SILDENAFIL CITRATE (Generic for REVATIO)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer doses approximately 4 to 6 hours apart.
-May be administered without regard to meals.
Oral Liquid Formulations
-Shake well for at least 10 seconds prior to each administration.
-Measure dosage 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). 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
NOTE: Very little data are available regarding the use of intravenous sildenafil in pediatric patients.

Intermittent IV Infusion
-Sildenafil injection is available as a ready to use solution; further dilution is not required.
-In a very small case series of 3 neonates, intermittent IV doses were initially infused over 3 hours. For doses less than 1.5 mg, the infusion duration was gradually weaned by 1 hour every 36 to 48 hours to a final infusion duration of each dose given over 1 hour.
-Administration of loading doses over 3 hours prior to continuous infusion in neonates has also been recommended based on data from a small study (n = 36).
-In adults, IV sildenafil is administered as an IV bolus injection.

Continuous IV Infusion
NOTE: Sildenafil is not approved by the FDA to be administered by continuous IV infusion.
-An infusion rate of 0.067 mg/kg/hour (1.6 mg/kg/day) was well tolerated in a small study of neonates with pulmonary hypertension (n = 36). Dilution/preparation information was not provided in the study.

Central nervous system (CNS) adverse reactions reported in pediatric patients during clinical trials of sildenafil include headache (1.6 to 16%) and dizziness (1.2 to 5%). In a randomized, double-blind, placebo-controlled dose escalation study in patients 1 to 17 years old, headache occurred in 16% of patients receiving the highest dose level (20 to 80 mg depending on body weight) compared to 13% of patients receiving placebo; rates of headache in patients receiving lower doses were similar to placebo. In adult patients receiving sildenafil for the treatment of pulmonary hypertension, dizziness has been associated with a sudden decrease in hearing. Additionally, MedWatch lists over 274 reports implicating sildenafil used in men for the treatment of erectile dysfunction as the primary suspect for emotional, neurological, and psychological disturbances during the time period January 4, 1998 through February 21, 2001. These adverse effects included abnormal dreams, abnormal thinking, aggression, agitation, anxiety, attempted suicide, attention disturbance, confusion, delirium, delusion, depersonalization, depression, disorientation, dizziness, emotional lability, euphoria, hostility, hallucinations, irritability, loss of consciousness, mania, nervousness, paranoia, personality disorders, suicide, and suicidal ideation. Since sildenafil does cross the blood-brain barrier, it is possible that sildenafil may be associated with these adverse effects. Further investigation is necessary to prove or disprove the role of sildenafil in these disturbances. Other CNS adverse effects reported in less than 2% of adults during sildenafil clinical trials for erectile dysfunction include abnormal dreams, ataxia, depression, hypertonia, hypoesthesia, hyporeflexia, insomnia, neuralgia, neuropathy, paresthesias, somnolence or drowsiness, tremor, and vertigo.

Increased erection has been reported in 2.6% to 13% of pediatric patients receiving sildenafil. In clinical trials in adults, no cases of priapism were reported with sildenafil. However, priapism related to sildenafil has been reported in post-marketing surveillance. Painful erections have lasted greater than 6 hours in duration. Because of the potential for permanent tissue damage, priapism is a medical emergency; advise patients and/or caregivers to report any erections lasting greater than 4 hours and seek medical attention.

Hypotension has been reported in 5.9% of pediatric patients receiving sildenafil in clinical trials and may be more prominent with parenteral administration. Monitor blood pressure when initiating sildenafil therapy or titrating the dosage. Post-marketing serious cardiovascular, cerebrovascular, and vascular adverse events have been reported in adult patients using sildenafil for erectile dysfunction and include myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage (stroke), transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages or intracranial bleeding, and pulmonary hemorrhage. A combination of factors including cardiac risk profile, sildenafil use, and sexual activity may have had a role in these events; limited information makes it impossible to make direct correlations or determine whether these events are possible with sildenafil use for pulmonary hypertension.

In adult patients receiving sildenafil with or without epoprostenol for the treatment of pulmonary arterial hypertension, cases of edema (which included peripheral edema) were reported in 25% of treated patients that received sildenafil with epoprostenol compared to 13% of patients that received epoprostenol alone.

Gastrointestinal adverse reactions that occurred in pediatric patients during sildenafil clinical trials include vomiting (7% to 14%), diarrhea (5% to 9%), nausea (5% to 7%), and abdominal pain (4% to 6%). Dyspepsia (8% to 13%) and diarrhea (9% to 12%) were reported in sildenafil-treated adult patients in pulmonary hypertension trials.

