قرص sildenafil tablets - کامل (هلپ کده)

خواص دارویی و گیاهی

1-{[3-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl}-4-methylpiperazin (IUPAC)

G04BE03

PDE-5-Hemmer

Enzymhemmung der Phosphodiesterase-5

Achtung

قرص sildenafil tablets

Sildenafil ist ein Arzneistoff aus der Gruppe der PDE-5-Hemmer, einer Gruppe gefäßerweiternder (vasodilatierender) Substanzen. Große Bekanntheit erlangte er als Wirkstoff des 1998 von dem US-amerikanischen Unternehmen Pfizer unter dem Namen Viagra auf den Markt gebrachten Arzneimittels zur Behandlung der erektilen Dysfunktion (Erektionsstörung) beim Mann. Diese Wirkung wurde zufällig im Rahmen der Entwicklung von Sildenafil als Mittel zur Behandlung von Bluthochdruck und Angina pectoris entdeckt. Außer als Potenzmittel ist Sildenafil seit 2006 ferner zur Behandlung der idiopathischen pulmonal-arteriellen Hypertonie und der pulmonalen Hypertonie in Verbindung mit einer Bindegewebskrankheit zugelassen (Markenname Revatio).

Sildenafil war der erste Arzneistoff der Wirkstoffklasse der PDE-5-Hemmer. Umgangssprachlich wird der Name Viagra gelegentlich auch als Sammelbegriff für andere Medikamente dieser Wirkstoffgruppe, beispielsweise Tadalafil (Cialis), Vardenafil (Levitra) oder Avanafil (Spedra) verwendet.

In Deutschland, Österreich und der Schweiz sind sildenafilhaltige Arzneimittel verschreibungspflichtig.

Ein Teil des physischen Prozesses der Erektion beinhaltet die Freisetzung von Stickstoffmonoxid (NO) im Corpus cavernosum. Dadurch wird das Enzym Guanylatcyclase aktiviert, welches die Ausschüttung von cyclischem Guanosinmonophosphat (cGMP) erhöht. So wird eine leichte Muskelentspannung im Corpus cavernosum ausgelöst, welche das Einströmen von Blut und damit die Erektion ermöglicht.

Sildenafil ist ein potenter selektiver Hemmer der cGMP-spezifischen Phosphodiesterase vom Typ 5 (PDE-5), der damit die Abbaurate von cGMP vermindert.[4] Als Resultat wird beim Einsatz von Sildenafil eine normale sexuelle Stimulation zu erhöhten Blutspiegeln von cGMP im Corpus cavernosum und damit zu einer verstärkten Erektion führen. Ohne eine sexuelle Stimulation und Aktivierung des NO/cGMP-Systems löst Sildenafil keine Erektion aus.

Der gleiche Wirkmechanismus trifft auch für die Substanzen Tadalafil, Vardenafil und Avanafil zu. Somit können selektive PDE-5-Inhibitoren zur Therapie der erektilen Dysfunktion eingesetzt werden.

Sildenafil wird durch Leberenzyme abgebaut und sowohl über die Leber als auch über die Nieren ausgeschieden. Wenn es mit fettreicher Nahrung eingenommen wird, ist ein verzögerter Abbau und eine verringerte Wirkung zu erwarten.

Sildenafil ist in Dosen von 25 mg, 50 mg oder 100 mg peroral wirksam. In einer Dosis-Eskalations-Studie bewirkte Sildenafil in Dosen von bis zu 100 mg bei 69 % der männlichen Patienten eine Erektion, die für die Dauer eines Geschlechtsverkehrs aufrechterhalten wurde, gegenüber 22 % in der Placebo-Gruppe.[5]

Ausmaß und Dauer einer Erektion hängen vom Blutzufluss und Blutabfluss in den Schwellkörpern des Penis ab. Die Blutzufuhr wird durch ringförmige Muskeln in der Arterienwand des Corpus cavernosum gesteuert. Im nicht erigierten Zustand sind diese angespannt und verschließen die Gefäße. Wird der Mann jedoch sexuell erregt, führt dies in den betreffenden Muskelzellen zur Bildung von cGMP (cyclischem Guanosinmonophosphat). Die Muskeln entspannen sich und der Gefäßquerschnitt wird vergrößert, was dazu führt, dass arterielles Blut in die Schwellkörper fließt und eine Erektion auslöst. Molekularer Gegenspieler des cGMP ist das Enzym Phosphodiesterase-5 (PDE-5), welches das cGMP spaltet. Sildenafil wirkt, indem es PDE-5 blockiert und dafür sorgt, dass auch geringe Mengen von cGMP zu einer Erektion führen. Anders als Potenzmittel wie etwa Alprostadil, das intrakavernös (in den Penisschwellkörper) gespritzt oder in die Harnröhre eingebracht wird, wirkt Sildenafil nur dann, wenn der Patient auch sexuell erregt ist.

Untersuchungen haben gezeigt, dass Arginin die Wirkung verstärken kann.[6] Zudem konnte bei Sildenafil eine Art Dosiseinsparungseffekt festgestellt werden. Arginin setzt ebenfalls Stickstoffmonoxid frei, welches eine Erweiterung (Dilatation) der Blutgefäße bewirkt.[6]

Seit 2006 ist Sildenafil unter dem Markennamen Revatio zur peroralen Behandlung der idiopathischen pulmonal-arteriellen Hypertonie bei Patienten im NYHA-Stadium II und III im Handel. Kritiker bemängeln, dass die zugelassene Dosierung von 3×20 mg für eine optimale Therapie nicht ausreichend sei und die wichtigsten Studien mit bis zu 3×80 mg Sildenafil durchgeführt wurden. Diese Dosierung ist aber in Deutschland nicht für die Therapie zugelassen.[7]

Außer den oben genannten Bereichen ist eine Wirkung und ein Einsatz von Sildenafil bei verschiedenen speziellen Krankheitsbildern beschrieben:

In der Neonatologie wird Sildenafil in letzter Zeit außerhalb der Arzneimittelzulassung (Off-Label-Use) zunehmend bei extremen Frühgeborenen mit bronchopulmonaler Dysplasie (BPD) zur Senkung des pulmonalen arteriellen Gefäßwiderstands eingesetzt.[8]

Es gibt erste Untersuchungen, nach denen Sildenafil die Auswirkungen des bei der Krankheit Mukoviszidose durch einen Gendefekt gestörten CFTR-Proteins korrigieren kann. Ebenfalls diskutiert wird der Einsatz von Sildenafil zur Behandlung des Schlaganfalls.

Doxorubicin wird in der Therapie des Prostatakarzinoms verwendet und weist als Nebenwirkung eine hohe Kardiotoxizität auf und kann im schlimmsten Fall auch Herzversagen hervorrufen. Einige kleinere Studien geben Hinweise darauf, dass die Kombination von beiden Wirkstoffen die chemotherapeutische Effizienz von Doxorubicin erhöht und die schädlichen Wirkungen auf das Herz verringert.[9][10]

Ein weiteres Anwendungsgebiet von Sildenafil ergibt sich bei der Behandlung des Raynaud-Syndroms. Bei dieser häufigen Krankheit verengen sich die Gefäße an Fingern und Zehen wodurch sich die Durchblutung in diesen Gebieten vermindert. Es gibt Hinweise, dass die Einnahme von Sildenafil die Gefäße in den betroffenen Regionen wieder erweitert.[11][12]

Eine Studie an Schwangeren mit Plazenta-Unterfunktion wurde 2018 abgebrochen. Eine Unterfunktion hemmt das Wachstum eines Ungeborenen erheblich. Durch Sildenafil sollte die Durchblutung der Plazenta gesteigert und die Entwicklung des Fötus beschleunigt werden. Fast 20 Prozent der Frauen brachten jedoch Kinder mit Lungenproblemen zur Welt, die mehrheitlich starben.[13]

2004 entschied der Pharmakonzern Pfizer nach mehrjähriger Forschung, die Entwicklung von Sildenafil zur Behandlung sexueller Funktionsstörungen der Frau einzustellen. Tests an rund 3000 Frauen mit sexuellen Funktionsstörungen hätten keine ausreichende Wirksamkeit gezeigt. Nach dem großen Erfolg von Sildenafil im Einsatz bei Männern sollte eigentlich ein ähnlich gewinnbringender Markt für Frauen aufgebaut werden. Das Unternehmen war jedoch (vor allem durch die Fachzeitschrift British Medical Journal) in die Kritik geraten, unter dem Namen „weibliche sexuelle Funktionsstörung“ (FSD) gezielt ein Krankheitsbild zu schaffen.

