text:
Active ingredient
- sildenafil citrate
Legal Category
POM: Prescription only medicine
POM: Prescription only medicine
This information is intended for use by health professionals
AdultsTreatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease.
Paediatric populationTreatment of paediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity or pulmonary haemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease (see section 5.1).
AdultsThe recommended dose is 20 mg three times a day (TID). Physicians should advise patients who forget to take Revatio to take a dose as soon as possible and then continue with the normal dose. Patients should not take a double dose to compensate for the missed dose.
Paediatric population (1 year to 17 years)For paediatric patients aged 1 year to 17 years old, the recommended dose in patients ≤ 20 kg is 10 mg three times a day and for patients > 20 kg is 20 mg three times a day. Higher than recommended doses should not be used in paediatric patients with PAH (see also sections 4.4 and 5.1). The 20 mg tablet should not be used in cases where 10 mg TID should be administered in younger patients. Other pharmaceutical forms are available for administration to patients ≤ 20 kg and other younger patients who are not able to swallow tablets.
Patients using other medicinal productsIn general, any dose adjustment should be administered only after a careful benefit-risk assessment. A downward dose adjustment to 20 mg twice daily should be considered when sildenafil is co-administered to patients already receiving CYP3A4 inhibitors like erythromycin or saquinavir. A downward dose adjustment to 20 mg once daily is recommended in case of co-administration with more potent CYP3A4 inhibitors clarithromycin, telithromycin and nefazodone. For the use of sildenafil with the most potent CYP3A4 inhibitors, see section 4.3. Dose adjustments for sildenafil may be required when co-administered with CYP3A4 inducers (see section 4.5).
Special populations
Elderly (≥ 65 years)Dose adjustments are not required in elderly patients. Clinical efficacy as measured by 6-minute walk distance could be less in elderly patients.Renal impairmentInitial dose adjustments are not required in patients with renal impairment, including severe renal impairment (creatinine clearance < 30 ml/min). A downward dose adjustment to 20 mg twice daily should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated.
Hepatic impairmentInitial dose adjustments are not required in patients with hepatic impairment (Child-Pugh class A and B). A downward dose adjustment to 20 mg twice daily should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated.Revatio is contraindicated in patients with severe hepatic impairment (Child-Pugh class C) (see section 4.3).
Paediatric populationThe safety and efficacy of Revatio in children below 1 year of age has not been established. No data are available.
Discontinuation of treatmentLimited data suggest that the abrupt discontinuation of Revatio is not associated with rebound worsening of pulmonary arterial hypertension. However to avoid the possible occurrence of sudden clinical deterioration during withdrawal, a gradual dose reduction should be considered. Intensified monitoring is recommended during the discontinuation period.
Method of administrationRevatio is for oral use only. Tablets should be taken approximately 6 to 8 hours apart with or without food.
Retinitis pigmentosaThe safety of sildenafil has not been studied in patients with known hereditary degenerative retinal disorders such as retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases) and therefore its use is not recommended.Vasodilatory actionWhen prescribing sildenafil, physicians should carefully consider whether patients with certain underlying conditions could be adversely affected by sildenafil's mild to moderate vasodilatory effects, for example patients with hypotension, patients with fluid depletion, severe left ventricular outflow obstruction or autonomic dysfunction (see section 4.4).
Cardiovascular risk factorsIn post-marketing experience with sildenafil for male erectile dysfunction, serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have been reported in temporal association with the use of sildenafil. Most, but not all, of these patients had pre-existing cardiovascular risk factors. Many events were reported to occur during or shortly after sexual intercourse and a few were reported to occur shortly after the use of sildenafil without sexual activity. It is not possible to determine whether these events are related directly to these factors or to other factors.
PriapismSildenafil should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia).Prolonged erections and priapism have been reported with sildenafil in post-marketing experience. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result (see section 4.8). Vaso-occlusive crises in patients with sickle cell anaemiaSildenafil should not be used in patients with pulmonary hypertension secondary to sickle cell anaemia. In a clinical study events of vaso-occlusive crises requiring hospitalisation were reported more commonly by patients receiving Revatio than those receiving placebo leading to the premature termination of this study.
Visual eventsCases of visual defects have been reported spontaneously in connection with the intake of sildenafil and other PDE5 inhibitors. Cases of non-arteritic anterior ischaemic optic neuropathy, a rare condition, have been reported spontaneously and in an observational study in connection with the intake of sildenafil and other PDE5 inhibitors (see section 4.8). In the event of any sudden visual defect, the treatment should be stopped immediately and alternative treatment should be considered (see section 4.3).
Alpha-blockersCaution is advised when sildenafil is administered to patients taking an alpha-blocker as the co-administration may lead to symptomatic hypotension in susceptible individuals (see section 4.5). In order to minimise the potential for developing postural hypotension, patients should be haemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Physicians should advise patients what to do in the event of postural hypotensive symptoms.
Bleeding disordersStudies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside in vitro. There is no safety information on the administration of sildenafil to patients with bleeding disorders or active peptic ulceration. Therefore sildenafil should be administered to these patients only after careful benefit-risk assessment.
Vitamin K antagonistsIn pulmonary arterial hypertension patients, there may be a potential for increased risk of bleeding when sildenafil is initiated in patients already using a Vitamin K antagonist, particularly in patients with pulmonary arterial hypertension secondary to connective tissue disease.Veno-occlusive diseaseNo data are available with sildenafil in patients with pulmonary hypertension associated with pulmonary veno-occlusive disease. However, cases of life threatening pulmonary oedema have been reported with vasodilators (mainly prostacyclin) when used in those patients. Consequently, should signs of pulmonary oedema occur when sildenafil is administered in patients with pulmonary hypertension, the possibility of associated veno-occlusive disease should be considered.Galactose intoleranceLactose monohydrate is present in the tablet film coat. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use of sildenafil with bosentanThe efficacy of sildenafil in patients already on bosentan therapy has not been conclusively demonstrated (see sections 4.5 and 5.1).Concomitant use with other PDE5 inhibitors The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitor products, including Viagra, has not been studied in PAH patients and such concomitant use is not recommended (see section 4.5).
