Sildenafil dosing question

In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment.

In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200% and 79%, respectively, in patients with severe renal impairment compared to patients with normal renal function. 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. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC 50 greater than 150 µM). 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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.

5.1 Hypotension

SUPER-1 (NCT00644605) - Sildenafil citrate monotherapy [20 mg, 40 mg, and 80 mg three times a day] A randomized, double-blind, placebo-controlled study of sildenafil citrate (SUPER-1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure≥25 mmHg at rest with a pulmonary capillary wedge pressure<15 mmHg).

Patients were randomized to receive placebo (n=70) or sildenafil tablet 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18 to 81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343).

17. Patient Counseling Information

The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18 to 81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343). Placebo-corrected mean increases in walk distance of 45 to 50 meters were observed with all doses of sildenafil citrate. These increases were significantly different from placebo, but the sildenafil citrate dose groups were not different from each other (see Figure 3), indicating no additional clinical benefit from doses higher than 20 mg three times a day. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in SUPER-1: Mean (95% Confidence Interval) Figure 4 displays subgroup efficacy analyses in SUPER-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. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by Study Subpopulation in SUPER-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.

Allergy warning

SUPER-2 (NCT00159887) Long-term Treatment of PAH In a long-term follow-up of patients who were treated with sildenafil (n=277), K-M estimates of survival at 1, 2, and 3 years were 94%, 88% , and 79%, respectively. PACES-1 (NCT00159861) - Sildenafil Citrate Co-administered with Epoprostenol A randomized, double-blind, placebo-controlled study (PACES-1) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients were randomized to placebo or sildenafil citrate (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 citrate group compared with the placebo group. Placebo-corrected mean increases in walk distance of 45 to 50 meters were observed with all doses of sildenafil citrate. These increases were significantly different from placebo, but the sildenafil citrate dose groups were not different from each other (see Figure 3), indicating no additional clinical benefit from doses higher than 20 mg three times a day. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in SUPER-1: Mean (95% Confidence Interval) Figure 4 displays subgroup efficacy analyses in SUPER-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. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by Study Subpopulation in SUPER-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. SUPER-2 (NCT00159887) Long-term Treatment of PAH In a long-term follow-up of patients who were treated with sildenafil (n=277), K-M estimates of survival at 1, 2, and 3 years were 94%, 88% , and 79%, respectively.

3. Dosage Forms and Strengths

In this trial, 27% of patients were <7 years old. Patients were WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). Patients were naïve for specific PAH therapy and the use of prostacyclin, prostacyclin analogues and endothelin receptor antagonists were not permitted in the study, and neither were arginine supplementation, nitrates, alpha-blockers and potent CYP450 3A4 inhibitors. The primary objective of the study was to assess the effect of Sildenafil citrate on percent change from baseline in PVO2, normalized to body weight, from baseline to week 16 as measured by the Cardiopulmonary Exercise Test (CPET) (patients who were developmentally able to perform the test, n = 115). Secondary endpoints included hemodynamic monitoring, symptom assessment, WHO Functional Class, change in background treatment, and quality of life measurements (n = 234).

Why it’s used

Patients were allocated to one of three sildenafil treatment groups (low, medium, or high) or placebo. Actual doses administered were dependent on body weight (see Table 5). Treatment Allocation by Dose and Body Weight in Pediatric Study The proportion of patients receiving supportive medicinal products at baseline (anticoagulants, digoxin, calcium channel blockers, diuretics and/or oxygen) was similar in the combined sildenafil treatment group (48%) and the placebo treatment group (42%). The primary endpoint was a percentage change in VO2peak from baseline to week 16 assessed by CPET. Mean baseline peak volume of oxygen consumed (VO2) values were similar across the sildenafil treatment groups (17 to 18 ml/kg/min), and slightly higher for the placebo treatment group (20 ml/kg/min). PACES-1 (NCT00159861) - Sildenafil Citrate Co-administered with Epoprostenol A randomized, double-blind, placebo-controlled study (PACES-1) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol.

Related/similar drugs

In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200% and 79%, respectively, in patients with severe renal impairment compared to patients with normal renal function. 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. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC 50 greater than 150 µM).

Dosage Forms and Strengths

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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. SUPER-1 (NCT00644605) - Sildenafil citrate monotherapy [20 mg, 40 mg, and 80 mg three times a day] A randomized, double-blind, placebo-controlled study of sildenafil citrate (SUPER-1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure≥25 mmHg at rest with a pulmonary capillary wedge pressure<15 mmHg). Patients were randomized to receive placebo (n=70) or sildenafil tablet 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. Patients were randomized to placebo or sildenafil citrate (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.