Aufgrund der Popularität von Sildenafil, die mit dem Markennamen „Viagra“ in Verbindung gebracht wird, hat sich seit den 90er Jahren ein Schwarzmarkt für Sildenafil und Sildenafil-haltige Produkte etabliert, die weit abseits ihrer Zulassung agieren.

So werden dem Medikament eine Reihe von Wirkungen zugesprochen, die wissenschaftlich nicht begründet sind, wie Steigerung der Libido, erhöhte Erektionsqualität oder Vergrößerung der Penislänge.[14][15] Studien konnten jedoch zeigen, dass der Wirkstoff beim Gesunden kaum eine Wirkung zeigt, die über die physiologische hinausgeht, mit der Ausnahme, dass die Erholungszeit nach Ejakulation verkürzt wird.[16]

Sildenafil dient genauso wie andere PDE-5-Hemmer als Verschnittmittel für als Partydroge gehandeltes MDMA, um deren Nebenwirkung der erektilen Dysfunktion entgegenzuwirken. Die Beimengung zu Amylnitrit kann zu gefährlichen additiven Wirkungen führen, welche zum Tod führen können.[17][15]

Eine Forschungsgruppe konnte zeigen, dass Sildenafil in Wasser gelöst in der Lage ist, die Lebensdauer von Schnittblumen signifikant zu verlängern.[18]

Die gleichzeitige Einnahme von Sildenafil mit nitrathaltigen Medikamenten (z. B. das bei älteren Menschen weit verbreitete Nitrolingual-Spray) oder Stickstoffmonoxid-Donatoren (Amylnitrit, Szene-Drogen „Poppers“) ist kontraindiziert. Durch die kombinierte Wirkung auf den Blutdruck droht ein akuter lebensbedrohlicher Blutdruckabfall.

Abgesehen von dieser Kontraindikation stellt der Einsatz bei Patienten mit koronarer Herzkrankheit dann ein Risiko dar, wenn der erfolgreiche Geschlechtsverkehr für den Kreislauf eine zu hohe Beanspruchung bedeutet.

Die Verstoffwechselung von Sildenafil wird durch die Cytochrom-P450 (CYP)-Isoenzyme 3A4 und 2C9 vermittelt. Es kann zu Wechselwirkungen mit Arzneistoffen kommen, die ebenfalls unter Beteiligung dieser Enzyme metabolisiert werden (z. B. Ketoconazol, Itraconazol, Erythromycin, Cimetidin, Saquinavir). Weiterhin kann der starke Cytochrom P450 3A4-Inhibitor Ritonavir zu gefährlich hohen Sildenafil-Plasmaspiegeln führen, da der Abbau von Sildenafil gehemmt wird.

Bei der Einnahme auftretende Nebenwirkungen: Kopfschmerzen (10,8 %), Gesichtsrötung (10,9 %), Magenbeschwerden (3 %), Rhinitis (4 %), abnorme visuelle Wahrnehmungen (2,8 %; z. B. blaue Schleier im Gesichtsfeld, erhöhte Lichtempfindlichkeit), Herabsetzung des Reaktionsvermögens, Schwindelgefühle, Rücken- und Muskelschmerzen, Dauererektion (Priapismus). Es wurden bereits Fälle von nichtarteriitischer anteriorer ischämischer Optikusneuropathie beobachtet.[19] Dies führt in seltenen Fällen zu Einbußen der Sehfähigkeit oder zur Erblindung. Die aktuellen Erkenntnisse zu diesen Nebenwirkungen führten im Sommer 2006 zur entsprechenden Änderung der Fachinformation für Sildenafil. Neuerdings liegen auch Hinweise vor auf plötzlich auftretende Hörstörungen im Zusammenhang mit Sildenafileinnahme.

In der Vergangenheit wurde Sildenafil hin und wieder durch großaufgemachte Pressemitteilungen bekannt, in welchen von Todesfällen berichtet wurde. Diese traten aber in allen nachvollziehbaren Fällen durch Nichtbeachtung der Kontraindikationen auf.

Die Bezeichnung Viagra ist ein rechtlich geschütztes Kunstwort. Angeblich setzt sie sich aus den Begriffen vigor (lateinisch für „Stärke“) und Niagara zusammen. Nebenbei ist „Viagra“ homophon zu vyā́ghra व्याघ्र, dem Sanskrit-Wort für Tiger.

Große Bekanntheit hat das Produkt erhalten, weil es im Internet millionenfach mittels Spam-Mails beworben wird. Internetversandhändler, meist aus den USA, versenden die entsprechenden Tabletten auch ohne das notwendige Rezept in alle Welt. Abgesehen von den Nebenwirkungen des Wirkstoffs setzt man sich dabei dem Risiko aus, gefälschte oder verunreinigte Produkte zu erhalten.[20]

Mit der Markteinführung von Sildenafil war die erektile Dysfunktion erstmals bei vielen Patienten ohne große Unannehmlichkeiten behandelbar. Dies hatte weitreichende Folgen für das Sexualleben dieser Patienten. Auf der einen Seite war vielen Patienten, die aufgrund von Erkrankungen wie Diabetes, Koronarer Herzkrankheit usw. nicht mehr in der Lage waren, eine Erektion zu erlangen, wieder die Möglichkeit zu einem erfüllten Liebesleben gegeben.

Auf der anderen Seite klagten schon bald Partnerinnen, die an den sexarmen Zustand „gewöhnt“ waren, dass ihr Partner für sie plötzlich anstrengender geworden sei, als sie es sich wünschen würden. Es stellte sich heraus, dass für den Einsatz von Viagra eine intensive Beratung nicht nur mit dem Arzt, sondern auch mit der Partnerin sinnvoll ist.

Viagra gilt als dasjenige Medikament, das als erstes nachweislich zu einer Verbesserung des internationalen Artenschutzes beigetragen hat: Vor allem in asiatischen Ländern werden traditionell von seltenen Tieren gewonnene Stoffe als Aphrodisiaka verwendet. Durch die weltweite Verbreitung von Sildenafil ist die Jagd auf bedrohte Tierarten zum Zweck der Potenzmittel-Gewinnung mittlerweile zurückgegangen.[21]

Bis Mitte 2013 wurden weltweit rund 37 Millionen Männern 1,8 Milliarden Tabletten verschrieben. Pfizer setzte damit 24,8 Milliarden US-Dollar um.[22]

Die Herstellung von Sildenafil war patentrechtlich bis zum 22. Juni 2013 in Deutschland geschützt; es durfte daher nur von dem Unternehmen Pfizer oder in dessen Lizenz auf den Markt gebracht werden. Bis Ende Mai 2013 hatten 28 Unternehmen die Produktion von sildenafilhaltigen Medikamenten beantragt. In Österreich waren es 16 Anbieter.[22] Auch in anderen westlichen europäischen Ländern wie Großbritannien lief das Patent im Juni 2013 ab. Inzwischen wurden mehrere generische Sildenafil-Präparate EU-weit und national (beispielsweise in Österreich und Deutschland) zugelassen,[23] die nach Patentablauf auf den Markt kamen.[24] Darunter sind als Darreichungsform neben Tabletten auch Kautabletten und Schmelztabletten vertreten. Bereits zum 1. Juni 2013 bot Pfizer ein eigenes Generikum an. Ausgehend von Juni 2013 kletterte der Monatsabsatz innerhalb eines Jahres von 750.000 Packungen auf mehr als 1,7 Millionen Einheiten im Juni 2014 – eine Steigerung um 130 Prozent. Hexal und Ratiopharm haben mit ihren Generika das Original Viagra nach Absatz deutlich und – was entscheidender ist – auch nach Umsatz überholt. Zusammen mit dem eigenen Generikum verteidigt Pfizer allerdings immer noch Platz 1.[25]
قرص sildenafil tablets