Effects of other medicinal products on sildenafil
In vitro studiesSildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. For dose recommendations, see sections 4.2 and 4.3.
In vivo studiesCo-administration of oral sildenafil and intravenous epoprostenol has been evaluated (see sections 4.8 and 5.1).The efficacy and safety of sildenafil co-administered with other treatments for pulmonary arterial hypertension (eg, ambrisentan, iloprost) has not been studied in controlled clinical trials. Therefore, caution is recommended in case of co-administration.The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitors has not been studied in pulmonary arterial hypertension patients (see section 4.4).Population pharmacokinetic analysis of pulmonary arterial hypertension clinical trial data indicated a reduction in sildenafil clearance and/or an increase of oral bioavailability when co-administered with CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. These were the only factors with a statistically significant impact on sildenafil pharmacokinetics in patients with pulmonary arterial hypertension. The exposure to sildenafil in patients on CYP3A4 substrates and CYP3A4 substrates plus beta-blockers was 43 % and 66 % higher, respectively, compared to patients not receiving these classes of medicines. Sildenafil exposure was 5-fold higher at a dose of 80 mg three times a day compared to the exposure at a dose of 20 mg three times a day. This concentration range covers the increase in sildenafil exposure observed in specifically designed drug interaction studies with CYP3A4 inhibitors (except with the most potent of the CYP3A4 inhibitors eg, ketoconazole, itraconazole, ritonavir). CYP3A4 inducers seemed to have a substantial impact on the pharmacokinetics of sildenafil in pulmonary arterial hypertension patients, which was confirmed in the in-vivo interaction study with CYP3A4 inducer bosentan.Co-administration of bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) 125 mg twice daily with sildenafil 80 mg three times a day (at steady state) concomitantly administered during 6 days in healthy volunteers resulted in a 63 % decrease of sildenafil AUC. A population pharmacokinetic analysis of sildenafil data from adult PAH patients in clinical trials including a 12 week study to assess the efficacy and safety of oral sildenafil 20 mg three times a day when added to a stable dose of bosentan (62.5 mg 125 mg twice a day) indicated a decrease in sildenafil exposure with bosentan co-administration, similar to that observed in healthy volunteers (see sections 4.4 and 5.1).Efficacy of sildenafil should be closely monitored in patients using concomitant potent CYP3A4 inducers, such as carbamazepine, phenytoin, phenobarbital, St John's wort and rifampicine.Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg twice daily) with sildenafil (100 mg single dose) resulted in a 300 % (4-fold) increase in sildenafil Cmax and a 1,000 % (11-fold) increase in sildenafil plasma AUC. At 24 hours, the plasma levels of sildenafil were still approximately 200 ng/ml, compared to approximately 5 ng/ml when sildenafil was administered alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates. Based on these pharmacokinetic results co-administration of sildenafil with ritonavir is contraindicated in pulmonary arterial hypertension patients (see section 4.3).Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state (1200 mg three times a day) with sildenafil (100 mg single dose) resulted in a 140 % increase in sildenafil Cmax and a 210 % increase in sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics. For dose recommendations, see section 4.2.When a single 100 mg dose of sildenafil was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days), there was a 182 % increase in sildenafil systemic exposure (AUC). For dose recommendations, see section 4.2. In healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its principal circulating metabolite. No dose adjustment is required. Cimetidine (800 mg), a cytochrome P450 inhibitor and a non-specific CYP3A4 inhibitor, caused a 56 % increase in plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy volunteers. No dose adjustment is required. The most potent of the CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected to have effects similar to ritonavir (see section 4.3). CYP3A4 inhibitors like clarithromycin, telithromycin and nefazodone are expected to have an effect in between that of ritonavir and CYP3A4 inhibitors like saquinavir or erythromycin, a seven-fold increase in exposure is assumed. Therefore dose adjustments are recommended when using CYP3A4 inhibitors (see section 4.2).The population pharmacokinetic analysis in pulmonary arterial hypertension patients suggested that co-administration of beta-blockers in combination with CYP3A4 substrates might result in an additional increase in sildenafil exposure compared with administration of CYP3A4 substrates alone.Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modest increases in plasma levels of sildenafil. No dose adjustment is required but the concomitant use of sildenafil and grapefruit juice is not recommended. Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability of sildenafil.Co-administration of oral contraceptives (ethinyloestradiol 30 μg and levonorgestrel 150 μg) did not affect the pharmacokinetics of sildenafil.Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component it has the potential to have serious interaction with sildenafil (see section 4.3).