Respiratory and infectious adverse reactions reported in pediatric patients receiving sildenafil in clinical trials include fever (7% to 15%), upper respiratory tract infection (9% to 16%), bronchitis (4% to 9%), cough (3% to 7%), nasopharyngitis/pharyngitis (1% to 7%), rhinorrhea (7% or less), epistaxis (4% or less), and nasal congestion (2.3%).

Seizures and seizure recurrence have been reported with post-marketing use of sildenafil in adult patients; a causal relationship to the drug is uncertain.

Back pain (9% to 13%), limb pain (7% to 15%), and myalgia (6% to 14%) were reported in adult patients treated with sildenafil in pulmonary hypertension clinical trials.

Flushing has been reported in 1.2% of pediatric patients receiving sildenafil. In pulmonary hypertension clinical trials, flushing was reported in 9% to 16% of sildenafil-treated adult patients. Hypersensitivity reactions, including anaphylactoid reactions and anaphylactic shock, have rarely been reported in patients receiving sildenafil. The majority of events were considered non-serious.

Reports of sudden changes in hearing including hearing loss or decrease in hearing, which may be accompanied by tinnitus and dizziness, have been reported during post-marketing surveillance in adult patients taking phosphodiesterase inhibitors, including sildenafil; the reports are associated with a strong temporal relationship to the dosing of these agents. Concomitant medical conditions or patient factors may play a role, although risk factors for the onset of sudden hearing loss have not been identified. Advise patients to contact their physician if they experience changes in hearing.

Optic neuropathy has been reported in a pediatric patient receiving sildenafil. In clinical trails of sildenafil in adult patients for the treatment of pulmonary hypertension, retinal hemorrhage occurred in 1.9% of sildenafil treated patients versus 0% of placebo treated patients and eye hemorrhage occurred in 1.4% of sildenafil and placebo treated patients. All patients experiencing hemorrhage had additional risk factors including anticoagulant therapy. Visual impairment, including color tinge, sensitivity to light, and blurred vision, were reported more frequently in patients receiving doses higher than 60 mg/day. These effects were mild and transient. Non-arteritic anterior ischemic optic neuropathy (NAION) has also been reported rarely in adult patients using phosphodiesterase type 5 (PDE5) inhibitors for the treatment of erectile dysfunction. It is thought that the vasoconstrictive effect of phosphodiesterase inhibitors may decrease blood flow to the optic nerve, especially in patients with a low cup to disk ratio. Symptoms, such as blurred vision and loss of visual field in one or both eyes, are usually reported within 24 hours of use. Most, but not all, of these patients who reported this adverse effect had underlying anatomic or vascular risk factors for development of NAION. Risk factors include, but are not limited to: low cup to disc ratio ('crowded disc'), age over 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. Additionally, two patients had retinal detachment and one patient had hypoplastic optic neuropathy. It is not yet possible to determine if these adverse events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors. The long-term impact on the vision of pediatric patients using sildenafil chronically is not known.

Sickle-cell crisis (vaso-occlusive crisis) requiring hospitalization has been reported in adult patients treated with sildenafil for pulmonary hypertension secondary to sickle cell disease. The manufacturer warns the safety and efficacy of sildenafil have not been established in this population.

Sildenafil is contraindicated in patients with a known hypersensitivity to any component of the tablet or injection.

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.

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.

Sildenafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil can potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form, including intermittent nitrate therapy, are not to receive sildenafil. It is unknown whether it is safe for patients to receive nitrates once sildenafil has been administered.

The following factors are associated with up to an eight time increase in plasma concentrations of sildenafil compared with healthy subjects: hepatic disease (e.g., cirrhosis, 80% increase) and severe renal impairment (i.e., CrCl < 30 mL/minute, 100% increase). Although the disposition of sildenafil in pediatric patients with renal or hepatic impairment has not been determined, dose adjustments are not recommended when sildenafil is used for the treatment of pulmonary hypertension in adult patients with renal impairment or mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been studied.

Consider whether individuals receiving sildenafil would be adversely affected by vasodilatory events. In particular, caution should be used if sildenafil is prescribed in the following patient groups: patients with resting hypotension; patients with fluid depletion (e.g., dehydration); patients with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis); and those with severely impaired autonomic control of blood pressure.