Das Patent für Sildenafil-Citrat ist am 21. Juni 2013 in Österreich, Dänemark, Frankreich, Deutschland, Irland, Italien, den Niederlanden, Spanien, Schweden, Großbritannien und der Schweiz abgelaufen.[26][27] Ein Patent von Pfizer über PDE5-Hemmer wurde 2000 aufgrund von naheliegender Schöpfungshöhe für ungültig erklärt und das Urteil 2002 bestätigt.[28][29]

In den USA ist Sildenafil als Generikum erhältlich,[30] zu ungefähr einem fünfzigstel des Preises des Markenprodukts.[30] Das Markenprodukt kostete 2015 in den USA zwischen 25,17 und 37,88 US-Dollar.[31] In den USA hielt Pfizer zwei Patente für Sildenafil, zur Behandlung von pulmonaler arterieller Hypertonie (Revatio, niedrigere Dosis, Patentschutz 1993–2012) und der erektilen Dysfunktion (Viagra, Patentschutz 2002–2019).[30] Generisches Sildenafil zur Behandlung von pulmonaler arterieller Hypertonie wird in kleinerer Dosierung als Viagra in den USA von verschiedenen Herstellern angeboten.[32] Generisches Sildenafil darf in den USA off-label zur Behandlung der erektilen Dysfunktion verschrieben werden.[30] Teva klagte 2011 gegen den Patentschutz von Pfizer für die Anwendung bei erektiler Dysfunktion und verlor.[33] Aufgrund einer Einigung mit Pfizer wird Teva Sildenafil ab 2017 anbieten.[30]

In Kanada wurde das Patent für die Anwendung bei pulmonaler arterieller Hypertonie 2010 nach Klage durch Ratiopharm für ungültig erklärt.[34][35] Im Jahr 2012 befand der oberste Gerichtshof Kanadas (Teva Canada Ltd. v. Pfizer Canada Inc.), dass das Patent für Viagra von Beginn an ungültig sei, da nicht ausreichende Informationen bei der Anmeldung veröffentlicht worden seien, die nach Abschnitt 27(3)b des Patentgesetzes jeden Fachkundigen in die Lage zu versetzen haben, es herzustellen.[36][37] Am Tag der Veröffentlichung der Entscheidung brachte Teva generisches Sildenafil-Citrat auf den kanadischen Markt.[38][39][40] Daraufhin senkte Pfizer den Preis von Viagra in Kanada.[41] Eine Revision[42] wurde abschlägig entschieden[43][44]

In Indien gibt es keinen Patentschutz für Sildenafil-Citrat. Es wird unter den Handelsnamen Kamagra (Ajanta Pharma), Silagra (Cipla), Edegra (Sun Pharmaceutical), Penegra (Zydus Cadila) und Zenegra (Alkem Laboratories) verkauft. In China wird der Patentschutz für Sildenafil nicht umgesetzt. In Brasilien lief der Patentschutz für Sildenafil-Citrat 2010 aus.[45] In Ägypten wird generisches Sildenafil-Citrat legal verkauft.[46]

Die Kosten für den Wirkstoff machen nur einen geringen Anteil des Abgabepreises aus: Im Jahr 2004 kostete der Rohstoff für Viagra, Sildenafilcitrat, 650 Euro pro Kilogramm. Daraus lassen sich 20.000 Tabletten mit einem Verkaufswert des Markenprodukts von 240.000 Euro herstellen, was einen Kostenanteil von 0,26 Prozent für den Wirkstoff bzw. 0,0325 Euro pro Tablette bedeutet.[47]

Die Kostenübernahme für das Medikament in Deutschland war seit dessen Einführung Ende der 1990er Jahre umstritten; eine Liste der Gerichtsentscheidungen aus der Sozialgerichtsbarkeit (GKV), der Zivilgerichtsbarkeit (PKV) und der Verwaltungsgerichtsbarkeit (beamtenrechtliche Beihilferegelungen des Bundes und der jeweiligen Länder) findet sich in dem Urteil des Verwaltungsgerichts Frankfurt am Main vom 12. August 2003 (Geschäftsnummer 10 E 5407/01).[48] Die Bewilligung ist von den jeweiligen Gerichten aller drei Gerichtsbarkeiten in der Regel bei medizinischer Indikation für berechtigt gehalten worden.

Seit dem 1. Januar 2004 schließt das GKV-Modernisierungsgesetz vom 14. November 2003 (BGBl. I S. 2190) in § 34 Abs. 1 Satz 7 und 8 SGB V die Arzneimittel aus, bei deren Anwendung eine Erhöhung der Lebensqualität im Vordergrund steht. Dazu zählen u. a. Arzneimittel, die überwiegend zur Behandlung der erektilen Dysfunktion oder der Anreizung sowie Steigerung der sexuellen Potenz dienen, wie Viagra. Auf die Ursache der Störung kommt es nach dem Gesetzestext nicht an. Eine Ausnahmeregelung sehen weder Gesetz noch die Arzneimittel-Richtlinien (Anlage 8) vor.

Auch nach der Rechtsänderung und der Einbeziehung der Hilfeempfänger nach dem SGB II und SGB XII in die gesetzliche Krankenversicherung und die dadurch begründete Zuständigkeit der Sozialgerichte änderte sich die Rechtsprechung nicht. Die Kosten für die Behandlung der pulmoarteriellen Hypertonie mit Revatio werden von den gesetzlichen Krankenkassen getragen. Das vielfach von Versicherungen vorgebrachte Argument, Potenzprobleme bei älteren Männern seien „normale altersbedingte Fehlfunktionen“ wurde in einem Verfahren gegen eine private Krankenversicherung vor dem Landgericht Dortmund (Az: 2 S 25/04) im September 2004 zurückgewiesen. Ebenso entschied das OLG Karlsruhe – 12 U 32/03 – 3. Juli 2003; OLG München – 25 U 4628/99 – 8. August 2000 (NJW 2000, 3442). Anders hatte noch das LG Köln (23.O.57/02) am 20. August 2003 entschieden, als es eine erektile Dysfunktion für keine Krankheit und Viagra für kein symptomatisches Medikament erklärte.

Das Bundesverwaltungsgericht hat mit Urteilen vom 28. Mai 2008 entschieden, dass Sildenafil nicht über die nach den ab 2004 geltenden Beihilferegeln erstattungsfähig ist (Aktenzeichen 2 C 24.07.[49] und 2 C 108.07[50]) Das Oberverwaltungsgericht Rheinland-Pfalz hatte mit Urteil vom 17. Mai 2002 (Az. 2 A 11755/01.OVG) entschieden, dass Sildenafil ein Arzneimittel ist, dessen Kosten nicht grundsätzlich von der Beihilfegewährung ausgeschlossen werden dürfen, eine entsprechende medizinische Indikation (hier: erektile Dysfunktion nach Prostatakrebsoperation) vorausgesetzt. Auf ähnlicher Linie lag ein Urteil des Verwaltungsgericht Düsseldorf vom 2. September 2005 (26 K 371/05), das Tadalafil als ein über die Beihilfe erstattungsfähiges Medikament behandelt. Die Rechtsprechung ist vielfach kritisiert worden.[51]

Mit Urteil vom 12. August 2003 hat das Verwaltungsgericht Frankfurt am Main (Geschäftsnummer 10 E 5407/01) entschieden, dass Kranken Krankenhilfe nach dem Bundessozialhilfegesetz (§ 37 BSHG) zu gewähren ist, wenn sie sich selbst nicht helfen können. Die Sozialhilfe-Behörde durfte die Leistung eines Arzneimittels als Krankenhilfe nicht mit dem Verweis auf die Arzneimittelrichtlinien der gesetzlichen Krankenversicherung ablehnen, wonach unterschiedslos jegliche Behandlung einer [erektilen Dysfunktion] mit Arzneimitteln verweigert wird. Die Richtlinien seien nicht einschlägig, wenn es um die Behandlung einer Krankheit gehe. Deshalb hätten „Kassenpatienten“ wie Sozialhilfeempfänger bei einer Krankheit Anspruch auf Behandlung mit Viagra.[52]

