Sildenafil

1. Sildenafi

Sildenafil

Generic name: sildenafil (oral) (sil DEN a fil)
Brand name: Revatio, Viagra
Drug class: Agents for pulmonary hypertension, Impotence agents

What is sildenafil?

Sildenafil relaxes muscles of the blood vessels and increases blood flow to particular areas of the body.

Sildenafil under the name Viagra is used to treat erectile dysfunction (impotence) in men.

Another brand of sildenafil is Revatio, which is used to treat pulmonary arterial hypertension and improve exercise capacity in men and women.

The efficacy of sildenafil in women with sexual dysfunction has not been established.

Do not take Viagra while also taking Revatio.

Sildenafil (Revatio, Viagra) Uses:

• Erectile dysfunction:

  • Viagra: Treatment of erectile dysfunction (ED)

• Pulmonary arterial hypertension:

  • Revatio: Treatment of pulmonary arterial hypertension (PAH) (WHO Group I; efficacy established predominately in patients with WHO/NYHA functional class II and III) in adults to improve exercise ability and delay clinical worsening.

• Off Label Use of Sildenafil in Adults:

  • Achalasia/Esophageal motility disorders;
  • Persistent pulmonary hypertension after recent left ventricular assist device placement;
  • Raynaud phenomenon

Sildenafil (Viagra) Dose in the treatment of Erectile dysfunction:

• Oral: Usual dose: 50 mg once daily 1 hour (range: 30 minutes to 4 hours) before sexual activity as required;
• dosing range: 25 to 100 mg once daily;
• maximum dose: 100 mg once daily.

Sildenafil Dose in the treatment of pulmonary arterial hypertension (PAH) (Revatio):

• IV: 2.5 mg or 10 mg 3 times daily
• Oral: 20 mg to 40 mg 3 times daily;
• may increase to a maximum of 80 mg 3 times daily in patients who do not achieve an adequate response.

• Manufacturer’s labeling:

  • Dosing in the prescribing information may not reflect current clinical practice.
  • 5 mg or 20 mg 3 times daily, administered 4 to 6 hours apart;
  • maximum dose: 20 mg 3 times daily

Sildenafil (Revatio, Viagra) Dose in the treatment of Raynaud phenomenon (off-label):

• Oral: 50 mg twice daily.

• Dosage considerations for patients stable on alpha-blockers:

  • Viagra: Initial: 25 mg

• Dosage adjustment for concomitant use of potent CYP34A inhibitors: Viagra:

  • Strong CYP3A inhibitors (eg, itraconazole, ketoconazole, saquinavir) or erythromycin:
    • Starting dose of 25 mg should be considered
  • Protease inhibitors:
    • Maximum sildenafil dose: 25 mg every 48 hours

 

Note:

• In pediatric patients (1 to 17 years of age) with PAH, increased mortality risk was associated with long-term use (>2 years) at dose levels of 0.88 to 2.5 mg/kg/dose administered three times a day.
• Use of Revatio, especially chronic use, is not advised in pediatric patients because of dose-dependent increased mortality risk reported in trials; however, situations may exist in which the benefit-risk profile of Revatio may make its use, with close monitoring, acceptable in individual pediatric patients, for example, when other treatment options are limited.
• Oral suspensions may be available in multiple concentrations (commercially available: 10 mg/mL; extemporaneous preparation: 2.5 mg/mL);
• dosing should be presented in mg of sildenafil;
• use extreme caution when verifying product formulation and calculation of dose volumes.

Sildenafil (Revatio, Viagra) Dose in the treatment of pulmonary hypertension:

• Infants:

  • Initial: 0.25 mg/kg/dose every 6 hours or 0.5 mg/kg/dose every 8 hours;
  • titrate as needed;
  • maximum reported dose range: 1 to 2 mg/kg/dose every 6 to 8 hours.

• Children and Adolescents <18 years of age:

Note: Dosage should not be increased; higher doses and long-term use are associated with increased mortality risk.