Effects of sildenafil on other medicinal productsIn vitro studiesSildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 > 150 μM). There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such as theophylline or dipyridamole.In vivo studiesNo significant interactions were shown when sildenafil (50 mg) was co-administered with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolised by CYP2C9.Sildenafil had no significant effect on atorvastatin exposure (AUC increased 11 %), suggesting that sildenafil does not have a clinically relevant effect on CYP3A4.No interactions were observed between sildenafil (100 mg single dose) and acenocoumarol. Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid (150 mg).Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with mean maximum blood alcohol levels of 80 mg/dl.In a study of healthy volunteers sildenafil at steady state (80 mg three times a day) resulted in a 50 % increase in bosentan AUC (125 mg twice daily). A population pharmacokinetic analysis of data from a study of adult PAH patients on background bosentan therapy (62.5 mg - 125 mg twice a day) indicated an increase (20% (95% CI: 9.8 - 30.8)) of bosentan AUC with co-administration of steady-state sildenafil (20 mg three times a day) of a smaller magnitude than seen in healthy volunteers when co-administered with 80 mg sildenafil three times a day (see sections 4.4 and 5.1).In a specific interaction study, where sildenafil (100 mg) was co-administered with amlodipine in hypertensive patients, there was an additional reduction on supine systolic blood pressure of 8 mmHg. The corresponding additional reduction in supine diastolic blood pressure was 7 mmHg. These additional blood pressure reductions were of a similar magnitude to those seen when sildenafil was administered alone to healthy volunteers. In three specific drug-drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 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, and mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively were observed. When sildenafil and doxazosin were administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and lightheadedness, but not syncope. Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension in susceptible individuals (see section 4.4).Sildenafil (100 mg single dose) did not affect the steady state pharmacokinetics of the HIV protease inhibitor saquinavir, which is a CYP3A4 substrate/inhibitor.Consistent with its known effects on the nitric oxide/cGMP pathway (see section 5.1), sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors or nitrates in any form is therefore contraindicated (see section 4.3).Riociguat: Preclinical studies showed additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment the hypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including sildenafil, is contraindicated (see section 4.3).Sildenafil had no clinically significant impact on the plasma levels of oral contraceptives (ethinyloestradiol 30 μg and levonorgestrel 150 μg).
Paediatric populationInteraction studies have only been performed in adults.
Women of childbearing potential and contraception in males and femalesDue to lack of data on effects of Revatio in pregnant women, Revatio is not recommended for women of childbearing potential unless also using appropriate contraceptive measures.
PregnancyThere are no data from the use of sildenafil in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy and embryonal/foetal development. Studies in animals have shown toxicity with respect to postnatal development (see section 5.3).Due to lack of data, Revatio should not be used in pregnant women unless strictly necessary.
Breast-feedingThere are no adequate and well controlled studies in lactating women. Data from one lactating woman indicate that sildenafil and its active metabolite N-desmethylsildenafil are excreted into breast milk at very low levels. No clinical data are available regarding adverse events in breast-fed infants, but amounts ingested would not be expected to cause any adverse effects. Prescribers should carefully assess the mother's clinical need for sildenafil and any potential adverse effects on the breast-fed child.
FertilityNon-clinical data revealed no special hazard for humans based on conventional studies of fertility (see section 5.3).
Summary of the safety profileIn the pivotal placebo-controlled study of Revatio in pulmonary arterial hypertension, a total of 207 patients were randomized to and treated with 20 mg, 40 mg, or 80 mg TID doses of Revatio and 70 patients were randomized to placebo. The duration of treatment was 12 weeks. The overall frequency of discontinuation in sildenafil treated patients at doses of 20 mg, 40 mg and 80 mg TID was 2.9 %, 3.0 % and 8.5 % respectively, compared to 2.9 % with placebo. Of the 277 subjects treated in the pivotal study, 259 entered a long-term extension study. Doses up to 80 mg three times a day (4 times the recommended dose of 20 mg three times a day) were administered and after 3 years 87 % of 183 patients on study treatment were receiving Revatio 80 mg TID.In a placebo-controlled study of Revatio as an adjunct to intravenous epoprostenol in pulmonary arterial hypertension, a total of 134 patients were treated with Revatio (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day, as tolerated) and epoprostenol, and 131 patients were treated with placebo and epoprostenol. The duration of treatment was 16 weeks. The overall frequency of discontinuations in sildenafil/epoprostenol treated patients due to adverse events was 5.2 % compared to 10.7 % in the placebo/epoprostenol treated patients. Newly reported adverse reactions, which occurred more frequently in the sildenafil/ epoprostenol group, were ocular hyperaemia, vision blurred, nasal congestion, night sweats, back pain and dry mouth. The known adverse reactions headache, flushing, pain in extremity and oedema were noted in a higher frequency in sildenafil/epoprostenol treated patients compared to placebo/epoprostenol treated patients. Of the subjects who completed the initial study, 242 entered a long-term extension study. Doses up to 80 mg TID were administered and after 3 years 68 % of 133 patients on study treatment were receiving Revatio 80 mg TID.In the two-placebo-controlled studies adverse events were generally mild to moderate in severity. The most commonly reported adverse reactions that occurred (greater or equal to 10 %) on Revatio compared to placebo were headache, flushing, dyspepsia, diarrhoea and pain in extremity.
Tabulated list of adverse reactionsAdverse reactions which occurred in > 1 % of Revatio-treated patients and were more frequent (> 1 % difference) on Revatio in the pivotal study or in the Revatio combined data set of both the placebo-controlled studies in pulmonary arterial hypertension, at doses of 20, 40 or 80 mg TID are listed in the table below by class and frequency grouping (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to ≤ 1/100) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.Reports from post-marketing experience are included in italics.