Der Hessische Verwaltungsgerichtshof hat mit Urteil vom 11. Oktober 2004 (Geschäftsnummer: 10 UE 2731/03) entschieden, dass der durch das GKV-Modernisierungsgesetz vom 14. November 2003 (BGBl. I S. 2190) ab dem 1. Januar 2004 in § 34 Abs. 1 Satz 8 SGB V eingeführte Ausschluss von Medikamenten zur Behandlung der erektilen Dysfunktion von der Versorgung im Rahmen der gesetzlichen Krankenversicherung wegen der gleichzeitig eingeführten strengen Akzessorietät auch im Rahmen der Krankenhilfe nach dem Bundessozialhilfegesetz zu beachten sei. Nach dieser Neufassung komme jedenfalls ab dem 1. Januar 2004 ein Anspruch eines Hilfeempfängers auf Übernahme der Kosten für das Medikament Viagra im Rahmen der genannten Hilfeart nicht mehr in Betracht.[53]

Mit Beschluss vom 1. September 2005 hat das Hessische Landessozialgericht (Geschäftsnummer L 8 KR 80/05 ER) entschieden, dass das Medikament „Caverject“ (oder auch „Viagra“) als Leistung in der gesetzlichen Krankenversicherung nicht mehr vorgesehen sei, denn durch Artikel 1 Nr. 22 des Gesetzes zur Modernisierung der gesetzlichen Krankenversicherung (GMG) vom 14. November 2003 (BGBl. I S. 2190) seien mit Wirkung vom 1. Januar 2004 sämtliche Arzneimittel, die der Behandlung der erektilen Dysfunktion dienen, von der Verordnung zu Lasten der gesetzlichen Krankenversicherung ausgeschlossen.[54]

Anfang der 1990er Jahre suchte ein Forschungsteam eines Pfizer-Forschungsinstituts in Sandwich in England ein Mittel gegen Herzbeschwerden. Das dabei gefundene Mittel UK-92480 blockierte das Enzym PDE-5. Während erste Versuche an Patienten vielversprechend verlaufen waren, berichteten einige Männer von mehreren Erektionen einige Tage nach Einnahme des Medikaments. Der zuständige Versuchsleiter sah in dieser Wirkung kein Potential; Pfizer meldete daher 1991 den Wirkstoff als Sildenafil Citrate zum Patent an.[55]

Nachdem sich das Medikament für Herzbeschwerden letztlich als wirkungslos erwies, wurde die sexuelle Wirkung des Wirkstoffs genauer betrachtet. Bei einer Studie an 300 Männern in England, Frankreich und Schweden berichteten 90 Prozent über Erektionen; Nebenwirkungen wurden kaum beobachtet. 1998 erhielt Pfizer von der US-Gesundheitsbehörde die Genehmigung, Viagra zu verkaufen. Das Time Magazine berichtete in einer Titelgeschichte über die Potenzpille.[55]

Im Jahre 2003 wurden zwei weitere Medikamente mit gleichem Wirkmechanismus auf den Markt gebracht: Levitra (Bayer) und Cialis (Eli Lilly). 2012 folgte ein neuer Wirkstoff namens Avanafil (Mitsubishi Pharma), das schneller als Viagra wirken soll; der Handelsname ist Stendra.[55] Seit April 2014 ist Spedra (Berlin-Chemie mit dem Wirkstoff Avanafil) in Deutschland erhältlich.

Im Jahre 2007 hielt Pfizer auf dem Weltmarkt für Substanzen gegen erektile Dysfunktion einen Anteil von 47 Prozent, 2013 waren es 36 Prozent. Im Jahre 2012 erwirtschaftete Pfizer mit Viagra einen Umsatz von zwei Milliarden US-Dollar.[55]

1-{[3-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl}-4-methylpiperazin (IUPAC)

G04BE03

PDE-5-Hemmer

Enzymhemmung der Phosphodiesterase-5

Achtung

قرص sildenafil tablets

In Deutschland, Österreich und der Schweiz sind sildenafilhaltige Arzneimittel verschreibungspflichtig.

Außer den oben genannten Bereichen ist eine Wirkung und ein Einsatz von Sildenafil bei verschiedenen speziellen Krankheitsbildern beschrieben:

Eine Forschungsgruppe konnte zeigen, dass Sildenafil in Wasser gelöst in der Lage ist, die Lebensdauer von Schnittblumen signifikant zu verlängern.[18]

Bis Mitte 2013 wurden weltweit rund 37 Millionen Männern 1,8 Milliarden Tabletten verschrieben. Pfizer setzte damit 24,8 Milliarden US-Dollar um.[22]

InChI=1S/C22H30N6O4S.C6H8O7/c1-5-7-17-19-20(27(4)25-17)22(29)24-21(23-19)16-14-15(8-9-18(16)32-6-2)33(30,31)28-12-10-26(3)11-13-28;7-3(8)1-6(13,5(11)12)2-4(9)10/h8-9,14H,5-7,10-13H2,1-4H3,(H,23,24,29);13H,1-2H2,(H,7,8)(H,9,10)(H,11,12) YKey:DEIYFTQMQPDXOT-UHFFFAOYSA-N Y

سیلدنافیل سیترات Sildenafil (ویاگرا)، که تحت نام تجاری Viagra، Revatio و اسامی دیگر به فروش می‌رسد، یکی از داروهای مورد استفاده در درمان اختلال در نعوظ و افزایش فشار خون شریانی ریوی (PAH) است. این دارو نخستین بار توسط شرکت داروسازی فایزر به بازار عرضه شد. سیلدنافیل باعث مهار نوع شماره ۵ آنزیم فسفودی استراز خاص cGMP می‌شود (PDE۵). این آنزیم جریان خون در آلت تناسلی مرد را تنظیم می‌کند. سیلدنافیل از زمانی که در سال ۱۹۹۸ در دسترس قرار گرفته‌است یکی از مهم‌ترین داروها برای درمان اختلال در نعوظ به‌شمار می‌رود.

مهم‌ترین مورد مصرف سیلدنافیل معده درمان اعصاب و رفلاکس معده است . در حال حاضر استفاده از آن درمان استاندارد برای نقص رفلاکس معده در غالب موارد، از جمله دیابت، محسوب می‌شود.

سیلدنافیل باعث مهار نوع شماره ۵ آنزیم فسفودی استراز خاص cGMP می‌شود (PDE۵). این آنزیم جریان خون در آلت تناسلی مرد را تنظیم می‌کند.

در مطالعات بالینی، شایع‌ترین عوارض جانبی استفاده از سیلدنافیل سردرد، گرگرفتگی، سوء هاضمه، گرفتگی بینی و اختلالات بینایی، از جمله نور ریزی و تاری دید ذکر شده‌اند. برخی پس از مصرف سیلدنافیل همه چیز را با سایه آبی رنگ می‌بینند (cyanopsia). برخی دیگر دچار از دست رفتن دید محیطی می‌شوند.
عوارض جانبی نادر ولی جدی شامل نعوظ پایدار priapism، افت شدید فشار خون، انفارکتوس میوکارد (سکته قلبی) آریتمی‌های بطنی، سکته مغزی، افزایش فشار داخل چشمی، و از دست رفتن ناگهانی شنوایی می‌باشند.
قرص sildenafil tablets

قرص سیلدنافیل. دریافت‌ شده در 15 ژوئن 2014.