• • 8 to 20 kg:
    • 10 mg three times daily
  • >20 kg to 45 kg:
    • 20 mg three times daily
  • >45 kg:
    • 40 mg three times daily

Sildenafil (Revatio, Viagra) Dose in the treatment of Pulmonary hypertension due to congenital heart surgery (postoperative):

• Oral (or nasogastric tube): Infants, Children, and Adolescents:

  • Initial: 0.5 mg/kg/dose upon admission to ICU;
  • increase in 0.5 mg/kg/dose increments every 4 to 6 hours up to a maximum dose of 2 mg/kg/dose as tolerated.
  • upon discontinuation of mechanical ventilation, sildenafil therapy can be tapered over 5 to 7 days;

• IV: Infants >60 days and Children:

  • Loading dose: Range: 0.04 to 0.35 mg/kg administered over 5 minutes
  • followed by a maintenance infusion: Reported range: 0.015 to 0.4 mg/kg/hour continued for 24 to 72 hours was used for pulmonary hypertension occurring within 48 hours of the end of cardiac surgery in a multicenter, randomized, double-blind, placebo-controlled dose-finding trial

Sildenafil Dose in the treatment of Pulmonary hypertension, facilitation of inhaled nitric oxide (iNO) wean (in patients who have not previously failed iNO wean): 

• Infants and Children ≤15 months:

  • Oral: Single dose: 0.4 mg/kg/dose (range: 0.3 to 0.5 mg/kg/dose) given once 60 minutes prior to NO discontinuation.

• Dosage considerations for patients taking alpha-blockers:

  • There are no pediatric-specific recommendations; in adult patients, dosing adjustment suggested.

• Dosage adjustment for concomitant use of potent CYP34A inhibitors:

  • There are no pediatric-specific recommendations; in adult patients receiving Revatio, the following dosing adjustment suggested:
    • Strong CYP3A inhibitors (eg, itraconazole, ketoconazole): Not recommended
    • Protease inhibitors: Concurrent use is contraindicated

 

Pregnancy Risk Category: B

• • • In an ex-vivo study of placenta perfusion, Sildenafil was found to cross the placenta.
    • Sildenafil is being studied for its ability to cause vasodilation of the uterus.
    • The use of sildenafil during pregnancy is not recommended due to adverse reactions in the newborn as a result of preliminary data from a study that evaluated sildenafil’s fetal growth restriction.
    • Limited information is available on sildenafil’s use in the treatment of pulmonary arterial Hypertension (PAH).
    • The risk of stroke, heart failure, preterm birth, and maternal/fetal deaths increases if PAH is not treated during pregnancy.
    • It is advised that women with PAH avoid pregnancy.

Use Sildenafil while breastfeeding

• • Breast milk contains sildenafil.
  • After treatment for PAH, a case report describing the excretion of sildenafil (and desmethyl sildenafil) in breast milk was published.

 

Sildenafil (Revatio, Viagra) Dose in Kidney Disease:

• CrCl ≥30 mL/minute:
  • No dosage adjustment required.
• CrCl <30 mL/minute:
  • Revatio: No dosage adjustment required.
  • Viagra: A starting dose of 25 mg should be considered.

 

Sildenafil (Revatio, Viagra) Dose in Liver disease:

• Mild to moderate impairment (Child-Pugh classes A and B):

  • Revatio:
    • No dosage adjustment required.
  • Viagra:
    • A starting dose of 25 mg should be considered.

• Severe impairment (Child-Pugh class C):

  • Revatio:
    • There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
  • Viagra:
    • A starting dose of 25 mg should be considered.

 

Side effects such as flushing, myalgia, diarrhea, and visual disturbances may be increased with adult doses exceeding 100 mg/24 hours)

Common Side Effects of Sildenafil (Revatio, Viagra):

• Cardiovascular:

  • Flushing

• Central Nervous System:

  • Headache

• Gastrointestinal:

  • Dyspepsia

• Ophthalmic:

  • Visual Disturbance

• Respiratory:

  • Epistaxis

Less Common Side Effects of Sildenafil (Revatio, Viagra):

• Central Nervous System:

  • Insomnia
  • Dizziness
  • Paresthesia

• Dermatologic:

  • Erythema
  • Skin Rash

• Gastrointestinal:

  • Diarrhea
  • Gastritis
  • Nausea

• Genitourinary:

  • Urinary Tract Infection

• Hepatic:

  • Increased Liver Enzymes

• Neuromuscular & Skeletal:

  • Myalgia
  • Back Pain

• Respiratory:

  • Nasal Congestion
  • Exacerbation Of Dyspnea
  • Nasal Congestion
  • Rhinitis
  • Sinusitis

• Miscellaneous:

  • Fever

 

Contraindications to Sildenafil (Revatio, Viagra):

• • • Hypersensitivity to sildenafil and any component of the formulation
    • concurrent use (regularly/intermittently) of organic nitrates in any form (eg, nitroglycerin, isosorbide dinitrate);
    • Concomitant use riociguat, a guanylate-cyclase stimulator.

According to manufacturers of protease inhibitors (atazanavir/ritonavir/nelfinavir/ritonavir), lopinavir/ritonavir saquinavir and tipranavir

• • • When sildenafil has been prescribed for pulmonary hypertension (eg Revatio), it is not recommended to use the drug in conjunction with a protease inhibitor treatment.

Canadian labeling: Additional contraindications not in US labeling

• • • Viagra
      • An episode of anterior ischemic optic nervepathy (NAION) that was not arteritic.
    • Revatio
      • An episode of anterior ischemic optic nervepathy (NAION) that was not arteritic.
      • Concurrent use of potent CYP3A4 inhibitors (eg, ketoconazole or itraconazole)
      • Pulmonary hypertension due to sickle cell disease;
      • Grave hepatic impairment
      • Recent history of stroke, MI, or life-threatening arrhythmias
      • Stable angina due to coronary artery disease
      • At the beginning, severe hypotension (90/50mm Hg).

Warnings and precautions

• • Color discrimination:

    • Might cause color discrimination impairment due to dose.
    • Patients with retinitis pigmentosa should be cautious. A minority of patients have retinal phosphodiesterases genetic disorders (no safety information).

  • Hearing loss:

    • It has been reported that sudden loss or decrease in hearing can be seen. Tinnitus and dizziness may also occur.
    • It is not known if therapy can be used to treat hearing loss.

  • Hypersensitivity

    • There have been hypersensitivity reactions including rash, urticaria and anaphylactic shock.

  • Hypotension

    • Vasodilator effects may cause a decrease in blood pressure. Patients with left ventricular obstruction (aortic stenting, hypertrophic obstructivecardiopathy) and those on antihypertensive treatment (aortic stenting, hypertrophic obstructivecardiopathy) should be cautious.
    • Before starting treatment at the lowest dose, patients should be hemodynamically stable.
    • When you take medications that lower blood pressure, monitor your blood pressure.
    • The risk of orthostasis and hypotension may be exacerbated by excessive ethanol consumption.
    • A lower intake of ethanol has not been shown to cause significant blood pressure drops or an increase in orthostatic symptoms.
    • Limit or avoid alcohol consumption

  • Priapism

    • Rarely, a painful erection lasting more than 6 hours has been reported.
    • Encourage the patient to seek medical attention for an erection lasting more than four hours.

  • Vision loss:

    • Sudden loss in vision may occur in either one or both eyes. This could be an indication of non-arteritic anterior Ischemic Optic Neuropathy (NAION).
    • If you have a history of vision impairment, the risk could be higher.
    • Another risk factor for NAION is a low cup to-disc ratio (“crowded disk”), coronary heart disease, diabetes, hypertension and smoking.
    • Sudden vision loss patients should immediately stop treatment and see a health care provider.
    • It is not known if therapy can cause vision loss.

  • Anatomical penis deformation:

    • Patients with anatomical deformations of the penis (angulation or cavernosal fisis) should be avoided.

  • Bleeding disorders:

    • Patients with bleeding disorders should be treated with caution. Safety has not been established.
    • Studies in vitro have shown a decrease in platelet aggregation.

