metabolized via the cytochrome CYP 3A4 isozyme. Grapefruit juice contains a compound that inhibits CYP3A4 in enterocytes in the GI tract. Sildenafil levels may increase; it is possible that sildenafil-induced side effects could also be increased in some individuals. One study has confirmed a potential interaction; sildenafil's AUC increased 23 percent with coadministration of grapefruit juice.
    Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Hydantoins: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, including sildenafil, leading to reduced efficacy of sildenafil.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Severe) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Hydrocodone; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Idelalisib: (Major) Coadministration of idelalisib is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving idelalisib. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Idelalisib is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Imatinib: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with imatinib is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor.
    Indinavir: (Major) Sildenafil is contraindicated for use with indinavir when used for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. In a small pharmacokinetic study, the coadministration of a single dose of sildenafil (25 mg) to patients receiving indinavir (800 mg every 8 hours) resulted in markedly increased sildenafil AUC values (340% increase), as compared to historical controls. In two of the six subjects, prolonged clinical effects of sildenafil were noted for 72 hours after a single dose of sildenafil.
    Isavuconazonium: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with isavuconazonium is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and isavuconazonium is a moderate CYP3A4 inhibitor.
    Isocarboxazid: (Moderate) Additive hypotensive effects may be seen when Monoamine oxidase inhibitors (MAOIs) are combined with sildenafil. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with sildenafil.
    Isoniazid, INH: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with isoniazid is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and isoniazid is a moderate CYP3A4 inhibitor.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with isoniazid is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and isoniazid is a moderate CYP3A4 inhibitor. (Minor) Sildenafil is metabolized principally by cytochrome P450 3A4 and 2C9 enzymes. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, such as rifampin, will decrease plasma levels of sildenafil, however, no interaction studies have been performed.
    Isoniazid, INH; Rifampin: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with isoniazid is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and isoniazid is a moderate CYP3A4 inhibitor. (Minor) Sildenafil is metabolized principally by cytochrome P450 3A4 and 2C9 enzymes. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, such as rifampin, will decrease plasma levels of sildenafil, however, no interaction studies have been performed.
    Isosorbide Dinitrate, ISDN: (Severe) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Isosorbide Mononitrate: (Severe) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Itraconazole: (Major) Avoid use of sildenafil for the treatment of pulmonary hypertension during and for 2 weeks after discontinuation of itraconazole treatment. When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving itraconazole. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Itraconazole is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Ivacaftor: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as sildenafil. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; sildenafil is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as sildenafil, can theoretically increase sildenafil exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Ketoconazole: (Major) Coadministration of ketoconazole is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving ketoconazole. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Ketoconazole is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of sildenafil; monitor for potential reduction in efficacy. Sildenafil is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of sildenafil; monitor for potential reduction in efficacy. Sildenafil is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Major) Monitor for an increase in sildenafil-related adverse reactions if coadministration with letermovir is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Concurrent use is not recommended in patients receiving sildenafil for pulmonary arterial hypertension and taking cyclosporine, because the magnitude of the interaction may be amplified. Consider a starting dose of 25 mg of sildenafil for erectile dysfunction in patients receiving letermovir with cyclosporine. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is metabolized principally by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
    Lopinavir; Ritonavir: (Major) Coadministration of ritonavir is contraindicated in patients receiving sildenafil for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use substantially increases the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Ritonavir, a strong CYP3A4 inhibitor, increased the AUC of sildenafil, a sensitive CYP3A4 substrate, by 11-fold in a drug interaction study. (Major) Sildenafil is contraindicated for use with lopinavir; ritonavir when used for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; lopinavir; ritonavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Lorcaserin: (Major) Lorcaserin is a serotonin 2C receptor agonist, and priapism is a potential effect of 5-HT2C receptor agonism. Because there is little experience with the combination of lorcaserin and medications indicated for erectile dysfunction (e.g., phosphodiesterase inhibitors), combined use should be approached with caution.
