3 DOSAGE FORMS AND STRENGTHS
Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).
- Sildenafil tablets should not be combined with certain medications like alpha-blockers.
- A healthcare provider will determine the appropriate dosage.
- Follow prescribed instructions precisely for safety.
Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major
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Sildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route). Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy volunteers. When a single 100 mg dose of sildenafil was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil Cmax and an 182% increase in sildenafil AUC. In addition, in a study performed in healthy male volunteers, co-administration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Population pharmacokinetic data from patients in clinical trials also indicated a reduction in sildenafil clearance when it was co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) [ see Dosage and Administration((2.2) and Drug Interactions (7.4)].
Adverse Reactions/Side Effects
In another study in healthy male volunteers, co-administration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with sildenafil (100 mg single sildenafil 50 mg tab dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1000% (11-fold) increase in sildenafil plasma AUC. This is consistent with ritonavir’s marked effects on a broad range of P450 substrates. Sildenafil had no effect on ritonavir pharmacokinetics [ see Dosage and Administration (2.2) and Drug Interactions (7.4)]. Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil citrate. Given sildenafil peak plasma concentrations of approximately 1 μM after recommended doses, it is unlikely that sildenafil will alter the clearance of substrates of these isoenzymes. metabolite of 20- and 38- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg.
- Sildenafil film tablets are available by prescription only.
- They may interact with nitrates, causing dangerous blood pressure drops.
- Alcohol can impair the effectiveness of these tablets.
Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.4 times the MRHD on a mg/m 2basis in a 50 kg subject.
| Population Group | Frequency |
|---|---|
| Adults with ED | Once per day as needed |
| Patients with PAH | As prescribed by physician |
| Special considerations | Avoid exceeding prescribed dosage |
There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC.
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The efficacy of SILDENAFIL ORAL FILM in the treatment of erectile dysfunction was established in part on the basis of efficacy data from trials with the tablet formulation of sildenafil.
- Sildenafil film tablets are often used for pulmonary arterial hypertension off-label.
- They work by relaxing blood vessels to improve blood flow.
- Medical guidance is essential for off-label or long-term use.
SILDENAFIL ORAL FILM was evaluated in one randomized, double-blind, placebo-controlled, flexible-dose study (25 mg, 50 mg, 75 mg, 100 mg) over 12 weeks study to evaluate the erectile function of men with erectile dysfunction (ED).
- Possible interactions include medications for HIV, antibiotics, and blood pressure.
- Overdose symptoms include severe headaches and chest pain.
- Seek immediate medical attention if adverse reactions occur.
The co-primary efficacy endpoints included both a 4-week assessment of sexual function based on the International Index of Erectile Function (IIEF) questionnaire and an assessment of sexual function after each sexual intercourse based on the Sexual Encounter Profile (SEP) on the daily diary. The six-item, 30-point, erectile function (EF) domain of the IIEF was assessed at baseline, at follow-up visits, and at the end of the study reflecting subjects’ sexual experience during the past 4 weeks.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Effects ofSildenafil on Vision:At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry. Effects ofSildenafilon Sperm: There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil in healthy volunteers. Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25-63%). Both sildenafil and the metabolite have terminal half-lives of about 4 hours.
How is sildenafil supplied (dosage forms)?
Figure6: Mean Sildenafil Plasma Concentrations in Healthy Male Volunteers Absorption and Distribution:SILDENAFIL ORAL FILM is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 300 minutes (median 80 minutes) of oral dosing in the fasted state. After a single dose of 100 mg of SILDENAFIL ORAL FILM in adult males, the mean (coefficient of variation, %) peak plasma concentration (Cmax) and area under the concentration curve (AUC) of sildenafil were 503.5 (37.7%) ng/mL and 1902.4 (36.3%) ng·h/mL, respectively. When SILDENAFIL ORAL FILM is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 87 minutes and a mean reduction in Cmax of 45%. In a clinical study in 35 healthy males (18-55 years old) where SILDENAFIL ORAL FILM 100 mg was administered in fed conditions with or without water, no clinically significant differences in pharmacokinetics of sildenafil and its major N-desmethyl metabolite was observed. The SEP Question 2 (“Were you able to insert your penis into your partner’s vagina”) and Question 3 (“Did your erection last long enough for you to have successful intercourse?”) were answered immediately after each sexual attempt with binary response (Yes=success, No=failure).
7.1 Nitrates
Metabolism and Excretion:Sildenafil is cleared predominantly by the CYP3A4 (major route) and 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 PDE selectivity profile similar to sildenafil and an in vitropotency for PDE5 approximately 50% of the parent drug. 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. Geriatrics:Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma AUC values of sildenafil sildenafil chewable tablets and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18-45 years).
5.2 Prolonged Erection and Priapism
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 [see Dosage and Administration (2.3), and Use in Specific Populations (8.5)] 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) were not altered. In volunteers with severe (CLcr <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 [see Dosage and Administration (2.3), and Use in Specific Populations (8.6)]. Hepatic Impairment:In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied [see Dosage and Administration (2.3), and Use in Specific Populations (8.7)]. A starting oral dose of 25 mg should be considered in those patients [ see Dosage and Administration(2.3)] . Sexual function data were recorded by patients in a daily diary.
| Brand Name | Manufacturer | Packaging |
|---|---|---|
| Viagra | Pfizer | Blister pack |
| Revatio | Pfizer | Bottle |
| Sildenafil Citrate | Various generic manufacturers | Varies |
A total of 475 patients were enrolled and received treatment with SILDENAFIL ORAL FILM, including subjects with comorbidities such as diabetes, dyslipidemia, hypertension and obesity.
What to avoid
All three were taking sildenafil 100 mg, and all three reported mild adverse events at the time of reductions in standing SBP, including vasodilation and lightheadedness. There were four subjects with a decrease from baseline in standing systolic BP >30 mmHg following sildenafil 100 mg, one subject with a decrease from baseline in standing systolic BP >30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP >30 mmHg following both sildenafil citrate and placebo. While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both sildenafil 50 mg and 100 mg. Effect ofSildenafilon Blood Pressure When Co-administered with Antihypertensives: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. Effect ofSildenafilon Blood Pressure When Co-administered with Alcohol:Sildenafil 50 mg did not potentiate the hypotensive effect of alcohol (0.5 g/kg) in healthy volunteers with mean maximum blood alcohol levels of 0.08%.
Clinical monitoring
The maximum recommended dose of 100 mg sildenafil was not evaluated in this study [see Drug Interactions (7.5)]. Effects ofSildenafilon Cardiac Parameters:Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers. Studies have produced relevant data on the effects of sildenafil citrate on cardiac output. In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or sildenafil for women sildenafil 100 mg 1 hour prior to exercise testing. These results demonstrated that the effect of sildenafil on the primary endpoint was statistically non-inferior to placebo.