  • Cardiovascular disease

    • Patients with:
      • hypotension (<90/50 mm Hg);
      • Uncontrolled hypertension (>170/110mm Hg);
      • Arrhythmias that can cause serious health problems.
      • stroke or MI in the past 6 months
      • Stable angina can be caused by cardiac failure or coronary disease.
    • These patients have not been tested for safety or efficacy.
    • Patients with left ventricular obstruction (eg, Aortic Steensis) should be cautious.
    • Sexual activity can pose a risk to your heart. Before you start any treatment for erectile problems, it is important that you consider your cardiovascular health.

  • Predisposing conditions to priapism

    • Patients with pre-existing conditions such as multiple myeloma, sickle cell anemia, or leukemia should be cautious.
    • If the erection takes longer than 4 hours, all patients should be directed to immediately seek medical attention.

  • Hepatic impairment

    • Patients with impaired liver function should be cautious. Use the lowest dose possible (25 mg).

  • Peptic ulcer disease:

    • Patients with active peptic ulcer disease should be cautious; safety has not yet been proven.

  • PAH:

    • Sudden discontinuation or interruption of sildenafil monotherapy can lead to an exacerbation in PAH.
    • Studies of short-term (12-16-week) efficacy were conducted on adult patients; safety for longer-term use is unknown.
    • After 2 years, a long-term trial with pediatric patients revealed an increase in mortality in higher doses (20-80 mg depending on weight)

  • Pulmonary venoocclusive disease

    • Patients with pulmonary vein-occlusive disease (PVOD), are not recommended for use. However, if pulmonary hypertension (PAH) occurs, consider using PVOD.

  • Renal impairment

    • Patients with kidney dysfunction should be cautious; dosage adjustment may be necessary. Use the lowest starting dose (25mg) in severe impairment (CrCl 30mL/minute).

  • Sickle cell anemia

    • This patient population might require more hospitalizations to treat pulmonary hypertension.
    • In pulmonary hypertension secondary sickle cell disease, sildenafil’s safety and effectiveness have not been proven.

 

Monitoring parameters:

Monitor blood pressure and pulse when used concurrently with medications that lower blood pressure;

Monitor for pulmonary edema.

 

How to administer Sildenafil (Revatio, Viagra)?

Oral:

• Revatio:
  • Administer doses at least 4 to 6 hours apart with or without food.
  • Shake the oral suspension well for ≥10 seconds before administering dose; do not mix with any other medication or additional flavoring agent.
• Viagra:
  • Administer with or without meals 30 minutes to 4 hours prior to sexual activity

IV:

• Revatio: Administer as an IV bolus.

 

Mechanism of action of sildenafil (Revatio, Viagra):

Erectile dysfunction:

• • • Although it does not directly cause penile dysfunction, it can affect the response to sexual stimulation.
    • The physiological mechanism for the erection and stimulation of the penis is the release of nitric dioxide (NO) from the corpus cavernosum.
    • NO activates the enzyme Guanylate Cyclase. This results in an increase in cyclic Guanosine Monophosphate (cGMP), which causes smooth muscle relaxation and blood flow to the corpus cavernosum.
    • Sildenafil increases the NO effect by inhibiting phosphodiesterase 5 (PDE-5), responsible for the degradation of cGMP within the corpus Cavernosum. When sexual stimulation causes local NO release, sildenafil’s inhibition of PDE-5 causes an increase in cGMP levels in the corpus Cavernosum. This results in smooth muscle relaxation and blood flow to the corpus Cavernosum. It is safe to use at recommended doses.

Pulmonary arterial hypertension, (PAH)

• • Inhibits phosphodiesterase 5 (PDE-5) in smooth muscle of the pulmonary vasculature, where PDE-5 is responsible to the degradation of cyclic Guanosine monophosphate.
  • An increase in cGMP levels can cause pulmonary vasculature relaxation. Vasodilation may also occur in the pulmonary bed or in the systemic circulation, but to a lesser extent.

The onset of action:

• Erectile dysfunction: ~60 minutes

Peak effect:

• Decrease blood pressure: Oral: 1 to 2 hours

Duration:

• Erectile dysfunction: 2 to 4 hours;
• Decrease blood pressure: <8 hours

Absorption:

• Rapid;
• slower with a high-fat meal;
• tablet and suspension are bioequivalent

Distribution:

• Distributes into tissues.