MedDRA system organ class (V.14.0)
Adverse reaction
Infections and infestations
cellulitis, influenza, bronchitis, sinusitis, rhinitis, gastroenteritis
Blood and lymphatic system disorders
Metabolism and nutrition disorders
fluid retention
Psychiatric disorders
insomnia, anxiety
Nervous system disorders
Very common
migraine, tremor, paraesthesia, burning sensation, hypoaesthesia
Eye disorders
retinal haemorrhage, visual impairment, vision blurred, photophobia, chromatopsia, cyanopsia, eye irritation, ocular hyperaemia
visual acuity reduced, diplopia, abnormal sensation in eye
Not known
Non-arteritic anterior ischaemic optic neuropathy (NAION)*, Retinal vascular occlusion*, Visual field defect*
Ear and labyrinth disorders
Not known
sudden hearing loss
Vascular disorders
Very common
Not Known
Respiratory, thoracic and mediastinal disorders
epistaxis, cough, nasal congestion
Gastrointestinal disorders
Very common
diarrhoea, dyspepsia
gastritis, gastrooesophageal reflux disease, haemorrhoids, abdominal distension, dry mouth
Skin and subcutaneous tissue disorders
alopecia, erythema, night sweats
Not known
Musculoskeletal and connective tissue disorders
Very common
pain in extremity
myalgia, back pain
Renal and urinary disorders
Reproductive system and breast disorders
penile haemorrhage, haematospermia, gynaecomastia
Not known
priapism, erection increased
General disorders and administration site conditions
Paediatric populationIn the placebo-controlled study of Revatio in patients 1 to 17 years of age with pulmonary arterial hypertension, a total of 174 patients were treated three times a day with either low (10 mg in patients > 20 kg; no patients ≤ 20 kg received the low dose), medium (10 mg in patients ≥ 8-20 kg; 20 mg in patients ≥ 20-45 kg; 40 mg in patients > 45 kg) or high dose (20 mg in patients ≥ 8-20 kg; 40 mg in patients ≥ 20-45 kg; 80 mg in patients > 45 kg) regimens of Revatio and 60 were treated with placebo.The adverse reactions profile seen in this paediatric study was generally consistent with that in adults (see table above). The most common adverse reactions that occurred (with a frequency ≥ 1 %) in Revatio patients (combined doses) and with a frequency > 1 % over placebo patients were pyrexia, upper respiratory tract infection (each 11.5%), vomiting (10.9%), erection increased (including spontaneous penile erections in male subjects) (9.0%), nausea, bronchitis (each 4.6%), pharyngitis (4.0%), rhinorrhoea (3.4%), and pneumonia, rhinitis (each 2.9%).Of the 234 paediatric subjects treated in the short-term, placebo-controlled study, 220 subjects entered the long-term extension study. Subjects on active sildenafil therapy continued on the same treatment regimen, while those in the placebo group in the short-term study were randomly reassigned to sildenafil treatment.The most common adverse reactions reported across the duration of the short-term and long-term studies were generally similar to those observed in the short-term study. Adverse reactions reported in >10% of 229 subjects treated with sildenafil (combined dose group, including 9 patients that did not continue into the long-term study) were upper respiratory infection (31%), headache (26%), vomiting (22%), bronchitis (20%), pharyngitis (18%), pyrexia (17%), diarrhoea (15%), and influenza, epistaxis (12% each). Most of these adverse reactions were considered mild to moderate in severity.Serious adverse events were reported in 94 (41%) of the 229 subjects receiving sildenafil. Of the 94 subjects reporting a serious adverse event, 14/55 (25.5%) subjects were in the low dose group, 35/74 (47.3%) in the medium dose group, and 45/100 (45%) in the high dose group. The most common serious adverse events that occurred with a frequency ≥ 1 % in sildenafil patients (combined doses) were pneumonia (7.4%), cardiac failure, pulmonary hypertension (each 5.2%), upper respiratory tract infection (3.1%), right ventricular failure, gastroenteritis (each 2.6%), syncope, bronchitis, bronchopneumonia, pulmonary arterial hypertension (each 2.2%), chest pain, dental caries (each 1.7%), and cardiogenic shock, gastroenteritis viral, urinary tract infection (each 1.3%).The following serious adverse events were considered to be treatment related, enterocolitis, convulsion, hypersensitivity, stridor, hypoxia, neurosensory deafness and ventricular arrhythmia.
Reporting of suspected adverse reactionsReporting 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.
Mechanism of actionSildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5), the enzyme that is responsible for degradation of cGMP. Apart from the presence of this enzyme in the corpus cavernosum of the penis, PDE5 is also present in the pulmonary vasculature. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Pharmacodynamic effectsStudies in vitro have shown that sildenafil is selective for PDE5. 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. 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. Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of cases, do not translate into clinical effects. After chronic dosing of 80 mg three times a day to patients with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9.4 mmHg and 9.1 mm Hg respectively. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mmHg). At the recommended dose of 20 mg three times a day no reductions in systolic or diastolic pressure were seen.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 pulmonary arterial hypertension no clinically relevant effects on the ECG were reported.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.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 visual tests conducted (visual acuity, Amsler grid, colour discrimination simulated traffic light, Humphrey perimeter and photostress).
