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Business casual is expected if not in scrubs. I even said to the peds hospitalist, "You can see the patient in the ED, and send him home if you would like", and her response was "I don't have time to do that&quot. Residents are very demanding of each other (especially during academics) which can be a little intense, but they apparently have very good Absite scores, so I guess it works! All from PSS shipped out to me in 1-2 days. We were in the middle of massive cost-cutting site-wide, and this was but a drop in the bucket. I "found" it during a time my eyes were not glazing over during this football banter between Zpak, WVU, Caverject, Spiriva, et al. My previous career would be considered a very non sildenafil citrate sildenafil citrate traditional one – I took my first science class nearly 20 years after high school. Hope that helps you but choose your field of practice on what you love, not how much money you make. I'm interested in selling two of my textbooks from Semester 1. Is it the location and what it offers. Would this surgical subspecialty happen to be ENT.

I'm still eligible to apply to residency for 3 years if things don't work out. Is this guy one of the best sildenafil citrate 20 DOs in the country, and have the connections to pull off a match. PS & BS – For the first 4 weeks, I intensely studied purely content, dedicating one week to each major science area of the exam. Keep yourself eating healthy, sleeping well, and exercising– you'll feel better, you'll study better, and you'll end up doing better. It's just no one I've ever even heard of gives a damn about the percentage. Oh wow–thanks for the update on the II.

We are all in the exact same courses so it works nicely. If you went to a big undergraduate school and loved your experience, you're going to hate this campus. So according to the admissions person they only need one physician letter. D. You have sildenafil a sildenafil citrate 100mg right to pursue accessing healthcare, but you have no right to force someone to provide it to you. I didn't have to move spouse job, move kids, so it ended up working out. Can someone who is a current student further elaborate upon the clinical rotation sites throughout the program.

I can't do both since there is like a 10 year commitment for pilots?

Anyway, this is a huge investment in you? No program totally excludes you from doing either, but there are programs that tailor to one or the other. How long after you submitted everything did you get an interview. I was complete 8/5 and I checked back today and it says my file has already "been reviewed. 15, and my sGPA is around a 3. sildenafil online I should probably blame myself and do whatever I can to help them. Forgive my ignorance but what does scope have to do with residency training. Instead, I wrote about my life experience and why I wanted to be a PT and talked about my mother going through PT and that I TRANSLATED for HER when she did her rehab. It's a known waste of time and back in the day you could miss a certain percentage of the lectures and get away with it. I will give opioids if the hemodynamics dictate, but I don't just blindly bolus narcotics. 4,500 words would be like a 10 page personal statement.

Anyways, the interview continued with the interviewers asking me about an ethical case along with an ethical situation I had been in.

I'll take 2 issues with how sildenafil generic you characterize things?

I know my info packet said for me to expect to need about -65k a year I think, which in the end wasn't much less than the estimates Penn was giving out for IS. And that person is going to make a great dermatologist and I was so happy for that person. We sildenafil citrate 100mg agree that my medicine residents are bad though! Discussion in 'Occupational Therapy [ O. Are Radiology Techs generally satisfied or are they too limited.

However, it is harder to get into because of the low number of positions. If not I would replace quebec schools with Ottawa and UWO, but keep Mcgill. She founded and was coordinator of the Agape Dermatology Clinic Student Volunteer Program which was a free health clinicHope you all get the phone call and not the email. Can this person swing by my apartment as well. He is highly involved in resident teaching and leads morning conferences (which we observed). MonkeyMD, Jan 31, 2011, in forum: MCAT Study Question Q&AGood luck today @TBRBiosadist hope you get the score you deserve. PhysiatristDoc, Mar 15, 2012, in forum: Internship, Residency and Fellowship PositionsIt is nothing sildenafil like real life at all. Boring, well that depends on what you're into. I would encourage senior/ longtime members to contribute constructive ideas towards this issue – maybe they could come up with even better suggestionsWhat exactly does the job entail on top of your clinical responsibilities. Pure clinical pharmacy in hospitals is probably going away. Additionally I was kidding, and said "it's your funeral" as a way to make light of the fact that at the end of the day there is no right answer to these things, and it's his decision ultimately. 70 sGPA/32Q MCAT so my stats are a bit below what they want? I have a full time job and am in the sildenafil citrate middle of finishing up some pre-req's? Also, in the experiences section, sildenafil generic I know this is always a vague questions but is there an unwritten limit/minimum for this and how far back have most of you gone in terms of listing prior volunteer/work experience. I would say don't bring it up voluntarily, but don't omit it in a sketchy way. So there's some hay to be made out there if you can find it.