More about sildenafil

The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil tablet 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 citrate 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 tablet (95% CI: -5.7, -2.1) (p = 0.00003). 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 sildenafil citrate -treated patients and that sildenafil citrate -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 5.

When and How to Take Sildenafil for Best Results

Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in PACES-1 Improvements in WHO Functional Class for PAH were also demonstrated in patients on sildenafil tablet compared to placebo. More than twice as many sildenafil citrate -treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH. Study A1481243 (NCT00323297) Sildenafil citrate Added to Bosentan sildenafil citrate drug 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 3 months. STARTS-1 (NCT00159913) - Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension A total of 234 patients with PAH aged 1 to 17 years were treated in a randomized, double-blind, multi-center, placebo-controlled parallel group, dose-ranging study. Patients (38% male and 62% female) had body weight ≥8 kg and had idiopathic pulmonary arterial hypertension (33%), or PAH associated with congenital heart disease (systemic-to-pulmonary shunt 37%, surgical repair 30%). 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 citrate group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil tablet 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 citrate 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 tablet (95% CI: -5.7, -2.1) (p = 0.00003). 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 sildenafil citrate -treated patients and that sildenafil citrate -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 5. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in PACES-1 Improvements in WHO Functional Class for PAH were also demonstrated in patients on sildenafil tablet compared to placebo. More than twice as many sildenafil citrate -treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH. Study A1481243 (NCT00323297) Sildenafil citrate Added to Bosentan sildenafil citrate drug 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 3 months. STARTS-1 (NCT00159913) - Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension A total of 234 patients with PAH aged 1 to 17 years were treated in a randomized, double-blind, multi-center, placebo-controlled parallel group, dose-ranging study. Patients (38% male and 62% female) had body weight ≥8 kg and had idiopathic pulmonary arterial hypertension (33%), or PAH associated with congenital heart disease (systemic-to-pulmonary shunt 37%, surgical repair 30%). In this trial, 27% of patients were <7 years old. Patients were WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%).

Patients were naïve for specific PAH therapy and the use of prostacyclin, prostacyclin analogues and endothelin receptor antagonists were not permitted in the study, and neither were arginine supplementation, nitrates, alpha-blockers and potent CYP450 3A4 inhibitors.

• Sildenafil may be less effective in men with certain health conditions like diabetes.
• Be aware of potential vision changes, such as blue-tinted vision.
• Discontinue use and consult a doctor if adverse reactions occur.
• Sildenafil can cause priapism, a painful prolonged erection needing urgent care.
• Safe sexual activity depends on your overall cardiovascular health.

The primary objective of the study was to assess the effect of Sildenafil citrate on percent change from baseline in PVO2, normalized to body weight, from baseline to week 16 as measured by the Cardiopulmonary Exercise Test (CPET) (patients who were developmentally able to perform the test, n = 115).

8.4 Pediatric Use

STARTS-2 (NCT00159874) - Long-Term Survival with Oral Sildenafil Monotherapy in Treatment-Naïve Pediatric Pulmonary Arterial Hypertension Of the 234 pediatric patients treated in the short-term, placebo-controlled study, 220 patients entered the long-term extension study. Secondary endpoints included hemodynamic monitoring, symptom assessment, WHO Functional Class, change in background treatment, and quality of life measurements (n = 234). Patients were allocated to one of three sildenafil treatment groups (low, medium, or high) or placebo. Actual doses administered were dependent on body weight (see Table 5). Treatment Allocation by Dose and Body Weight in Pediatric Study The proportion of patients receiving supportive medicinal products at baseline (anticoagulants, digoxin, calcium channel blockers, diuretics and/or oxygen) was similar in the combined sildenafil treatment group (48%) and the placebo treatment group (42%).

• Patient support resources are available for those taking sildenafil.
• Many pharmaceutical manufacturers offer patient assistance programs.
• Non-profit organizations provide information and support for ED and PAH.
• The Pulmonary Hypertension Association offers resources for PAH patients.
• Urology care foundations provide educational materials on ED treatments.
• Online forums and support groups can offer peer support and shared experiences.
• Healthcare providers are the primary source for personalized medical advice.
• Pharmacists are an excellent resource for information on dosing and side effects.
• Mental health professionals can help address psychological aspects of ED.
• Cardiac rehabilitation may be recommended for some PAH patients.
• A multidisciplinary approach often yields the best patient outcomes.