Clinical efficacy and safety
Efficacy in adult patients with pulmonary arterial hypertension (PAH)A randomised, double-blind, placebo-controlled study was conducted in 278 patients with primary pulmonary hypertension, PAH associated with connective tissue disease, and PAH following surgical repair of congenital heart lesions. Patients were randomised to one of four treatment groups: placebo, sildenafil 20 mg, sildenafil 40 mg or sildenafil 80 mg, three times a day. Of the 278 patients randomised, 277 patients received at least 1 dose of study drug. The study population consisted of 68 (25 %) men and 209 (75 %) women with a mean age of 49 years (range: 18-81 years) and baseline 6-minute walk test distance between 100 and 450 metres inclusive (mean: 344 metres). 175 patients (63 %) included were diagnosed with primary pulmonary hypertension, 84 (30 %) were diagnosed with PAH associated with connective tissue disease and 18 (7 %) of the patients were diagnosed with PAH following surgical repair of congenital heart lesions. Most patients were WHO Functional Class II (107/277, 39 %) or III (160/277, 58 %) with a mean baseline 6 minute walking distance of 378 meters and 326 meters respectively; fewer patients were Class I (1/277, 0.4 %) or IV (9/277, 3 %) at baseline. Patients with left ventricular ejection fraction < 45 % or left ventricular shortening fraction < 0.2 were not studied.Sildenafil (or placebo) was added to patients' background therapy which could have included a combination of anticoagulation, digoxin, calcium channel blockers, diuretics or oxygen. The use of prostacyclin, prostacyclin analogues and endothelin receptor antagonists was not permitted as add-on therapy, and neither was arginine supplementation. Patients who previously failed bosentan therapy were excluded from the study.The primary efficacy endpoint was the change from baseline at week 12 in 6-minute walk distance (6MWD). A statistically significant increase in 6MWD was observed in all 3 sildenafil dose groups compared to those on placebo. Placebo corrected increases in 6MWD were 45 metres (p < 0.0001), 46 metres (p < 0.0001) and 50 metres (p < 0.0001) for sildenafil 20 mg, 40 mg and 80 mg TID respectively. There was no significant difference in effect between sildenafil doses. For patients with a baseline 6MWD < 325 m improved efficacy was observed with higher doses (placebo-corrected improvements of 58 metres, 65 metres and 87 metres for 20 mg, 40 mg and 80 mg doses TID, respectively).When analysed by WHO functional class, a statistically significant increase in 6MWD was observed in the 20 mg dose group. For class II and class III, placebo corrected increases of 49 metres (p = 0.0007) and 45 metres (p = 0.0031) were observed respectively.The improvement in 6MWD was apparent after 4 weeks of treatment and this effect was maintained at weeks 8 and 12. Results were generally consistent in subgroups according to aetiology (primary and connective tissue disease-associated PAH), WHO functional class, gender, race, location, mean PAP and PVRI.Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) compared to those on placebo. Placebo-corrected treatment effects with mPAP were 2.7 mmHg (p = 0.04), -3.0 mm Hg (p = 0.01) and -5.1 mm Hg (p < 0.0001) for sildenafil 20 mg, 40 mg and 80 mg TID respectively. Placebo-corrected treatment effects with PVR were -178 dyne.sec/cm5 (p=0.0051), -195 dyne.sec/cm5 (p=0.0017) and -320 dyne.sec/cm5 (p<0.0001) for sildenafil 20 mg, 40 mg and 80 mg TID, respectively. The percent reduction at 12 weeks for sildenafil 20 mg, 40 mg and 80 mg TID in PVR (11.2 %, 12.9 %, 23.3 %) was proportionally greater than the reduction in systemic vascular resistance (SVR) (7.2 %, 5.9 %, 14.4 %). The effect of sildenafil on mortality is unknown.A greater percentage of patients on each of the sildenafil doses (i.e. 28 %, 36 % and 42 % of subjects who received sildenafil 20 mg, 40 mg and 80 mg TID doses, respectively) showed an improvement by at least one WHO functional class at week 12 compared to placebo (7 %). The respective odds ratios were 2.92 (p=0.0087), 4.32 (p=0.0004) and 5.75 (p<0.0001).
Long-term survival data in naive populationPatients enrolled into the pivotal study were eligible to enter a long term open label extension study. At 3 years 87 % of the patients were receiving a dose of 80 mg TID. A total of 207 patients were treated with Revatio in the pivotal study, and their long term survival status was assessed for a minimum of 3 years. In this population, Kaplan-Meier estimates of 1, 2 and 3 year survival were 96 %, 91 % and 82 %, respectively. Survival in patients of WHO functional class II at baseline at 1, 2 and 3 years was 99 %, 91 %, and 84 % respectively, and for patients of WHO functional class III at baseline was 94 %, 90 %, and 81 %, respectively.
Efficacy in adult patients with PAH (when used in combination with epoprostenol)A randomised, double-blind, placebo controlled study was conducted in 267 patients with PAH who were stabilised on intravenous epoprostenol. The PAH patients included those with Primary Pulmonary Arterial Hypertension (212/267, 79 %) and PAH associated with connective tissue disease (55/267, 21 %). Most patients were WHO Functional Class II (68/267, 26 %) or III (175/267, 66 %); fewer patients were Class I (3/267, 1 %) or IV (16/267, 6 %) at baseline; for a few patients (5/267, 2 %), the WHO Functional Class was unknown. Patients were randomised to placebo or sildenafil (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day as tolerated) when used in combination with intravenous epoprostenol.The primary efficacy endpoint was the change from baseline at week 16 in 6-minute walk distance. There was a statistically significant benefit of sildenafil compared to placebo in 6-minute walk distance. A mean placebo corrected increase in walk distance of 26 metres was observed in favour of sildenafil (95 % CI: 10.8, 41.2) (p = 0.0009). For patients with a baseline walking distance ≥ 325 metres, the treatment effect was 38.4 metres in favour of sildenafil; for patients with a baseline walking distance < 325 metres, the treatment effect was 2.3 metres in favour of placebo. For patients with primary PAH, the treatment effect was 31.1 metres compared to 7.7 metres for patients with PAH associated with connective tissue disease. The difference in results between these randomisation subgroups may have arisen by chance in view of their limited sample size.Patients on sildenafil achieved a statistically significant reduction in mean Pulmonary Arterial Pressure (mPAP) compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favour of sildenafil (95 % CI: -5.7, -2.1) (p = 0.00003). Time to clinical worsening was a secondary endpoint as defined as the time from randomisation 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). Treatment with sildenafil significantly delayed the time to clinical worsening of PAH compared to placebo (p = 0.0074). 23 subjects experienced clinical worsening events in the placebo group (17.6 %) compared with 8 subjects in the sildenafil group (6.0 %).