Whatever the reason for the attrition, I felt it reflected poorly on Ross. All of the following were listed in the press release last year regarding new 2014 residencies, however none of them currently have EM residency webpages on their hospital's site. I was very forthcoming with my reasons for failing and was re-assured numerous times by my student Dean that the committee will be "sympathetic. You do not need a course to pass this exam unless you have some anxiety or knowledge issues. Unfortunately, I'm kind of small. Maybe the interview actually did make a big difference! A few B's there really dragged me down. Although I did really well in residency, probably the strongest in my residency class, there sildenafil were so many parts of OBGYN that I disliked. Results are expected to be around mid-october for the 10 seats. And the website says this " It is important to complete the sildenafil citrate 100mg supplemental as soon as you have received an email from us acknowledging your AACOMAS application and directing you to the supplemental. You could also address it in the "reason you left" box when you enter it as prior training — but I don't know how much room they give you there, and whether you can adequately address it there. The entire entry model into audiology needs to change. In 1962, Yale was awarded one of the original NIH Program Project Grants in Radiation Therapy and Radiobiology.

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  • Can get through the major sections easily in 2 days. Any and all advice would be greatly appreciate.
  • When the number of members reach 10 we will start >> if not we will start in 3 days. I would think, this often goes hand in hand with younger faculty.
  • Also, with a pass/fail there is one less measure for residency directors to gauge your performance (even though grades are farther down on the list, it is still nice to be able to prove you did more than the bare minimum).
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I applied OOS from California without any strong ties to Florida and I'll be starting classes this fall. )Both maternal and paternal family history includes premature coronary artery disease, HTN, and hyperlipidemia. Yo se q se requere tener USCE peor es muy variable lo q cierto programas califican como Clinical experience. I know of at least one general surgeon who works as a surgical hospitalist. That money, unfortunately, is not matched by the state or the university. FREIDA lists link for Neuro non-interventional program, but seperate website looks like anethesia.

My recommendation letters should be very good from PT's i have worked with and know. I know if I was a philanthropist, this would be something worth my money.

Don't think it would fly in an audit though.

If you let things slip or if you want something competitive in a desirable area, very very hard. If so then everyone applying to a DPT has a four-year degree and you will. Since most of my family lives in Dallas UTSW is my top choice and I have some kind of ties (although moderate) with some members on admissions there.

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  7. Any newly admitted students who have had the opportunity to visit and speak with current students and staff.
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  15. During my interview day I was told that they do not send out any decision letters until some time in January. Poor resident lady says "wait, wait, can sildenafil you go back.

* Reported during post-marketing surveillance only

**Visual colour distortions: Chloropsia, Chromatopsia, Cyanopsia, Erythropsia and Xanthopsia

***Lacrimation disorders: Dry eye, Lacrimal disorder and Lacrimation increased

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard

Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie ; E-mail: medsafety@hpra.ie .

In single dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased. Doses of 200 mg did not result in increased efficacy but the incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, altered vision) was 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 not eliminated in the urine.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Urologicals; Drugs used in erectile dysfunction. ATC Code: G04B E03.

Mechanism of action

Sildenafil is an oral therapy for erectile dysfunction. In the natural setting, i.e. with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis.

The physiological mechanism responsible for erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood.

Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for degradation of cGMP. Sildenafil has a peripheral site of action on erections. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but potently enhances the relaxant effect of NO on this tissue. When the NO/cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP. Therefore sexual stimulation is required in order for sildenafil to produce its intended beneficial pharmacological effects.