InChI=1S/C22H19N3O4/c1-24-10-19(26)25-16(22(24)27)9-14-13-4-2-3-5-15(13)23-20(14)21(25)12-6-7-17-18(8-12)29-11-28-17/h2-8,16,21,23H,9-11H2,1H3/t16-,21-/m1/s1 YKey:WOXKDUGGOYFFRN-IIBYNOLFSA-N Y

تادالافیل (به انگلیسی: Tadalafil)

رده درمانی: درمان ناتوانی جنسی مردان

اشکال دارویی: قرص

تادالافیل باعث مهار نوع شماره ۵ آنزیم فسفودی استراز خاص cGMP می‌شود.
قرص sildenafil tablets

سردرد، گرگرفتگی، سوء هاضمه، گرفتگی بینی و دردهای عضلانی، درد قفسه سینه ،خشکی دهان، افزایش تعداد ضربان قلب، گیجی , خستگی مفرط , تشنج , تاری دید , بثورات جلدی، خارش شدید , افزایش فشارخون و کاهش فشارخون

کلومیفن سیترات (به انگلیسی: CLOMIPHEN CITRATE) جزو داروهای مدولاتور انتخابی گیرنده استروژن بوده و در شکل دارویی قرص در بازار موجود است. این دارو به‌طور گسترده برای تحریک تخمک‌گذاری در مشکل عدم تخمک‌گذاری یا اُلیگواوولاسیون تجویز می‌گردد.[۱][۲]

کلومیفن عمدتاً دارای اثرات ضداستروژنی بوده و بعضاً خواص‌استروژنی نیز دارد. این دارو با اتصال‌رقابتی به گیرنده‌های استروژن در سلولهای هیپوتالاموس، مانع اثر مهاری استروژن‌بر آزادشدن گنادوتروپین‌ها و در نتیجه‌افزایش LH و FSH می‌گردد. افزایش ترشح گنادوتروپین هاموجب بلوغ فولیکول‌های تخمدانی، افزایش پیک LH قبل از تخمک‌گذاری، تخمک‌گذاری‌و در نهایت تکامل جسم زرد می‌شود. درناباروری مردان نیز از طریق افزایش‌ترشح LH و FSH، اثر درمانی خود را اعمال‌می‌کند.[۵]

مهم‌ترین عوارض عبارتنداز تشکیل کیست تخمدان، بزرگ شدن بیش‌از حد تخمدان، بزرگ شدن بافت فیبروئید رحم، شکم درد و بروز سندرم قبل از قاعدگی . همچنین در حاملگی به دنبال مصرف کلومیفن احتمال چندقلوزایی وجود دارد.

اثر بر آزمایشهای تشخیصی
کلومیفن ممکن است سطح سرمی تیرونین، گلوبولین پیوند یابنده به تیروکسین، گلوبولین پیوند یابنده به هورمون‌های جنسی را افزایش دهد. همچنین، این دارو ممکن است احتباس سولفوبرموفتالئین و ترشح FSH و LH را افزایش دهد.
قرص sildenafil tablets

اعصاب مرکزی: سردرد، بی‌قراری، بی‌خوابی، سرگیجه، احساس منگی، افسردگی، خستگی، فشار روحی.

قلبی ـ عروقی: برافروختگی‌های وازوموتور شبیه گرگرفتگی‌های یائسگی، زیادی فشارخون.

پوست: کهیر، بثورات پوستی یا درماتیت آلرژیک.

چشم: تاری دید، دوبینی، احساس برق زدن در چشم‌ها، فتوفوبی (علائم مسمومیت چشمی قریب‌الوقوع ).

دستگاه گوارش: تهوع، استفراغ، نفخ، اتساع، ناراحتی یا درد شکم، زیاد شدن اشتها، افزایش وزن بدن، زرد شدن پوست و چشم‌ها (نشانه مسمومیت کبدی).

ادراری ـ تناسلی: تکرر ادرار و پر ادراری، کیست و بزرگی تخمدان (به‌طور خودبه‌خود با قطع دارو برطرف می‌شود)، خون‌ریزی زیاد در قاعدگی، چندقلوزایی.

سایر عوارض: آلوپِسی قابل برگشت، احساس ناراحتی در پستان، سرفه، تنگی نفس.

توجه: در صورت بروز هرگونه عوارض بینایی طی درمان، باید مصرف دارو قطع شود.

در صورت رشد کیست تخمدان یا بزرگی تخمدان‌ها، مصرف دارو تا زمان برگشت تخمدان‌ها به اندازه قبل از درمان، قطع شده و سپس، درمان با مقدار کمتر و به مدت کوتاه تری شروع می‌شود.

ناباروری

هایپرتنسیون ریوی یا پُرفشاری شش در پزشکی به افزایش فشار خون در سرخرگ ریوی یا سیاهرگ ریوی و بطورکل افزایش فشار خون در عروق شش‌ها شناخته شده‌است و منجر به تنگی نفس، سرگیجه، غش کردن، تورم پا و علائم دیگر می‌شود. فشار خون ریوی می‌تواند یک بیماری شدید با کاهش در تحمل فعالیت بدنی و نارسایی قلبی در نظر گرفته شود.[۱]

علائم این بیماری بسیار پله‌پله و آرام ظاهر می‌شوند بطوریکه ممکن است بیمار پس از سال‌ها به پزشک مراجعه کند.
این علایم به‌طور معمول تنگی نفس، خستگی، سرفه بدون خلط، آنژین صدری، غش یا سنکوپ، ادم محیطی (تورم اطراف مچ پا و پاها) و نیز به ندرت هموپتیزی (سرفه خونی) هستند.

طی نشست سال ۱۹۷۳ سازمان بهداشت جهانی برای نخستین‌بار اقدام به طبقه‌بندی پرفشاری خون ریوی٬ تمایز بین پرفشاری اولیه و ثانویه نمود.[۲]

چنانچه در خصوص “سیلدینافیل ” سوالی دارید، عارضه خاصی مشاهده نموده اید و یا مطلب ویژه ای به نظرتان می رسد با دیگران به اشتراک بگذارید

اختلال نعوظ

عملكرد ايجاد نعوظ : سيلدنافيل هيچ اثر شُل‌كنندگي مستقيم بر كارپوس كاورنوزوم انسان ندارد، اما به واسطه مهار فسفودي‌استراز نوع 5 كه مسئول تخريب cGMP در كارپوس كاورنوزوم مي‌باشد، منجر به افزايش اثرات نيتريك اكسيد (NO) مي‌گردد.
زماني كه محرك جنسي منجر به افزايش رهاسازي NO مي‌گردد، مهار فسفودي‌استراز نوع 5 توسط سيلدنافيل باعث افزايش سطح cGMP در كارپوس كاورنوزوم شده، عضلات صاف شُل‌ گشته و خون به كارپوس كاورنوزوم جريان مي‌يابد.

در حساسيت مفرط به دارو يا هر يك از اجزاء فرمولاسيون و مصرف همزمان (منظم يا غير منظم) نيترات‌هاي ارگانيك به هر شکل دارويي منع مصرف دارد.
در بيماران دچار انسداد مسير خروجي بطن چپ (تنگي آئورت يا كارديوميوپاتي انسدادي هايپرتروفيك) بيماري عروق كرونري، ديابت، هايپرتانسيون كنترل نشده، هايپرليپيدمي، سيگاري‌ها، افراد بالاي 50 سال، بيماري‌هاي دژنراتيو رتين، بيماران دچار اختلالات آناتوميك آلت تناسلي، بيماري‌هاي خونريزي‌دهنده، هايپوتانسيون، آريتمي‌هاي تهديدكننده حيات، استروك يا انفاركتوس قلبي طي 6 ماه گذشته، نارسايي قلبي، شرايطي كه بيمار را مستعد پرياپيسم مي‌كند، نارسايي كبدي، زخم فعال گوارشي، هايپرتانسيون شريان ريوي و نارسايي كليوي بايد مصرف دارو با احتياط صورت گيرد.

اعصاب مرکزي: سردرد، بي‌خوابي، گيجي، تب، افسردگي، تشنج، ميگرن، نورآلژي، سرگيجه.
دستگاه گوارش: سوءهاضمه، اسهال، گاستريت، ديس‌فاژي، خونريزي از ركتوم، استفراغ، کوليت.
قلبي – عروقي: فلاشينگ، آنژين، بلوك AV، ايست قلبي، كارديوميوپاتي، ترومبوز مغزي، خونريزي داخل مغزي، ادم، نارسايي قلبي، هايپوتانسيون، هايپرتانسيون، ايسكمي ميوكارد، انفاركتوس قلبي، طپش قلب، افت فشار خون وضعيتي، شوك، تاكيكاردي، سنكوپ، آريتمي بطني.
متابوليك: هايپرگلاسيمي، هايپوگلاسيمي، هايپرناترمي، هايپراوريسمي.
عضلاني – اسكلتي: درد عضلاني، پارسترني، پارگي تاندون.
پوست: قرمزي، راش، درماتيت.
ادراري تناسلي: عفونت مجاري ادراري، سيستيت.
چشم: ديد غير طبيعي، خونريزي چشمي، افزايش فشار داخل چشمي، ميدرياز، بيماري عروق رتين يا خونريزي رتين، کاهش ميدان بينايي، حساسيت به نور.
گوش، حلق، بيني: خونريزي‌ بيني، كاهش شنوايي، كري، تشديد تنگي نفس، احتقان و آبريزش بيني، سينوزيت.
ساير عوارض: افزايش آنزيم‌هاي كبدي، واكنش‌هاي آلرژيك.