    Lumacaftor; Ivacaftor: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as sildenafil. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; sildenafil is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as sildenafil, can theoretically increase sildenafil exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Mifepristone: (Major) Coadministration of chronic mifepristone is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving chronic mifepristone. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown. Mifepristone is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Mitotane: (Major) Use caution if mitotane and sildenafil are used concomitantly, and monitor for decreased efficacy of sildenafil and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and sildenafil is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers.
    Monoamine oxidase inhibitors: (Moderate) Additive hypotensive effects may be seen when Monoamine oxidase inhibitors (MAOIs) are combined with sildenafil. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with sildenafil.
    Nebivolol: (Moderate) The AUC and Cmax of sildenafil were decreased by 21% and 23%, respectively, when coadministered with nebivolol. A similar decrease in the concentration of d-nebivolol (less than 20% in the AUC and Cmax) was also observed with the coadministration of sildenafil. If sildenafil and nebivolol are to be used concomitantly, patients should be monitored closely.
    Nebivolol; Valsartan: (Moderate) The AUC and Cmax of sildenafil were decreased by 21% and 23%, respectively, when coadministered with nebivolol. A similar decrease in the concentration of d-nebivolol (less than 20% in the AUC and Cmax) was also observed with the coadministration of sildenafil. If sildenafil and nebivolol are to be used concomitantly, patients should be monitored closely.
    Nefazodone: (Major) Coadministration of nefazodone is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving nefazodone. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Nefazodone is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Nelfinavir: (Major) Sildenafil is contraindicated for use with nelfinavir when used for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Nesiritide, BNP: (Major) No formal drug interaction trials have been conducted with nesiritide. Sildenafil use within 24 hours was an exclusion criteria for nesiritide treatment during clinical trials. Although not identified during clinical trials, the potential for symptomatic hypotension may be significantly increased when coadministering nesiritide with sildenafil. Sildenafil should be avoided within 24 hours before or after nesiritide use.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with netupitant; palonosetron is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor.
    Nevirapine: (Minor) Sildenafil is metabolized principally by cytochrome P450 3A4 and 2C9 enzymes. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, such as nevirapine, will decrease plasma levels of sildenafil.
    Nicardipine: (Moderate) Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates, such as sildenafil.
    Nifedipine: (Moderate) Nifedipine can have additive hypotensive effects when administered with phosphodiesterase inhibitors (PDE 5 inhibitors). The patient should be monitored carefully and the dosage should be adjusted based on clinical response. For example, in patients whose hypertension was controlled with nifedipine, vardenafil produced mean additional supine systolic/diastolic blood pressure reductions of 3 to 4 mmHg (age group 65 to 69 years) and 5 to 6 mmHg (age group 70 to 80 years) compared to placebo.
    Nilotinib: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with nilotinib is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor.
    Nitrates: (Severe) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Nitroglycerin: (Severe) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Nitroprusside: (Moderate) The hypotensive effects of nitroprusside may be augmented by phosphodiesterase inhibitors. Monitor blood pressure when co-administering phosphodiesterase inhibitors and blood pressure lowering medications, like nitroprusside. Phosphodiesterase inhibitors have vasodilatory properties, and nitroprusside is a potent vasodilator. In addition, phosphodiesterase type-5 (PDE5) is found in platelets, and PDE5 inhibitors may potentiate the nitric oxide-mediated platelet anti-aggregatory activity of nitroprusside.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration of ritonavir is contraindicated in patients receiving sildenafil for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use substantially increases the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Ritonavir, a strong CYP3A4 inhibitor, increased the AUC of sildenafil, a sensitive CYP3A4 substrate, by 11-fold in a drug interaction study.
    Opiate Agonists: (Moderate) Prolonged erections have been reported in two patients taking sildenafil with dihydrocodeine. Although more data are needed, use caution when prescribing opiate agonists and sildenafil concomitantly.
    Oritavancin: (Moderate) Coadministration of oritavancin and sildenafil may result in increases or decreases in sildenafil exposure and may increase side effects or decrease efficacy of sildenafil. Sildenafil is primarily metabolized by CYP3A4, but is also metabolized by CYP2C9. Oritavancin weakly induces CYP3A4, while weakly inhibiting CYP2C9. If these drugs are administered concurrently, monitor the patient for signs of toxicity or lack of efficacy.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and sildenafil, a CYP3A4 substrate, may cause an increase in systemic concentrations of sildenafil. Use caution when administering these drugs concomitantly.