Studies in vitro have shown that sildenafil is selective for PDE5, which is involved in the erection process. Its effect is more potent on PDE5 than on other known phosphodiesterases. There is a 10-fold selectivity over PDE6 which is involved in the phototransduction pathway in the retina. At maximum recommended doses, there is an 80-fold selectivity over PDE1, and over 700-fold over PDE 2, 3, 4, 7, 8, 9, 10 and 11. In particular, sildenafil has greater than 4,000-fold selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility.

Clinical efficacy and safety

Two clinical studies were specifically designed to assess the time window after dosing during which sildenafil could produce an erection in response to sexual stimulation. In a penile plethysmography (RigiScan) study of fasted patients, the median time to onset for those who obtained erections of 60% rigidity (sufficient for sexual intercourse) was 25 minutes (range 12-37 minutes) on sildenafil. In a separate RigiScan study, sildenafil was still able to produce an erection in response to sexual stimulation 4-5 hours post-dose.

Sildenafil causes mild and transient decreases in blood pressure which, in the majority of cases, do not translate into clinical effects. The mean maximum decreases in supine systolic blood pressure following 100 mg oral dosing of sildenafil was 8.4 mmHg. The corresponding change in supine diastolic blood pressure was 5.5 mmHg. These decreases in blood pressure are consistent with the vasodilatory effects of sildenafil, probably due to increased cGMP levels in vascular smooth muscle. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG.

In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (>70% stenosis of at least one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7% and 6% respectively compared to baseline. Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil showed no effect on cardiac output, and did not impair blood flow through the stenosed coronary arteries.

A double-blind, placebo-controlled exercise stress trial evaluated 144 patients with erectile dysfunction and chronic stable angina who regularly received anti-anginal medicinal products (except nitrates). The results demonstrated no clinically relevant differences between sildenafil and placebo in time to limiting angina.

Mild and transient differences in colour discrimination (blue/green) were detected in some subjects using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident after 2 hours post-dose. The postulated mechanism for this change in colour discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil has no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients with documented early age-related macular degeneration (n=9), sildenafil (single dose, 100 mg) demonstrated no significant changes in the visual tests conducted (visual acuity, Amsler grid, colour discrimination simulated traffic light, Humphrey perimeter and photostress).

There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil in healthy volunteers (see section 4.6).

Further information on clinical trials

In clinical trials sildenafil was administered to more than 8000 patients aged 19-87. The following patient groups were represented: elderly (19.9%), patients with hypertension (30.9%), diabetes mellitus (20.3%), ischaemic heart disease (5.8%), hyperlipidaemia (19.8%), spinal cord injury (0.6%), depression (5.2%), transurethral resection of the prostate (3.7%), radical prostatectomy (3.3%). The following groups were not well represented or excluded from clinical trials: patients with pelvic surgery, patients post-radiotherapy, patients with severe renal or hepatic impairment and patients with certain cardiovascular conditions (see section 4.3).

In fixed dose studies, the proportions of patients reporting that treatment improved their erections were 62% (25 mg), 74% (50 mg) and 82% (100 mg) compared to 25% on placebo. In controlled clinical trials, the discontinuation rate due to sildenafil was low and similar to placebo.

Across all trials, the proportion of patients reporting improvement on sildenafil were as follows: psychogenic erectile dysfunction (84%), mixed erectile dysfunction (77%), organic erectile dysfunction (68%), elderly (67%), diabetes mellitus (59%), ischaemic heart disease (69%), hypertension (68%), TURP (61%), radical prostatectomy (43%), spinal cord injury (83%), depression (75%). The safety and efficacy of sildenafil was maintained in long term studies.

The European Medicines Agency has waived the obligation to submit the results of studies with VIAGRA in all subsets of the paediatric population for the treatment of erectile dysfunction. See section 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties

Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute oral bioavailability is 41% (range 25-63%). After oral dosing of sildenafil AUC and Cmax increase in proportion with dose over the recommended dose range (25-100 mg).