مهاركننده‌هاي فسفودي‌‌استراز نوع 5 منجر به افزايش اثرات كاهش فشار بلوك‌كننده‌هاي 1? مي‌شوند. استثناء در اين مورد داپي‌ پرازول مي‌باشد.
تركيبات ضد قارچ (مشتقات آزول، سيستميك) منجر به كاهش مهاركننده‌هاي فسفودي‌استراز نوع 5 مي‌شوند.
بوسنتان غلظت پلاسمايي مهاركننده‌هاي فسفودي‌استراز 5 را كاهش داده و اين داروها منجر به افزايش غلظت سرمي بوسنتان مي‌شوند.
متابوليسم سيلدنافيل توسط مهاركننده‌هاي CYP3A4 كاهش مي‌يابد.
دازاتينيب (Dasatinib) غلظت سرمي سيلدنافيل را افزايش مي‌دهد.
دفرازيروكس و اتراويرين غلظت سرمي سيلدنافيل را كاهش مي‌دهند.
سيلدنافيل منجر به كاهش متابوليسم استاتين‌ها به استثناء فلوواستانين، پراواستاتين و روزوواستاتين مي‌گردد.
آنتي‌بيوتيك‌هاي ماكروليدي و مهاركننده‌هاي پروتئاز منجر به كاهش متابوليسم سيلدنافيل مي‌شوند.
Peg: اينترفرون غلظت سرمي سيلدنافيل را كاهش مي‌دهد.قرص sildenafil tablets

FDA طبقه بندی: B. هيچ مطالعه كافي و كنترل شده‌اي در مورد سيلدنافيل در بارداري وجود ندارد.

ترشح سيلدنافيل در شير مشخص نيست و لازم است در خانم‌هاي باردار با احتياط مصرف شود.

برای اطلاع از مقدار و نحوه مصرف دارو با پزشک مشورت کنید.

قبل از استفاده از سيلدنافيل به عنوان درمان اختلال نعوظ، لازم است ساير علل ايجادكننده اين اختلال بررسي شود.
مصرف همزمان با آب‌ گريپ‌فروت منجر به افزايش خطر سميت مي‌شود و بايد از مصرف همزمان آنها پرهيز شود.

1- در صورت مصرف هر نوع تركيب نيترات، لازم است به پزشك معالج اطلاع داده شود.
2- در صورت بروز كاهش بينايي، مصرف دارو را قطع نموده و به پزشك اطلاع داده شود.
3- استفاده از سيلدنافيل هيچ‌گونه حفاظتي در مقابل بيماري‌هاي قابل انتقال توسط تماس جنسي ايجاد نمي‌كند.
مصرف در سالمندان: لازم است مصرف اين دارو در سالمندان با احتياط صورت گيرد و ممكن است لازم باشد دوز دارو تنظيم گردد.

Tablet: 25, 50, 100mg

اهران تجارت     تولید شده      TABLET           ERECTO® 100MG TAB
بهستان دارو     تولید شده    TABLET           SILDENAFIL CITRATE 100MG TAB
بهستان دارو     تولید شده    TABLET           VIAGRA® 100MG TAB
پورسينا     تولید شده TABLET          SILDENAFIL CITRATE 100MG TAB
خوارزمي     تولید شده TABLET          SILDENAFIL CITRATE 100MG TAB
خوارزمي     تولید شده       TABLET          SILERECT® 100MG TAB
رازك     تولید شده TABLET          VIGRAZ® 100MG TAB
روز دارو     تولید شده    TABLET          SILDENAFIL CITRATE 100MG TAB
شهر دارو     تولید شده    TABLET          SILDENAFIL CITRATE 100MG TAB
فارماشيمي     تولید شده    TABLET          SILDENAFIL CITRATE 100MG TAB
فارماشيمي     تولید شده       TABLET          SILDENAFIL-PHARMA® 100MG TAB
شهر دارو     تولید شده    TABLET          SILDENAFIL CITRATE 25MG TAB
بهستان دارو     تولید شده    TABLET          VIAGRA® 50MG TAB
شهر دارو     تولید شده     TABLET          SILDENAFIL (SHAHREDAROU) 50MG TAB

روز دارو     تولید شده F.C. Tablet     SILDENAFIL (RUZDAROU) 100MG TAB
شهر دارو     تولید شده F.C. Tablet     SILDENAFIL (PURSINA) 100MG TAB
شهر دارو     تولید شده     F.C. Tablet     SILDENAFIL (SHAHREDAROU) 100MG TAB
شهر دارو     تولید شده    F.C. Tablet     SILDENAFIL (SHAHREDAROU) 25MG TAB
بهستان دارو     تولید شده   F.C. Tablet     SILDENAFIL CITRATE 50MG TAB
پورسينا     تولید شده       F.C. Tablet     SILDENAFIL CITRATE 50MG TAB
رازك     تولید شده       F.C. Tablet     SILDENAFIL (RAZAK) 50MG TAB
رازك     تولید شده       F.C. Tablet     SILDENAFIL CITRATE 50MG TAB
روز دارو     تولید شده    F.C. Tablet     SILDENAFIL (RUZDAROU) 50MG TAB
روز دارو     تولید شده       F.C. Tablet     SILDENAFIL CITRATE 50MG TAB

مرهم دارو تولید شده Scored F.C.Tablet SILDENAFIL (MARHAM DAROU) 100MG TAB

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پاسخ سوالات بر اساس تاریخ پرسش سوال

مطلب از سایر رسانه ها

Updated

April 2, 2018

If you are a consumer or patient please visit this version.

Warnings and Precautions, Visual Loss (5.5) 7/2017

Sildenafil tablets are phosphodiesterase-5 (PDE-5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in adults to improve exercise ability and delay clinical worsening. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with NYHA Functional Class II-III symptoms. Etiologies were idiopathic (71%) or associated with connective tissue disease (25%). (1)

Limitation of Use: Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity. (1, 14) قرص sildenafil tablets

Tablets: 20 mg three times a day, 4 to 6 hours apart (2.1)

Most common adverse reactions greater than or equal to 3% and more frequent than placebo were epistaxis, headache, dyspepsia, flushing, insomnia, erythema, dyspnea, and rhinitis. (6.1, 6.2)

To report SUSPECTED ADVERSE REACTIONS, contact Vensun Pharmaceuticals, Inc. at 1-800-385-1540 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 4/2018

Sildenafil tablets are indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when Sildenafil tablets were added to background epoprostenol therapy [see Clinical Studies (14)].

Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%).

Limitation of Use: Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity [see Clinical Studies (14)].

The recommended dose of sildenafil tablets is 20 mg three times a day. Administer sildenafil tablet doses 4–6 hours apart. In the clinical trial no greater efficacy was achieved with the use of higher doses. Treatment with doses higher than 20 mg three times a day is not recommended.

Sildenafil Tablets, USP

Sildenafil tablets, USP as white round, biconvex film coated tablets, debossed with R on one side and 20 on the other, containing sildenafil citrate equivalent to 20 mg of sildenafil.

Sildenafil tablets are contraindicated in patients with:

In a long-term trial in pediatric patients with PAH, an increase in mortality with increasing sildenafil tablets dose was observed. Deaths were first observed after about 1 year and causes of death were typical of patients with PAH. Use of sildenafil tablets, particularly chronic use, is not recommended in children. [see Use in Specific Populations (8.4)].

Sildenafil tablets has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing sildenafil tablets, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension [BP less than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil tablets.

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of sildenafil tablets to patients with veno-occlusive disease, administration of sildenafil tablets to such patients is not recommended. Should signs of pulmonary edema occur when sildenafil tablets are administered, consider the possibility of associated PVOD.

The incidence of epistaxis was 13% in patients taking sildenafil tablets with PAH secondary to CTD. This effect was not seen in idiopathic PAH (sildenafil tablets 3%, placebo 2%) patients. The incidence of epistaxis was also higher in sildenafil tablets-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist).