    Perindopril; Amlodipine: (Moderate) Monitor for additive hypotension if amlodipine is administered concurrently with sildenafil, as both agents act independently to reduce blood pressure. When sildenafil 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure (SBP) was 8 mmHg systolic and 7 mmHg diastolic
    Phenelzine: (Moderate) Additive hypotensive effects may be seen when Monoamine oxidase inhibitors (MAOIs) are combined with sildenafil. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with sildenafil.
    Phenoxybenzamine: (Moderate) Patients should be stable on alpha-blocker therapy before initiating therapy with sildenafil or other phosphodiesterase type 5 (PDE5) inhibitors; the lowest dose should be used to initiate therapy. Conversely, patients already receiving an optimized dose of a PDE5 inhibitor should be started on the lowest dose of an alpha-blocker; increases in the alpha-blocker dose should be done in a stepwise fashion. Using sildenafil and alpha-blockers together may reduce blood pressure significantly in some patients and may lead to symptomatic hypotension. PDE5 inhibitors and alpha blockers are both vasodilators with blood pressure lowering effects. Sildenafil doses greater than 25 mg should not be taken within 4 hours of taking alpha-blockers.The manufacturer reports on 3 studies assessing the interaction between sildenafil with doxazosin. In these studies, healthy patients with BPH were stabilized on doxazosin for at least 14 days before receiving sildenafil or placebo. Patients receiving the combination of sildenafil and doxazosin had greater decreases in blood pressure than those receiving doxazosin and placebo. No episodes of syncope were reported in these studies. In one published study, sildenafil and doxazosin were used together in patients with non-organic erectile dysfunction refractory to sildenafil monotherapy; blood pressure was not significantly altered in this study. The safety of using PDE5 inhibitors and alpha-blockers together may also be affected by other factors, such as intravascular volume depletion and coadministration of other antihypertensive medications.
    Phentolamine: (Moderate) Patients should be stable on alpha-blocker therapy before initiating therapy with sildenafil or other phosphodiesterase type 5 (PDE5) inhibitors; the lowest dose should be used to initiate therapy. Conversely, patients already receiving an optimized dose of a PDE5 inhibitor should be started on the lowest dose of an alpha-blocker; increases in the alpha-blocker dose should be done in a stepwise fashion. Using sildenafil and alpha-blockers together may reduce blood pressure significantly in some patients and may lead to symptomatic hypotension. PDE5 inhibitors and alpha blockers are both vasodilators with blood pressure lowering effects. Sildenafil doses greater than 25 mg should not be taken within 4 hours of taking alpha-blockers.The manufacturer reports on 3 studies assessing the interaction between sildenafil with doxazosin. In these studies, healthy patients with BPH were stabilized on doxazosin for at least 14 days before receiving sildenafil or placebo. Patients receiving the combination of sildenafil and doxazosin had greater decreases in blood pressure than those receiving doxazosin and placebo. No episodes of syncope were reported in these studies. In one published study, sildenafil and doxazosin were used together in patients with non-organic erectile dysfunction refractory to sildenafil monotherapy; blood pressure was not significantly altered in this study. The safety of using PDE5 inhibitors and alpha-blockers together may also be affected by other factors, such as intravascular volume depletion and coadministration of other antihypertensive medications.
    Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Phenylephrine; Promethazine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Posaconazole: (Major) Coadministration of posaconazole is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving posaconazole. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Posaconazole is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Prazosin: (Moderate) Patients should be stable on alpha-blocker therapy before initiating therapy with sildenafil or other phosphodiesterase type 5 (PDE5) inhibitors; the lowest dose should be used to initiate therapy. Conversely, patients already receiving an optimized dose of a PDE5 inhibitor should be started on the lowest dose of an alpha-blocker; increases in the alpha-blocker dose should be done in a stepwise fashion. Using sildenafil and alpha-blockers together may reduce blood pressure significantly in some patients and may lead to symptomatic hypotension. PDE5 inhibitors and alpha blockers are both vasodilators with blood pressure lowering effects. Sildenafil doses greater than 25 mg should not be taken within 4 hours of taking alpha-blockers.The manufacturer reports on 3 studies assessing the interaction between sildenafil with doxazosin. In these studies, healthy patients with BPH were stabilized on doxazosin for at least 14 days before receiving sildenafil or placebo. Patients receiving the combination of sildenafil and doxazosin had greater decreases in blood pressure than those receiving doxazosin and placebo. No episodes of syncope were reported in these studies. In one published study, sildenafil and doxazosin were used together in patients with non-organic erectile dysfunction refractory to sildenafil monotherapy; blood pressure was not significantly altered in this study. The safety of using PDE5 inhibitors and alpha-blockers together may also be affected by other factors, such as intravascular volume depletion and coadministration of other antihypertensive medications.