When sildenafil is taken with food, 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 (Vd ) for sildenafil is 105 l, indicating distribution into the tissues. After a single oral dose of 100 mg, the mean maximum total plasma concentration of sildenafil is approximately 440 ng/mL (CV 40%). Since sildenafil (and its major circulating N-desmethyl metabolite) is 96% bound to plasma proteins, this results in the mean maximum free plasma concentration for sildenafil of 18 ng/mL (38 nM). Protein binding is independent of total drug concentrations.

In healthy volunteers receiving sildenafil (100 mg single dose), less than 0.0002% (average 188 ng) of the administered dose was present in ejaculate 90 minutes after dosing.

Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% that of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil. The N-desmethyl metabolite is further metabolised, with a terminal half life of approximately 4 h.

The total body clearance of sildenafil is 41 L/h with a resultant terminal phase half life of 3-5 h. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the faeces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of administered oral dose).

Pharmacokinetics in special patient groups

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%.

In volunteers with mild to moderate renal impairment (creatinine clearance = 30-80 mL/min), the pharmacokinetics of sildenafil were not altered after receiving a 50 mg single oral dose. The mean AUC and Cmax of the N-desmethyl metabolite increased up to 126% and up to 73% respectively, compared to age-matched volunteers with no renal impairment. However, due to high inter-subject variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance < 30 mL/min), sildenafil clearance was reduced, resulting in mean increases in AUC and Cmax of 100% and 88% respectively compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax values were significantly increased by 200% and 79% respectively.

In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh A and B) sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function have not been studied.

5.3 Preclinical safety data

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.

6. Pharmaceutical particulars

Uncommon: heart rate increased

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

In single dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased. Doses of 200 mg did not result in increased efficacy but the incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, altered vision) was 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 not eliminated in the urine.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Urologicals; Drugs used in erectile dysfunction, ATC Code: G04BE03.

Mechanism of action

Sildenafil is an oral therapy for erectile dysfunction. In the natural setting, i.e. with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis.

The physiological mechanism responsible for erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood.

Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for degradation of cGMP. Sildenafil has a peripheral site of action on erections. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but potently enhances the relaxant effect of NO on this tissue. When the NO/cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP. Therefore sexual stimulation is required in order for sildenafil to produce its intended beneficial pharmacological effects.

Studies in vitro have shown that sildenafil is selective for PDE5, which is involved in the erection process. Its effect is more potent on PDE5 than on other known phosphodiesterases. There is a 10-fold selectivity over PDE6 which is involved in the phototransduction pathway in the retina. At maximum recommended doses, there is an 80-fold selectivity over PDE1, and over 700-fold over PDE2, 3, 4, 7, 8, 9, 10 and 11. In particular, sildenafil has greater than 4,000-fold selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility.

Clinical efficacy and safety

Two clinical studies were specifically designed to assess the time window after dosing during which sildenafil could produce an erection in response to sexual stimulation. In a penile plethysmography (RigiScan) study of fasted patients, the median time to onset for those who obtained erections of 60% rigidity (sufficient for sexual intercourse) was 25 minutes (range 12-37 minutes) on sildenafil. In a separate RigiScan study, sildenafil was still able to produce an erection in response to sexual stimulation 4-5 hours post-dose.

Sildenafil causes mild and transient decreases in blood pressure which, in the majority of cases, do not translate into clinical effects. The mean maximum decreases in supine systolic blood pressure following 100 mg oral dosing of sildenafil was 8.4 mmHg. The corresponding change in supine diastolic blood pressure was 5.5 mmHg. These decreases in blood pressure are consistent with the vasodilatory effects of sildenafil, probably due to increased cGMP levels in vascular smooth muscle. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG.

In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (>70% stenosis of at least one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7% and 6% respectively compared to baseline. Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil showed no effect on cardiac output, and did not impair blood flow through the stenosed coronary arteries.