Long-term Survival Data in the background epoprostenol studyPatients enrolled into the epoprostenol add-on therapy study were eligible to enter a long term open label extension study. At 3 years 68 % of the patients were receiving a dose of 80 mg TID. A total of 134 patients were treated with Revatio in the initial study, and their long term survival status was assessed for a minimum of 3 years. In this population, Kaplan-Meier estimates of 1, 2 and 3 year survival were 92 %, 81 % and 74 %, respectively.
Efficacy and safety in adult patients with PAH (when used in combination with bosentan)A randomized, double-blind, placebo controlled study was conducted in 103 clinically stable subjects with PAH (WHO FC II and III) who were on bosentan therapy for a minimum of three months. The PAH patients included those with primary PAH, and PAH associated with connective tissue disease. 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 three times a day) and placebo (13.62 m (95% CI: -3.89 to 31.12) and 14.08 m (95% CI: -1.78 to 29.95), respectively).Differences in 6MWD were observed between patients with primary PAH and PAH associated with connective tissue disease. For subjects with primary PAH (67 subjects), mean changes from baseline were 26.39 m (95% CI: 10.70 to 42.08) and 11.84 m (95% CI: -8.83 to 32.52) for the sildenafil and placebo groups, respectively. However, for subjects with PAH associated with connective tissue disease (36 subjects) mean changes from baseline were -18.32 m (95% CI: -65.66 to 29.02) and 17.50 m (95% CI: -9.41 to 44.41) for the sildenafil and placebo groups, respectively.Overall, the adverse events were generally similar between the two treatment groups (sildenafil plus bosentan vs. bosentan alone), and consistent with the known safety profile of sildenafil when used as monotherapy (see sections 4.4 and 4.5).
Paediatric populationA total of 234 subjects aged 1 to 17 years were treated in a randomized, double-blind, multi-centre, placebo controlled parallel group, dose ranging study. Subjects (38 % male and 62 % female) had a body weight ≥ 8 kg, and had primary pulmonary hypertension (PPH) [33 %], or PAH secondary to congenital heart disease [systemic-to-pulmonary shunt 37 %, surgical repair 30 %]. In this trial, 63 of 234 (27 %) patients were < 7 years old (sildenafil low dose = 2; medium dose = 17; high dose = 28; placebo = 16) and 171 of 234 (73 %) patients were 7 years or older (sildenafil low dose = 40; medium dose = 38; and high dose = 49; placebo = 44). Most subjects were WHO Functional Class I (75/234, 32 %) or II (120/234, 51 %) at baseline; fewer patients were Class III (35/234, 15 %) or IV (1/234, 0.4 %); for a few patients (3/234, 1.3 %), the WHO Functional Class was unknown.Patients were naïve for specific PAH therapy and the use of prostacyclin, prostacyclin analogues and endothelin receptor antagonists was not permitted in the study, and neither was arginine supplementation, nitrates, alpha-blockers and potent CYP450 3A4 inhibitors. The primary objective of the study was to assess the efficacy of 16 weeks of chronic treatment with oral sildenafil in paediatric subjects to improve exercise capacity as measured by the Cardiopulmonary Exercise Test (CPET) in subjects who were developmentally able to perform the test, n = 115). Secondary endpoints included haemodynamic monitoring, symptom assessment, WHO functional class, change in background treatment, and quality of life measurements.Subjects were allocated to one of three sildenafil treatment groups, low (10 mg), medium (10-40 mg) or high dose (20-80 mg) regimens of Revatio given three times a day, or placebo. Actual doses administered within a group were dependent on body weight (see Section 4.8). The proportion of subjects receiving supportive medicinal products at baseline (anticoagulants, digoxin, calcium channel blockers, diuretics and/or oxygen) was similar in the combined sildenafil treatment group (47.7 %) and the placebo treatment group (41.7 %). The primary endpoint was the placebo-corrected percentage change in peak VO2 from baseline to week 16 assessed by CPET testing in the combined dose groups (Table 2). A total of 106 out of 234 (45 %) subjects were evaluable for CPET, which comprised those children ≥ 7 years old and developmentally able to perform the test. Children < 7 years (sildenafil combined dose = 47; placebo = 16) were evaluable only for the secondary endpoints. Mean baseline peak volume of oxygen consumed (VO2) values were comparable across the sildenafil treatment groups (17.37 to 18.03 ml/kg/min), and slightly higher for the placebo treatment group (20.02 ml/kg/min). The results of the main analysis (combined dose groups versus placebo) were not statistically significant (p = 0.056) (see Table 2). The estimated difference between the medium sildenafil dose and placebo was 11.33 % (95 % CI: 1.72 to 20.94) (see Table 2).Table 2: Placebo Corrected % Change from Baseline in Peak VO2 by Active Treatment Group
Treatment group
Estimated difference
95% confidence interval
Low dose
-6.11, 13.73
Medium dose
1.72, 20.94
High dose
-1.64, 17.60
Combined dose groups
(p = 0.056)
-0.19, 15.60
n=29 for placebo groupEstimates based on ANCOVA with adjustments for the covariates baseline peak VO2, etiology and weight groupDose related improvements were observed with pulmonary vascular resistance index (PVRI) and mean pulmonary arterial pressure (mPAP). The sildenafil medium and high dose groups both showed PVRI reductions compared to placebo, of 18 % (95 % CI: 2 % to 32 %) and 27 % (95 % CI: 14 % to 39 %), respectively; whilst the low dose group showed no significant difference from placebo (difference of 2 %). 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; whilst the low dose group showed little difference from placebo (difference of 1.6 mmHg). 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.Significant improvements in functional class were demonstrated only in subjects on sildenafil high dose compared to placebo. Odds ratios for the sildenafil low, medium and high dose groups compared to placebo were 0.6 (95 % CI: 0.18, 2.01), 2.25 (95 % CI: 0.75, 6.69) and 4.52 (95 % CI: 1.56, 13.10), respectively.