    Quinidine: (Moderate) Sildenafil is metabolized principally by the hepatic isoenzymes CYP3A4 and CYP2C9. Inhibitors of these isoenzymes, such as quinidine, may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects.
    Quinine: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with quinine is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and quinine is a moderate CYP3A4 inhibitor.
    Ranolazine: (Moderate) Sildenafil is metabolized principally by the hepatic CYP3A4 (major route) and 2C9 (minor route) isoenzymes. 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. Population data from patients in clinical trials did indicate a reduction in sildenafil clearance when it was coadministered with CYP3A4 inhibitors. CYP3A4 inhibitors include ranolazine.
    Rasagiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with vasodilators. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with sildenafil is necessary, as the systemic exposure of sildenafil may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a CYP3A4 inhibitor and sildenafil is a CYP3A4 substrate. Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with sildenafil is necessary, as the systemic exposure of sildenafil may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a CYP3A4 inhibitor and sildenafil is a CYP3A4 substrate. Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors.
    Rifabutin: (Minor) Sildenafil is metabolized principally by cytochrome P450 3A4 and 2C9 enzymes. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, such as rifabutin, will decrease plasma levels of sildenafil, however, no interaction studies have been performed.
    Rifampin: (Minor) Sildenafil is metabolized principally by cytochrome P450 3A4 and 2C9 enzymes. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, such as rifampin, will decrease plasma levels of sildenafil, however, no interaction studies have been performed.
    Rifapentine: (Minor) Rifapentine induces hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by CYP3A4 and CYP2C8/9, such as sildenafil, may require dosage adjustments when administered concurrently with rifapentine.
    Riociguat: (Severe) Coadministration of riociguat and sildenafil is contraindicated due to the risk of hypotension. Do not administer riociguat within 24 hours of sildenafil. Monitor for signs and symptoms of hypotension during transition of therapy. The addition of riociguat to a stable sildenafil regimen (20 mg 3 times daily) resulted in additive hemodynamic effects in an exploratory interaction study in 7 patients with pulmonary arterial hypertension (PAH). Among patients with PAH on stable sildenafil treatment and riociguat there was 1 death, possibly related to the combination of these drugs, and a high rate of discontinuation for hypotension.
    Ritonavir: (Major) Coadministration of ritonavir is contraindicated in patients receiving sildenafil for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use substantially increases the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Ritonavir, a strong CYP3A4 inhibitor, increased the AUC of sildenafil, a sensitive CYP3A4 substrate, by 11-fold in a drug interaction study.
    Sapropterin: (Moderate) Sapropterin acts as a cofactor in the synthesis of nitric oxide and may cause vasorelaxation. Caution should be exercised when administering sapropterin in combination with drugs that affect nitric oxide-mediated vasorelaxation such as phosphodiesterase inhibitors. When given together these agents may produce an additive reduction in blood pressure. The combination of sapropterin and a phosphodiesterase (PDE5) inhibitor did not significantly reduce blood pressure when administered concomitantly in animal studies. The additive effect of these agents has not been studied in humans.
    Saquinavir: (Major) Sildenafil is contraindicated for use with saquinavir when used for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. Coadministration of saquinavir increased the sildenafil AUC by about 3-fold in a drug interaction study.
    Selegiline: (Moderate) Additive hypotensive effects may be seen when Monoamine oxidase inhibitors (MAOIs) are combined with sildenafil. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with sildenafil.
    Silodosin: (Major) Patients should be stable on alpha-blocker therapy before initiating therapy with sildenafil. Conversely, patients already receiving an optimized dose of a PDE5 inhibitor should be started on the lowest dose of an alpha-blocker; increases in the alpha-blocker dose should be done in a stepwise fashion. Using sildenafil and alpha-blockers together may reduce blood pressure significantly in some patients and may lead to symptomatic hypotension. Sildenafil doses greater than 25 mg should not be taken within 4 hours of taking alpha-blockers.
    Simeprevir: (Moderate) Coadministration of sildenafil with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in sildenafil plasma concentrations. No dose adjustments are required when treating erectile dysfunction. If treating pulmonary arterial hypertension, start at the lowest sildenafil dose and increase as needed while monitoring clinically.