A double-blind, placebo-controlled exercise stress trial evaluated 144 patients with erectile dysfunction and chronic stable angina who regularly received anti-anginal medicinal products (except nitrates). The results demonstrated no clinically relevant differences between sildenafil and placebo in time to limiting angina.

Mild and transient differences in colour discrimination (blue/green) were detected in some subjects using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident after 2 hours post-dose. The postulated mechanism for this change in colour discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil has no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients with documented early age-related macular degeneration (n=9), sildenafil (single dose, 100 mg) demonstrated no significant changes in the visual tests conducted (visual acuity, Amsler grid, colour discrimination simulated traffic light, Humphrey perimeter and photostress).

There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil in healthy volunteers (see section 4.6).

Further information on clinical trials

In clinical trials sildenafil was administered to more than 8000 patients aged 19-87. The following patient groups were represented: elderly (19.9%), patients with hypertension (30.9%), diabetes mellitus (20.3%), ischaemic heart disease (5.8%), hyperlipidaemia (19.8%), spinal cord injury (0.6%), depression (5.2%), transurethral resection of the prostate (3.7%), radical prostatectomy (3.3%). The following groups were not well represented or excluded from clinical trials: patients with pelvic surgery, patients post-radiotherapy, patients with severe renal or hepatic impairment and patients with certain cardiovascular conditions (see section 4.3).

In fixed dose studies, the proportions of patients reporting that treatment improved their erections were 62% (25 mg), 74% (50 mg) and 82% (100 mg) compared to 25% on placebo. In controlled clinical trials, the discontinuation rate due to sildenafil was low and similar to placebo.

Across all trials, the proportion of patients reporting improvement on sildenafil were as follows: psychogenic erectile dysfunction (84%), mixed erectile dysfunction (77%), organic erectile dysfunction (68%), elderly (67%), diabetes mellitus (59%), ischaemic heart disease (69%), hypertension (68%), TURP (61%), radical prostatectomy (43%), spinal cord injury (83%), depression (75%). The safety and efficacy of sildenafil was maintained in long-term studies.

The European Medicines Agency has waived the obligation to submit the results of studies with the reference medicinal product containing sildenafil in all subsets of the paediatric population for the treatment of erectile dysfunction. See 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties

Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute oral bioavailability is 41% (range 25-63%). After oral dosing of sildenafil AUC and Cmax increase in proportion with dose over the recommended dose range (25-100 mg).

When sildenafil is taken with food, 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 (Vd ) for sildenafil is 105 l, indicating distribution into the tissues. After a single oral dose of 100 mg, the mean maximum total plasma concentration of sildenafil is approximately 440 ng/mL (CV 40%). Since sildenafil (and its major circulating N-desmethyl metabolite) is 96% bound to plasma proteins, this results in the mean maximum free plasma concentration for sildenafil of 18 ng/mL (38 nM). Protein binding is independent of total drug concentrations.

In healthy volunteers receiving sildenafil (100 mg single dose), less than 0.0002% (average 188 ng) of the administered dose was present in ejaculate 90 minutes after dosing.

Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% that of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil. The N-desmethyl metabolite is further metabolised, with a terminal half-life of approximately 4 h.

The total body clearance of sildenafil is 41 L/h with a resultant terminal phase half-life of 3-5 h. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the faeces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of administered oral dose).

Pharmacokinetics in special patient groups

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%.

In volunteers with mild to moderate renal impairment (creatinine clearance=30-80 mL/min), the pharmacokinetics of sildenafil were not altered after receiving a 50 mg single oral dose. The mean AUC and Cmax of the N-desmethyl metabolite increased 126% and 73% respectively, compared to age-matched volunteers with no renal impairment. However, due to high inter-subject variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance <30 mL/min), sildenafil clearance was reduced, resulting in mean increases in AUC and Cmax of 100% and 88% respectively compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax values were significantly increased 79% and 200% respectively.

In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh A and B) sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function have not been studied.

5.3 Preclinical safety data

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.

6. Pharmaceutical particulars

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