The safety of sildenafil tablets is unknown in patients with bleeding disorders or active peptic ulceration.

When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE-5) inhibitors, including sildenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. Based on published literature, the annual incidence of NAION is 2.5–11.8 cases per 100,000 males aged ≥ 50 per year in the general population.

An observational case-crossover study evaluated the risk of NAION when PDE-5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE-5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies.

Neither the rare postmarketing reports, nor the association of PDE-5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE-5 inhibitor use and NAION [see Adverse Reactions (6.2)].

Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking PDE-5 inhibitors, including sildenafil tablets. Physicians should also discuss the increased risk of NAION with patients who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE-5 inhibitors.قرص sildenafil tablets

There are no controlled clinical data on the safety or efficacy of sildenafil tablets in patients with retinitis pigmentosa, a minority whom have genetic disorders of retinal phosphodiesterases. Prescribe sildenafil tablets with caution in these patients.

Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including sildenafil tablets. In some of the cases, medical conditions and other factors were reported that may have played a role. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of Sildenafil tablets, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors.

Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE-5 inhibitors, including sildenafil tablets.

Sildenafil is also marketed as VIAGRA®;. The safety and efficacy of combinations of sildenafil tablets with VIAGRA or other PDE-5 inhibitors have not been studied. Inform patients taking sildenafil tablets not to take VIAGRA or other PDE-5 inhibitors.

Use sildenafil tablets with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients who have conditions, which may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erection greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result.

In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received sildenafil tablets than by those randomized to placebo. The effectiveness and safety of sildenafil tablets in the treatment of PAH secondary to sickle cell anemia has not been established.

The following serious adverse events are discussed elsewhere in the labeling:

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Safety data of sildenafil tablets in adults were obtained from the 12-week, placebo-controlled clinical study (Study 1) and an open-label extension study in 277 sildenafil tablets-treated patients with PAH, WHO Group I. [see Clinical Studies (14)].

The overall frequency of discontinuation in sildenafil tablets-treated patients on 20 mg three times a day was 3% and was the same for the placebo group.

In Study 1, the adverse reactions that were reported by at least 3% of sildenafil tablets-treated patients (20 mg three times a day) and were more frequent in sildenafil tablets-treated patients than in placebo-treated patients are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature.

At doses higher than the recommended 20 mg three times a day, there was a greater incidence of some adverse reactions including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were predominately color-tinge to vision, but also increased sensitivity to light or blurred vision.

The incidence of retinal hemorrhage with sildenafil tablets 20 mg three times a day was 1.4% versus 0% placebo and for all sildenafil tablets doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both 20 mg three times a day and at all doses studied was 1.4% for sildenafil tablets versus 1.4% for placebo. The patients experiencing these reactions had risk factors for hemorrhage including concurrent anticoagulant therapy.

In a placebo-controlled fixed dose titration study (Study 2) of sildenafil tablets (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, the adverse reactions that were more frequent in the sildenafil tablets + epoprostenol group than in the epoprostenol group (greater than 6% difference) are shown in Table 2 [see Clinical Studies (14)].

^includes peripheral edema

The following adverse reactions have been identified during post approval use of sildenafil (marketed for both PAH and erectile dysfunction). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular Events

In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after use concurrent with sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient’s underlying cardiovascular disease, or to a combination of these or other factors.

Nervous system

Seizure, seizure recurrence

Ophthalmologic

NAION [see Warnings and Precautions (5.5) and Patient Counseling Information (17) ].

Nitrates

Concomitant use of sildenafil tablets with nitrates in any form is contraindicated [see Contraindications (4)].

Ritonavir and other Potent CYP3A Inhibitors

Concomitant use of sildenafil tablets with ritonavir and other potent CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3)].

Other drugs that reduce blood pressure

Alpha blockers. In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-blocker doxazosin (4 mg or 8 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, were observed. Mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively, were also observed. There were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-headedness, but not syncope.

Amlodipine. When sildenafil 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.

Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil tablets [see Warnings and Precautions (5.2)].

Risk Summary

Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations). Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32-and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively (See Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death.

Data

Animal Data

No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m2 basis, 32-and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre-and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m2 basis).

Risk Summary

Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. There is insufficient information about the effects of sildenafil on the breastfed infant and no information on the effects of sildenafil on milk production. Limited clinical data during lactation preclude a clear determination of the risk of sildenafil tablets to an infant during lactation.

In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body weight, to three dose levels of sildenafil tablets, or placebo, for 16 weeks of treatment. Most patients had mild to moderate symptoms at baseline: WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 37%; surgical repair in 30%). Sixty-two percent of patients were female. Drug or placebo was administered three times a day.

The primary objective of the study was to assess the effect of sildenafil tablets on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). Administration of sildenafil tablets did not result in a statistically significant improvement in exercise capacity in those patients. No patients died during the 16-week controlled study.

After completing the 16-week controlled study, a patient originally randomized to sildenafil tablets remained on his/her dose of sildenafil tablets or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose sildenafil tablets. After all patients completed 16 weeks of follow-up in the controlled study, the blind was broken and doses were adjusted as clinically indicated. Patients treated with sildenafil were followed for a median of 4.6 years (range 2 days to 8.6 years). Mortality during the long-term study, by originally assigned dose, is shown in Figure 6:

Figure 6: Kaplan-Meier Plot of Mortality by Sildenafil Tablets Dose

During the study, there were 42 reported deaths, with 37 of these deaths reported prior to a decision to titrate subjects to a lower dosage because of a finding of increased mortality with increasing sildenafil tablets doses. For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007. Causes of death were typical of patients with PAH. Use of sildenafil tablets, particularly chronic use, is not recommended in children.

Clinical studies of sildenafil tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see Clinical Pharmacology (12.3)].

No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [see Clinical Pharmacology (12.3)].

In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased.

In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.

Sildenafil Tablets, USP phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5). Sildenafil is also marketed as VIAGRA® for erectile dysfunction.

Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula:

Sildenafil tablets: Sildenafil tablets is white round, biconvex film coated tablets, debossed with R on one side and 20 on the other, containing sildenafil citrate equivalent to 20 mg of sildenafil. In addition to the active ingredient, sildenafil citrate , each tablet contains the following inactive ingredients: Crospovidone, Hypromellose, Hydrophobic colloidal silica, Lactose monohydrate, Magnesium stearate, Microcrystalline cellulose, Titanium dioxide, and Triacetin.

Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilatation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.

Studies in vitro have shown that sildenafil is selective for PDE-5. Its effect is more potent on PDE-5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology (12.2)].

In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo.

Effects of Sildenafil tablets on Hemodynamic Measures

Patients on all sildenafil tablets doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [Study 1 in Clinical Studies (14)]. Data on other hemodynamic measures for the sildenafil tablets 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6-minute walk distance is unknown.

mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate

*The number of patients per treatment group varied slightly for each parameter due to missing assessments.

In another study evaluating lower doses of sildenafil 1 mg, 5 mg and 20 mg [Study 3 in Clinical Studies (14)], there were no significant differences in the effects on hemodynamic variables between doses.

Effects of Sildenafil on Blood Pressure

Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1–2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications (4)].

Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported.

After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively.

After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively.

After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg).

Effects of Sildenafil tablets on Vision

At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil tablets on visual acuity, intraocular pressure, or pupillometry.

Absorption and Distribution

Sildenafil tablets is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25–63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil tablets 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%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.

Metabolism and Excretion

Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil’s pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours.

After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).

Population Pharmacokinetics

Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH.

In patients with PAH, the average steady-state concentrations were 20–50% higher when compared to those of healthy volunteers. There was also a doubling of Cmin levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers.

Geriatric Patients

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18–45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively.

Renal Impairment

In volunteers with mild (CLcr = 50–80 mL/min) and moderate (CLcr = 30–49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, 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 200 % and 79 %, respectively, in subjects with severe renal impairment compared to subjects with normal renal function.

Hepatic Impairment

In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class 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. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

Drug Interaction Studies

In vitro studies

Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.

Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than 150 µM).

Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations.

In vivo studies

The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 7 and Figure 8, respectively.