    Streptogramins: (Major) Coadministration of dalfopristin; quinupristin is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving dalfopristin; quinupristin. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Dalfopristin; quinupristin is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Tacrolimus: (Moderate) Consider initiating sildenafil at a low dose (25 mg) in kidney transplant recipients receiving tacrolimus. In a study of renal transplant patients, coadministration of tacrolimus with a single 50 mg dose of sildenafil resulted in an increase in the AUC, Cmax, and half-life of sildenafil. Decreases in blood pressure were also observed. No significant effect on the pharmacokinetic parameters of tacrolimus were observed.
    Tamsulosin: (Major) There is al risk of enhanced hypotensive effects in individual patients when tamsulosin is co-administered with phosphodiesterase (PDE5) inhibitors. Concurrent use of PDE5 inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Sildenafil doses greater than 25 mg should not be taken within 4 hours of taking an alpha-blocker. Patients should be stabilized on their alpha blocker therapy prior to starting either avanafil, tadalafil or vardenafil, or if already receiving an optimum dose of these PDE5 inhibitors, the alpha blocker therapy should be started at the lowest possible dose.
    Telaprevir: (Severe) Sildenafil, when used for pulmonary arterial hypertension (PAH), is contraindicated with telaprevir. Coadministration of telaprevir with phosphodiesterase type 5 (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. Telaprevir can be used cautiously with sildenafil for erectile dysfunction; use sildenafil at a reduced dose of 25 mg no more frequently than every 48 hours with increased monitoring for adverse reactions.
    Telithromycin: (Major) Coadministration of telithromycin is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving telithromycin. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Telithromycin is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and sildenafil is necessary, as the systemic exposure of sildenafil may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of sildenafil; consider increasing the dose of sildenafil if necessary. Sildenafil is primarily a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Terazosin: (Moderate) Patients should be stable on alpha-blocker therapy before initiating therapy with sildenafil or other phosphodiesterase type 5 (PDE5) inhibitors; the lowest dose should be used to initiate therapy. Conversely, patients already receiving an optimized dose of a PDE5 inhibitor should be started on the lowest dose of an alpha-blocker; increases in the alpha-blocker dose should be done in a stepwise fashion. Using sildenafil and alpha-blockers together may reduce blood pressure significantly in some patients and may lead to symptomatic hypotension. PDE5 inhibitors and alpha blockers are both vasodilators with blood pressure lowering effects. Sildenafil doses greater than 25 mg should not be taken within 4 hours of taking alpha-blockers.The manufacturer reports on 3 studies assessing the interaction between sildenafil with doxazosin. In these studies, healthy patients with BPH were stabilized on doxazosin for at least 14 days before receiving sildenafil or placebo. Patients receiving the combination of sildenafil and doxazosin had greater decreases in blood pressure than those receiving doxazosin and placebo. No episodes of syncope were reported in these studies. In one published study, sildenafil and doxazosin were used together in patients with non-organic erectile dysfunction refractory to sildenafil monotherapy; blood pressure was not significantly altered in this study. The safety of using PDE5 inhibitors and alpha-blockers together may also be affected by other factors, such as intravascular volume depletion and coadministration of other antihypertensive medications.
    Tezacaftor; Ivacaftor: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as sildenafil. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; sildenafil is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as sildenafil, can theoretically increase sildenafil exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Tipranavir: (Major) Sildenafil is contraindicated for use with tipranavir when used for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Trandolapril; Verapamil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with verapamil is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor.
    Tranylcypromine: (Moderate) Additive hypotensive effects may be seen when Monoamine oxidase inhibitors (MAOIs) are combined with sildenafil. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with sildenafil.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and sildenafil may result in altered concentrations of sildenafil. Vemurafenib is an inhibitor of CYP2C9 and an inducer of CYP3A4. Sildenafil is a substrate of CYP2C9 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Verapamil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with verapamil is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor.
    Vigabatrin: (Major) Vigabatrin should not be used with phosphodiesterase inhibitors, which is associated with serious ophthalmic effects (e.g., retinopathy or glaucoma) unless the benefit of treatment clearly outweighs the risks.
    Voriconazole: (Major) Coadministration of voriconazole is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving voriconazole. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Voriconazole is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Zafirlukast: (Minor) Sildenafil is metabolized principally by the hepatic cytochrome P450 CYP 3A4 and 2C9 isoenzymes. Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects.
    Zileuton: (Minor) Sildenafil is metabolized principally by CYP3A4. Inhibitors of these isoenzymes like zileuton may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects.