Long term extension dataOf the 234 paediatric subjects treated in the short-term, placebo-controlled study, 220 subjects entered the long-term extension study. Subjects who had been in the placebo group in the short-term study were randomly reassigned to sildenafil treatment; subjects weighing ≤ 20 kg entered the medium or high dose groups (1:1), while subjects weighing > 20 kg entered the low, medium or high dose groups (1:1:1). Of the total 229 subjects who received sildenafil, there were 55, 74, and 100 subjects in the low, medium and high dose groups, respectively. Across the short-term and long-term studies, the overall duration of treatment from start of double-blind for individual subjects ranged from 3 to 3129 days. By sildenafil treatment group, median duration of sildenafil treatment was 1696 days (excluding the 5 subjects who received placebo in double-blind and were not treated in the long-term extension study).Kaplan-Meier estimates of survival at 3 years in patients > 20 kg in weight at baseline were 94 %, 93 % and 85 % in the low, medium and high dose groups, respectively; for patients ≤ 20 kg in weight at baseline, the survival estimates were 94 % and 93 % for subjects in the medium and high dose groups respectively (see sections 4.4 and 4.8). During the conduct of the study, there were a total of 42 deaths reported, whether on treatment or reported as part of the survival follow-up. 37 deaths occurred prior to a decision taken by the Data Monitoring Committee to down titrate subjects to a lower dosage, based on an observed mortality imbalance with increasing sildenafil doses. Among these 37 deaths, the number (%) of deaths was 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively. An additional 5 deaths were reported subsequently. The causes of deaths were related to PAH. Higher than recommended doses should not be used in paediatric patients with PAH (see sections 4.2 and 4.4).Peak VO2 was assessed 1 year after the start of the placebo-controlled study. Of those sildenafil treated subjects developmentally able to perform the CPET 59/114 subjects (52 %) had not shown any deterioration in Peak VO2 from start of sildenafil. Similarly 191 of 229 subjects (83 %) who had received sildenafil had either maintained or improved their WHO Functional Class at 1 year assessment. The European Medicines Agency has deferred the obligation to submit the results of studies with Revatio in newborns with pulmonary arterial hypertension (see section 4.2 for information on paediatric use).
AbsorptionSildenafil 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 three times a day dosing of sildenafil, AUC and Cmax increase in proportion with dose over the dose range of 20-40 mg. After oral doses of 80 mg three times a day a more than dose proportional increase in sildenafil plasma levels has been observed. In pulmonary arterial hypertension patients, the oral bioavailability of sildenafil after 80 mg three times a day was on average 43 % (90 % CI: 27 % - 60 %) higher compared to the lower doses. 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 % however, the extent of absorption was not significantly affected (AUC decreased by 11 %).
DistributionThe mean steady state volume of distribution (Vss) for sildenafil is 105 l, indicating distribution into the tissues. After oral doses of 20 mg three times a day, the mean maximum total plasma concentration of sildenafil at steady state is approximately 113 ng/ml. Sildenafil and its major circulating N-desmethyl metabolite are approximately 96 % bound to plasma proteins. Protein binding is independent of total drug concentrations.
BiotransformationSildenafil 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. The N-desmethyl metabolite is further metabolised, with a terminal half-life of approximately 4 h. In patients with pulmonary arterial hypertension, plasma concentrations of N-desmethyl metabolite are approximately 72 % those of sildenafil after 20 mg three times a day dosing (translating into a 36 % contribution to sildenafil's pharmacological effects). The subsequent effect on efficacy is unknown.
EliminationThe 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
ElderlyHealthy 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 %.
Renal insufficiencyIn 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. 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 subjects with severe renal impairment compared to subjects with normal renal function.
Hepatic insufficiencyIn volunteers with mild to moderate hepatic cirrhosis (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. In addition, N-desmethyl metabolite AUC and Cmax values were significantly increased by 154 % and 87 %, respectively in cirrhotic subjects compared to subjects with normal hepatic function. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function have not been studied.
Population pharmacokineticsIn patients with pulmonary arterial hypertension, the average steady state concentrations were 20-50 % higher over the investigated dose range of 2080 mg three times a day compared to healthy volunteers. There was a doubling of the Cmin compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with pulmonary arterial hypertension compared to healthy volunteers.
Paediatric populationFrom the analysis of the pharmacokinetic profile of sildenafil in patients involved in the paediatric clinical trials, body weight was shown to be a good predictor of drug exposure in children. Sildenafil plasma concentration half-life values were estimated to range from 4.2 to 4.4 hours for a range of 10 to 70 kg of body weight and did not show any differences that would appear as clinically relevant. Cmax after a single 20 mg sildenafil dose administered PO was estimated at 49, 104 and 165 ng/ml for 70, 20 and 10 kg patients, respectively. Cmax after a single 10 mg sildenafil dose administered PO was estimated at 24, 53 and 85 ng/ml for 70, 20 and 10 kg patients, respectively. Tmax was estimated at approximately 1 hour and was almost independent from body weight.
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text:
George Clooney in Accident!
E! is reporting that George Clooney and his new girlfriend, Sarah Larson, both suffered broken bones due to a motorcycle accident in New Jersey. Apparently, they were sideswiped by a car. OUCH!