Protein binding, plasma:

• Neonates: Sildenafil: 93.9% ± 2.5%;
• N-desmethyl metabolite: 92% ± 3%.
• Adults: Sildenafil and N-desmethyl metabolite: ~96%

Metabolism:

• Hepatic via CYP3A4 (major) and CYP2C9 (minor route);
• major metabolite (UK103320 or desmethylsildenafil) is formed via N-desmethylation pathway and has half the activity of sildenafil

Bioavailability:

• Oral: Mean: 41%;
• range: 25% to 63%;
• Bioavailability may be higher in patients with PAH compared to healthy volunteers;
• Note: A 10 mg dose of the injection is predicted to have an effect equal to a 20 mg oral dose taking into consideration the parent drug and active metabolite

Half-life elimination:

Sildenafil: Terminal:

• Neonates: PNA 1 day: 55.9 hours.
• Neonates: PNA 7 days: 47.7 hours.
• Adults: 4 hours

Active N-desmethyl metabolite: Terminal:

• Neonates: 11.9 hours
• Adults: 4 hours

Time to peak:

• Oral: Fasting: 30 to 120 minutes (median 60 minutes);
• delayed by 60 minutes with a high-fat meal

Excretion:

• Feces (~80%, as metabolites);
• urine (~13%).

What happens if I miss a dose?

Since Viagra is used as needed, you are not likely to miss a dose.

If you miss a dose of Revatio, take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

 

International Brand Names of Sildenafil:

• Revatio
• Viagra
• ACT Sildenafil
• AG-Sildenafil
• APO-Sildenafil
• APO-Sildenafil R
• AURO-Sildenafil
• GD Sildenafil
• JAMP-Sildenafil
• M-Sildenafil
• Mar-Sildenafil
• MINT-Sildenafil
• MYL-Sildenafil
• NRA-Sildenafil
• PMS-Sildenafil
• PMS-Sildenafil R
• Priva-Sildenafil
• PRZ-Sildenafil
• RAN-Sildenafil
• Revatio
• RIVA-Sildenafil
• SANDOZ Sildenafil
• TEVA-Sildenafil
• TEVA-Sildenafil R
• VANSildenafil
• Viagra
• Acmegra
• Adegra
• Adonix
• Aladin
• Amfidor
• Andagra
• Andros
• Androz
• Androz 100
• Aphrodil
• Avigra
• Avixar
• Azulsix
• Balcoga
• Baleoga
• Blugral
• Bultis Film
• Caprenafil
• Cilafil
• Conegra
• Cupid
• Daygra
• Direktan
• Dragul
• Ecriten
• Edegra
• Edyfil
• Ejertol
• Elonza
• Ereccil
• Erecstar
• Erectil
• Erectol
• Erilin
• Ernafil
• Eroton
• Eroxim
• Ezequel
• Facsid
• Fexion
• For MR.
• Fortera Orally Soluble Film
• Freeya
• Funcional
• Grandipam
• Granpidam
• Happigra Gran
• Hippigra
• Hydenex
• Idilico
• Immense
• Iqnyde
• Ivagra
• Kamagra
• Katora
• Lekap
• Maxigra
• Mysildecard
• Neo-Up
• Nipatra
• Olvion
• Orisild
• Osigra
• Pahtension
• Palpal Chew Tab
• Patrex
• Penegra
• Please
• Pramil
• Pulmolan
• Remenafil
• Revatio
• Rigix
• Ripol
• Sanbenafil
• Seregra
• Serivia Gran
• Sidegra
• Sidena
• Silagra
• Silatio
• Silchemo
• Sildava
• Sildefil
• Sildegra
• Sildenon
• Sildera
• Sildex
• Silvie
• Supra
• Tagazepin
• Tarim
• Tigerfil
• Tonafil
• Topgra
• V-Gra
• Varonil
• Vasigra
• Viagra
• Viajoy
• Viasin Powder
• Viner
• Vivic
• Vizarsin
• Willmon-100
• Wingora
• X-cite
• Xcite
• Xex
• Zilden
• Zwagra

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