Figure 7. Effects of Other Drugs on Sildenafil Pharmacokinetics

Figure 8 Effects of Sildenafil on Other Drugs

CYP3A Inhibitors and Beta Blockers

Population pharmacokinetic analysis of data from patients in clinical trails indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir).

CYP3A4 inducers including bosentan

Concomitant administration of potent CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil.

Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers.

Epoprostenol

The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known.

No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.

Alcohol

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.

Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33- and 37- times, for male and female rats respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m2 basis.

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

There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19- and 38- times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day.

Studies of Adults with Pulmonary Arterial Hypertension

Study 1 (Sildenafil tablets monotherapy (20 mg, 40 mg, and 80 mg three times a day))

A randomized, double-blind, placebo-controlled study of sildenafil tablets (Study 1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure of greater than or equal to 25 mmHg at rest with a pulmonary capillary wedge pressure less than 15 mmHg). Patients were predominantly World Health Organization (WHO) functional classes II–III. Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Subjects who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied.

Patients were randomized to receive placebo (n=70) or sildenafil tablets, 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. They had either primary pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18–81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343).

The primary efficacy endpoint was the change from baseline at week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Placebo-corrected mean increases in walk distance of 45–50 meters were observed with all doses of sildenafil tablets. These increases were significantly different from placebo, but the sildenafil tablets dose groups were not different from each other (see Figure 9), indicating no additional clinical benefit from doses higher than 20 mg three times a day. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12.

Figure 9. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in Study 1: Mean (95% Confidence Interval)

Figure 10 displays subgroup efficacy analyses in Study 1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age and hemodynamic parameters.

Figure 10. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by study subpopulation in Study 1: Mean (95% Confidence Interval)

Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily.

Of the 277 treated patients, 259 entered a long-term, uncontrolled extension study. At the end of 1 year, 94% of these patients were still alive. Additionally, walk distance and functional class status appeared to be stable in patients taking sildenafil tablets. Without a control group, these data must be interpreted cautiously.

Study 2 (Sildenafil tablets co-administered with epoprostenol)

A randomized, double-blind, placebo controlled study (Study 2) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 349 meters). Patients were randomized to placebo or sildenafil tablets (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy.

At baseline patients had PPH (80%) or PAH secondary to CTD (20%);WHO functional class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian.

There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil tablets group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil tablets group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009).

Patients on sildenafil tablets achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil tablets (95% CI: -5.7, -2.1) (p = 0.00003).

Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Table 4 displays the number of patients with clinical worsening events in Study 2. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than the sildenafil tablets-treated patients and that sildenafil tablets-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 11.

Figure 11. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH (in Study 2)

Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil tablets compared to placebo. More than twice as many sildenafil tablets-treated patients (36%) as the placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH.

Study 3 (Sildenafil tablets monotherapy (1 mg, 5 mg, and 20 mg three times a day))

A randomized, double-blind, parallel dose study (Study 3) was planned in 219 patients with PAH. This study was prematurely terminated with 129 subjects enrolled. Patients were required to have a mPAP greater than or equal to 25 mmHg and a PCWP less than or equal to 15 mmHg at rest via right heart catheterization within 12 weeks before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 345 meters). Patients were randomized to 1 of 3 doses of Sildenafil tablets: 1 mg, 5 mg, and 20 mg, three times a day.

At baseline patients had PPH (74%) or secondary PAH (26%); WHO functional class II (57%), III (41%), or IV (2%); the mean age was 44 years; and 67% were female. The majority of subjects were Asian (67%), and 28% were Caucasian.

The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Similar increases in walk distance (mean increase of 38-41 meters) were observed in the 5 and 20 mg dose groups. These increases were significantly better than those observed in the 1 mg dose group (Figure 12).

Figure 12. Mean Change from Baseline in Six Minute Walk (meters) by Visit to Week 12 – ITT Population Sildenafil Protocol A1481244

Study 4 (Sildenafil Tablets added to bosentan therapy – lack of effect on exercise capacity)

A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of three months. The PAH patients included those with primary PAH, and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5-125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6MWD. The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone.

Sildenafil Tablets, USP 20 mg are supplied as white round, biconvex film coated tablets debossed with “R” on one side and “20” on the other side, containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows:

Recommended Storage for Sildenafil Tablets, USP: Store at controlled room temperature 20°C -25°C (68°F -77°F); excursions permitted to 15°C -30°C (59°F -86°F) [see USP Controlled Room Temperature].

See FDA-approved patient labeling ( Patient Information).

Manufactured for:

Vensun Pharmaceuticals, Inc.

Yardley, PA 19067

Manufactured by:

Rubicon Research Private Limited

Ambernath (E),

Dist: Thane, 421 506

Maharashtra, India.

Rev. 02, FEBUARY 2018

PATIENT INFORMATION

Sildenafil (sil-DEN-a-fil) Tablets

Read this Patient Information before you start taking sildenafil tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about Sildenafil tablets, ask your doctor or pharmacist.

What is the most important information I should know about sildenafil tablets?

Never take sildenafil tablets with any nitrate or guanylate cyclase stimulator medicines. Your blood pressure could drop quickly to an unsafe level.

Nitrate medicines include:

Guanylate cyclase stimulators include:

Ask your doctor or pharmacist if you are not sure if you are taking a nitrate or a guanylate cyclase stimulator medicine.

What are sildenafil tablets?

Sildenafil tablets are prescription medicine used in adults to treat pulmonary arterial hypertension (PAH). With PAH, the blood pressure in your lungs is too high. Your heart has to work hard to pump blood into your lungs.

Sildenafil tablets improves the ability to exercise and can slow down worsening changes in your physical condition.

Sildenafil tablets contain the same medicine as VIAGRA® (sildenafil), which is used to treat erectile dysfunction (impotence). Do not take sildenafil tablets with VIAGRA or other PDE-5 inhibitors.

Who should not take sildenafil tablets?

Do not take sildenafil tablets if you:

What should I tell my doctor before taking sildenafil tablets?

Tell your doctor about all of your medical conditions, including if you

Tell your doctor about all of the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal products. Sildenafil tablets and certain other medicines can cause side effects if you take them together. The doses of some of your medicines may need to be adjusted while you take Sildenafil tablets.

Especially tell your doctor if you take

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

How should I take sildenafil tablets?

Sildenafil tablets may be prescribed to you as

What are the possible side effects of sildenafil tablets?

The most common side effects with sildenafil tablets include:

Nosebleed, headache, upset stomach, getting red or hot in the face (flushing), trouble sleeping, as well as fever, erection increased respiratory infection, nausea, vomiting, bronchitis, pharyngitis, runny nose, and pneumonia in children.

Tell your doctor if you have any side effect that bothers you or doesn’t go away.

These are not all the possible side effects of sildenafil tablets. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088

How should I store sildenafil tablets?

General information about sildenafil tablets

Medicines are sometimes prescribed for purposes that are not in the patient leaflet. Do not use Sildenafil tablets for a condition for which it was not prescribed. Do not give Sildenafil tablets to other people, even if they have the same symptoms you have. It could harm them.

This patient leaflet summarizes the most important information about sildenafil tablets. If you would like more information about sildenafil tablets talk with your doctor. You can ask your doctor or pharmacist for information about sildenafil tablets that is written for health professionals.

What are the ingredients in sildenafil tablets?

Active ingredients: sildenafil citrate

Inactive ingredients: Crospovidone, Hypromellose, Hydrophobic colloidal silica, Lactose monohydrate, Magnesium stearate, Microcrystalline cellulose, Titanium dioxide, and Triacetin.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured for:

Vensun Pharmaceuticals, Inc.

Yardley, PA 19067

Manufactured by:

Rubicon Research Private Limited

Ambernath (E),

Dist: Thane, 421 506

Maharashtra, India.

Rev. 02, FEBUARY 2018

NDC 42543-005-90

Sildenafil Tablets, USP

20 mg

PHARMACIST: Please dispense with the patient information sheet.

Rx only

Vensun Pharmaceuticals, Inc.

90 Tablets

NDC 42543-005-10

Sildenafil Tablets, USP

20 mg

PHARMACIST: Please dispense with the patient

information sheet.

Rx only

Vensun Pharmaceuticals, Inc.

1000 Tablets

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