Use sildenafil with caution in patients with penile structural abnormality (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions that may predispose them to priapism (such as sickle cell anemia, leukemia, multiple myeloma, polycythemia, or a history of priapism). Counsel patients and/or caregivers to seek medical attention immediately if the patient experiences an erection that lasts longer than 4 hours. Although sildenafil is used for pulmonary hypertension and not erectile dysfunction in pediatric patients, serious adverse events related to priapism may still occur.

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; administer sildenafil with caution to these patients.

Use sildenafil cautiously in patients with pre-existing visual disturbance. Advise patients to seek immediate medical attention in the event of a sudden loss of vision in 1 or both eyes while taking sildenafil. Postmarketing 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). Most reports of NAION associated with sildenafil have had underlying anatomic or vascular risk factors, including low cup to disc ratio ('crowded disc'). There is no safety or efficacy information on the administration of sildenafil to patients with retinitis pigmentosa. A minority of patients with the inherited condition have genetic disorders of retinal phosphodiesterases; therefore, use of sildenafil in patients with retinitis pigmentosa is not recommended.

Sildenafil should be used cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Sildenafil can decrease the tone of the lower esophageal sphincter and inhibit esophageal motility.

Safety and efficacy of sildenafil has not been established in the treatment of pulmonary hypertension secondary to sickle cell disease. Vaso-occlusive crisis (sickle-cell crisis) requiring hospitalization has been reported more frequently in patients with pulmonary hypertension secondary to sickle cell disease who received sildenafil than by those who received placebo. Also, although sildenafil is not used for erectile dysfunction in pediatric patients, patients with sickle cell disease are still at increased risk for priapism; therefore, use sildenafil with caution in this population and counsel patients and/or caregivers about the risk of priapism.

Description: Sildenafil is a phosphodiesterase inhibitor administered orally or intravenously for the treatment of pulmonary arterial hypertension (PAH). Sildenafil was originally developed as an antianginal agent but was found to be more effective in treating erectile dysfunction in adults and subsequently PAH. Studies have shown sildenafil to be effective in treating pediatric patients with primary and secondary PAH. In order to minimize the risk of adverse events such as hypotension, dosing regimens of sildenafil used in studies were often started low and titrated to clinical effect (up to a specified maximum dose). The use of sildenafil in pediatric patients with PAH has become relatively common practice; the Pediatric Pulmonary Hypertension Network (PPHNet) recommends cautious initiation and titration of sildenafil, avoidance of high doses, and consultation and/or referral to providers experienced in the treatment of pulmonary hypertension in pediatric patients. Pediatric pulmonary hypertension guidelines from the American Heart Association and the American Thoracic Society recommend use of low dose sildenafil for adjunctive therapy in neonates with persistent pulmonary hypertension of the newborn (PPHN) who are refractory to inhaled nitrous oxide (iNO) and in children with lower-risk PAH. They also recommend sildenafil use to prevent rebound PAH and facilitate the weaning of iNO in patients with evidence of increased pulmonary artery pressure upon iNO withdrawal. Systematic review of 21 studies (8 randomized controlled trials and 13 observational studies) suggests phosphodiesterase inhibitors improve oxygenation and hemodynamic parameters and may improve exercise tolerance while reducing the incidence of pulmonary hypertensive crisis in pediatric patients, with few toxic effects when used in low to moderate doses. Sildenafil is contraindicated in patients taking nitrate therapy due to the risk of cardiovascular adverse reactions. Sildenafil is FDA-approved in pediatric patients as young as 1 year for the treatment of PAH and has been used off-label in patients as young as neonates.

General Dosing Information
-Pediatric pulmonary arterial hypertension guidelines from the American Heart Association and the American Thoracic Society recommend use of low dose sildenafil for adjunctive therapy in neonates with persistent pulmonary hypertension of the newborn (PPHN) who are refractory to inhaled nitric oxide (iNO) and in children with lower-risk PAH.