    PREGNANCY AND LACTATION

    Pregnancy

    Limited data do not report a clear association with the use of sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. No evidence of teratogenicity or embryofetal toxicity was observed in animal reproduction studies using sildenafil at doses 32- and 65-times the recommended human dose. There are risks to the mother and fetus from untreated pulmonary arterial hypertension.

    Limited clinical data preclude a clear determination of the risk of sildenafil to an infant during breast-feeding. Data from a case report describe the presence of sildenafil and its active metabolite in human milk. There is insufficient information on the effects of sildenafil on the breast-fed infant and no information on the effects of sildenafil on milk production.

    MECHANISM OF ACTION

    Mechanism of Action: Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cGMP. Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined. Phosphodiesterase type 5 is responsible for degradation of cGMP in the corpus cavernosum. Sildenafil enhances the effect of NO by inhibiting PDE5 thereby raising concentrations of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum and, at recommended doses, has no effect in the absence of sexual stimulation. In vitro studies show that sildenafil is selective for PDE5 and its effect is more potent on PDE5 than on other known phosphodiesterases (>80-fold for PDE1, >1,000-fold for PDE2, PDE3, and PDE4). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is one-tenth as potent for PDE6, an enzyme found in the retina, as it is for PDE5; this lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma concentrations of the drug.As reported by the manufacturer, the pharmacodynamic response to sildenafil was assessed in eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction. In these studies sexual stimulation resulted in improved erections, as assessed by penile plethysmography, after sildenafil administration compared with placebo. Most studies evaluated the efficacy of sildenafil approximately 60 minutes post dose. The erectile response, as determined by penile plethysmography, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study. The effects of sildenafil were evident for up to 4 hours but the response was diminished compared to 2 hours.Sildenafil can inhibit PDE5 present in esophageal smooth muscle, lung tissue, and brain tissue. Inhibition of PDE5 in lung tissue results in relaxation of pulmonary vascular smooth muscle and subsequently pulmonary vasodilation, thereby making sildenafil an effective agent in treating pulmonary hypertension. Inhibition of PDE5 present in esophageal smooth muscle can cause a marked inhibition of esophageal motility as well as a reduction in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD). Sildenafil has been shown to cross the blood-brain barrier and inhibit PDE5 in cerebral blood vessels. The areas of the brain that have the highest activity of PDE5 are the hippocampus, cerebral cortex, and basal ganglia. Although clinical studies have not proven this effect, inhibition of PDE5 by sildenafil in the brain may result in emotional, neurological, and psychological effects (see Adverse Reactions).

    PHARMACOKINETICS

    Sildenafil is administered orally or intravenously. The mean steady state volume of distribution (Vss) is 105 L, indicating widespread tissue distribution. 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 0.001% of the administered dose may appear in the semen of patients.
     
    Sildenafil is predominantly metabolized by hepatic cytochrome P450 (CYP) enzymes. CYP3A4 is the major metabolizing enzyme and CYP2C9 the minor one. One active metabolite with properties similar to the parent drug has been identified and is formed by N-desmethylation of sildenafil. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil and accounts for about 20% of the pharmacologic effects of sildenafil. The metabolite is further metabolized to inactive compounds.
     
    Sildenafil is excreted as metabolites primarily in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Both sildenafil and its active metabolite have terminal half-lives of about 4 hours. Sildenafil levels at 24 hours post a single 100 mg oral dose average 2 ng/ml (compared to peak plasma levels of approximately 440 ng/ml).
     
    Affected cytochrome P450 isoenzymes and drug transporters:  CYP3A4, CYP2C9
    Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure may result in an increase in sildenafil-induced adverse effects. The manufacturer recommends dosage reduction in patients receiving potent cytochrome CYP3A4 inhibitors.

    Oral Route

    Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of about 41% (25% to 63%). Its pharmacokinetics are dose-proportional over the recommended dose range. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%.

    Intravenous Route

    A 10 mg IV dose is predicted to provide a pharmacological effect of sildenafil and its N-desmethyl metabolite equivalent to that of a 20 mg PO dose.