The primary endpoint was a percentage change in VO2peak from baseline to week 16 assessed by CPET. Mean baseline peak volume of oxygen consumed (VO2) values were similar across the sildenafil treatment groups (17 to 18 ml/kg/min), and slightly higher for the placebo treatment group (20 ml/kg/min).

8.2 Lactation

A total of 45% of patients were evaluable for CPET, which comprised those children ≥7 years old and developmentally able to perform the test. Children <7 years were evaluable only for the secondary endpoints. Mean increases in VO2peak percentage change from baseline at Week 16, were observed with all 3 sildenafil doses (range of 6% to 13%, Figure 6), with little change with placebo (0.5%). Percentage Change from Baseline in VO2Peak: Mean (95% Confidence Intervals) The estimated difference between the combined sildenafil doses and placebo was 8% (95% CI: 0.2 to 16). The results of the main analysis (combined dose groups versus placebo) were not statistically significant (p=0.056).

5.5 Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives

The estimated difference between the sildenafil medium dose group and placebo was 11±5% (95% CI: 2 to 21). Impact on Hemodynamic Parameters Dose related improvements were observed with PVRI and mPAP. Statistically significant PVRI reductions compared to placebo were seen with the sildenafil medium and high dose groups (18% [95% CI: -32% to -2%] and 27% [95% CI: -39% to -14%], respectively) but not the low dose group (2% (95% CI: -20%, 20%). The sildenafil medium and high dose groups displayed mPAP changes from baseline compared to placebo, of -3.5 mmHg (95% CI: -8.9, 1.9) and -7.3 mmHg (95% CI: -12.4, -2.1), respectively; while the low dose group showed little difference from placebo (difference of 1.6 mmHg [95% CI: -4.5, 7.6]). Improvements were observed with cardiac index with all three sildenafil groups over placebo, 10%, 4%, and 15% for the low, medium, and high dose groups, respectively [see Clinical Pharmacology (12.2)]. A total of 45% of patients were evaluable for CPET, which comprised those children ≥7 years old and developmentally able to perform the test. Children <7 years were evaluable only for the secondary endpoints.

Mean increases in VO2peak percentage change from baseline at Week 16, were observed with all 3 sildenafil doses (range of 6% to 13%, Figure 6), with little change with placebo (0.5%). Percentage Change from Baseline in VO2Peak: Mean (95% Confidence Intervals) The estimated difference between the combined sildenafil doses and placebo was 8% (95% CI: 0.2 to 16). The results of the main analysis (combined dose groups versus placebo) were not statistically significant (p=0.056). The estimated difference between the sildenafil medium dose group and placebo was 11±5% (95% CI: 2 to 21). Impact on Hemodynamic Parameters Dose related improvements were observed with PVRI and mPAP. Statistically significant PVRI reductions compared to placebo were seen with the sildenafil medium and high dose groups (18% [95% CI: -32% to -2%] and 27% [95% CI: -39% to -14%], respectively) but not the low dose group (2% (95% CI: -20%, 20%). The sildenafil medium and high dose groups displayed mPAP changes from baseline compared to placebo, of -3.5 mmHg (95% CI: -8.9, 1.9) and -7.3 mmHg (95% CI: -12.4, -2.1), respectively; while the low dose group showed little difference from placebo (difference of 1.6 mmHg [95% CI: -4.5, 7.6]). Improvements were observed with cardiac index with all three sildenafil groups over placebo, 10%, 4%, and 15% for the low, medium, and high dose groups, respectively [see Clinical Pharmacology (12.2)]. STARTS-2 (NCT00159874) - Long-Term Survival with Oral Sildenafil Monotherapy in Treatment-Naïve Pediatric Pulmonary Arterial Hypertension Of the 234 pediatric patients treated in the short-term, placebo-controlled study, 220 patients entered the long-term extension study.

• Regulatory status of sildenafil varies by country but generally requires a prescription.
• In the UK, it is a Prescription Only Medicine (POM) but can be prescribed by pharmacists.
• In some countries, it may be available in limited quantities without a prescription.
• The FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for Revatio.
• The REMS is designed to inform healthcare providers about the serious risks.
• This includes the risk of use with nitrates and the potential for hearing loss.
• The medication is subject to controlled substance regulations in some regions.
• Traveling with prescription medication requires carrying it in original packaging.
• It is advisable to have a copy of the prescription or a doctor's note when traveling.
• Laws regarding the importation of prescription drugs are strict and vary.
• Always check the legal status of the medication in your destination country.