For the treatment of pulmonary hypertension:
-for the treatment of pulmonary hypertension to improve exercise ability and delay clinical worsening in patients with WHO Group 1 pulmonary hypertension:
Oral dosage:
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.
Children weighing 20 kg or less: 10 mg PO 3 times daily. Avoid higher dosing due to a greater risk of mortality in pediatric patients (age 1 to 17 years) treated with high dose sildenafil monotherapy.
Children and Adolescents weighing 21 to 44 kg: 20 mg PO 3 times daily. Avoid higher dosing due to a greater risk of mortality in pediatric patients (age 1 to 17 years) treated with high dose sildenafil monotherapy.
Children and Adolescents weighing 45 kg or more: 20 mg PO 3 times daily. A maximum dose in pediatric patients has not been identified. Based on experience in adults, the dose may be titrated as needed to a maximum of 40 mg PO 3 times daily based on symptoms and tolerability. Avoid higher dosing due to a greater risk of mortality in pediatric patients (age 1 to 17 years) treated with high dose sildenafil monotherapy.
-for weaning of inhaled nitric oxide (iNO) in patients with pulmonary hypertension*:
Oral dosage:
Neonates: 0.22 to 0.5 mg/kg/dose PO administered as a 1 time dose 1 hour prior to discontinuing iNO or given 4 times daily has been studied. None of the 15 patients receiving a 1 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.
Infants and Children: 0.22 to 0.5 mg/kg/dose PO administered as a 1 time dose 1 hour prior to discontinuing iNO or given 4 times daily has been studied. None of the 15 patients receiving a 1 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 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.

Maximum Dosage Limits:
-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.
-Infants
Safety and efficacy have not been established. Guidelines recommend 1 mg/kg/dose PO every 8 hours.
-Children
Weight 20 kg or less: 10 mg PO 3 times daily.
Weight 21 to 44 kg: 20 mg PO 3 times daily.
Weight 45 kg or more: 40 mg PO 3 times daily.
-Adolescents
Weight 21 to 44 kg: 20 mg PO 3 times daily.
Weight 45 kg or more: 40 mg PO 3 times daily.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in pediatric patients with hepatic impairment are not available. Dosage adjustments are not recommended by the manufacturer in adult patients with pulmonary hypertension and mild to moderate hepatic impairment; patients with severe hepatic impairment have not been studied.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in pediatric patients with renal impairment are not available. Dosage adjustments are not recommended by the manufacturer in adult patients with pulmonary hypertension and renal impairment.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). 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, > 700-fold for PDE2, PDE3, and PDE4). The approximately 4000-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.

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.

Pharmacokinetics: Sildenafil is administered orally or intravenously. The mean steady state volume of distribution (Vss) for sildenafil in adults 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. Sildenafil is predominantly metabolized by hepatic cytochrome P450 (CYP) enzymes. 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 in adults.

Affected cytochrome P450 isoenzymes: CYP3A4 and CYP2C9
Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4; CYP2C9 is also involved to a lesser degree. Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects. Dosage reductions are recommended for patients receiving potent cytochrome CYP3A4 inhibitors.


-Route-Specific Pharmacokinetics
Oral Route
Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of about 41% (25 to 63%). In adult patients, its pharmacokinetics are dose-proportional over the recommended dose range, and 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.


-Special Populations
Pediatrics
Neonates
Sildenafil clearance increases threefold over the first week of life, approaching adult values by day 7; this increase in clearance is attributed to maturation of CYP isoenzyme activity responsible for sildenafil metabolism. In an open-label study of 36 term neonates with persistent pulmonary hypertension of the newborn (PPHN) or hypoxic respiratory failure receiving sildenafil infusions of 0.01 to 0.22 mg/hour for a mean duration of 77 hours, the mean terminal elimination half-life was 56 and 48 hours in 1- and 7-day-old neonates, respectively. The volume of distribution of sildenafil in neonates was fourfold higher than in adults (22.4 L or 456 L/70 kg when scaled allometrically to adult values), which was attributed to a lower protein binding in neonates versus adults. There was significant interpatient variability in this study.

Children and Adolescents
Body weight has been shown to be a good predictor of sildenafil drug exposure in children. Sildenafil plasma half-life values are estimated to range from 2.9 to 4.4 hours (for weight range of 10 to 70 kg) and Tmax is estimated at approximately 1 hour.

Hepatic Impairment
The disposition of sildenafil in pediatric patients with hepatic impairment has not been determined; however, in adult volunteers with hepatic cirrhosis (Child-Pugh A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment.

Renal Impairment
The disposition of sildenafil in pediatric patients with renal impairment has not been determined; however, in adult volunteers with mild (CrCl = 50 to 80 mL/minute) and moderate (CrCl = 30 to 49 mL/minute) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) were not altered. In volunteers with severe renal impairment (CrCl 30 mL/minute or less), sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax values were significantly increased by 200% and 79%, respectively, in subjects with severe renal impairment compared to subjects with normal renal function.