Clooney, an avid biker, was treated for a hairline fracture of a rib and "road rash" at Palisades Medical Center in North Bergen, New Jersey, not far from the New York border.
Aside from the injury being "very painful" and likely taking "a long time to heal," Rosenfield said Clooney is "doing fine."
Larson sustained a broken foot, the publicist said.
They were released shortly after entering the facility.
Feel better you two.
I wonder how is will affect the filming of his new movie "Burn after reading"??

subset: commoncrawl


text:
Teachers can use Win the White House as a stand-alone mini-civics lesson during election season, or as part of a larger civics curriculum, and teachers and students can even choose a grade level (Elementary, Middle, High), which customizes the content. Students can play the game as a homework assignment, sharing their results in class via the printable certificate given at the end of the game. This game provides a rich context for discussion about political parties and issues, the Electoral College, and other campaign-related topics. Of course, Win the White House will shine during election season, and teachers can encourage students to watch election coverage, browse websites, and read newspaper articles to follow along with the real campaigns. Encourage students to then write about or discuss how the actual candidates' campaigns compare to their own from the game.
The new Extension Pack for this game can also be used to add pre-game and post-game context, complete with a PowerPoint presentation, student worksheets, assessment, and plenty of discussion questions. It also includes a fun activity where students create ads for their own student body presidential run. You could even hold a mock election in the classroom for the student with the best ad!Continue reading Show less
Win the White House is an iCivics game available on the web and as an iOS or Android app that places students in complete control of a run for the U.S. presidency. After choosing a grade level, they select a political party and important campaign issues, choosing either five from their own party, or four from their party and one "maverick" issue from the opposing party. Next, students can choose to experience the Primary season, as a (very short) tutorial. They then head to the convention where they select a running mate -- who is mostly pointless and could be better used in the game as a surrogate on the campaign trail -- and begin the 10-week general election season. There, students will first raise funds to poll voters, attend personal appearances, and run media campaigns, where they either promote one of their own issues or run a negative campaign against their opponent. By campaigning in a state, students gain momentum, which keeps the popular support tally leaning toward their side -- but students must keep an eye on the national map to monitor their gains and losses. The opposing candidate can influence states as well, so gaining and maintaining momentum early -- especially in battleground states -- is important to capture their electoral votes.
If students prioritize their spending appropriately and focus on campaigning in the right states, they'll likely win the general election, accumulating enough electoral votes to beat out their opponent (the computer). Although the game is a very simplified simulation of how election seasons actually work (e.g., more campaigning doesn't automatically translate into more votes, in the real world), it's an empowering introduction to presidential campaigns and the electoral process.
Full Disclosure: iCivics and Common Sense Education share a funder; however, that relationship does not impact Common Sense Education's editorial independence and this learning rating.
Win the White House teaches students about the process of electing a U.S. president. Learning how to campaign in states across the country will give them an idea of how politicians make choices during election season. During the campaign season, they'll need to promote political issues that are important to them and to their constituents, and make difficult choices about how and where to allocate campaign funds to attract the most popular (and electoral) votes. Students choose their preferred issues, explain why they are important, and, in some cases, show how they'll address those issues, in an easy, multiple-choice kind of way. Still, the issues are real-life campaign issues and not just theoretical options.
Although students will lose ground in some states, they have 10 rounds to gain (or gain back) enough states and electoral votes to win the election. The game shows how quickly the tide can turn, both in students' favor and against them. Students will learn to strategically weigh options about which states are worth their campaign money and effort. Large population states have the most electoral votes, but players must also court the vote of at least some of the small population states. After the general election, a printable certificate shows details from the campaign, including the number of electoral votes received, battleground states, states that flipped sides, issues chosen, how persuasive and efficient the campaign was, and more. In the end, students will be more familiar with the Electoral College, how media influences voting habits, and how parts of a system can influence the outcome of the larger picture. They'll also learn how important money is to the campaign process. Though it simplifies the process of campaigning and political support, the game's general idea is very sound.
Overall Rating
Key Standards Supported
Reading History/Social Studies
Identify key steps in a text's description of a process related to history/social studies (e.g., how a bill becomes law, how interest rates are raised or lowered).
Determine the meaning of words and phrases as they are used in a text, including vocabulary specific to domains related to history/social studies.
Describe how a text presents information (e.g., sequentially, comparatively, causally).
Distinguish among fact, opinion, and reasoned judgment in a text.
By the end of grade 8, read and comprehend history/social studies texts in the grades 6–8 text complexity band independently and proficiently.
Determine the meaning of words and phrases as they are used in a text, including vocabulary describing political, social, or economic aspects of history/social science.
By the end of grade 10, read and comprehend history/social studies texts in the grades 9–10 text complexity band independently and proficiently.


text: One of my favorite pizza joints is Lou Malnati's , and there are several locations in the Chicagoland area. Their sauce is their own special recipe with select tomatoes, and their crust is buttery and delicious. As much as I love their crust though, what I really love them for is their crustless pizza, nice for those of us on a low carb or gluten free diet. The "crust" is a layer of italian sausage, topped with their tangy sauce and whatever toppings you want. I like onions, mushrooms, spinach, sliced fresh tomatoes and of course plenty of mozzarella. Each slice contains 210 calories, 3 grams of carbohydrates, 2 grams of fiber, one gram of sugar, and 18 grams of protein. I think I'll have another slice 🙂


text:
Wyman Bed & Breakfast
- Free cooked-to-order breakfast, free WiFi, and free parking
- Collect nights
Great overnight stay! The room was small, but comfy. A mirror somewhere in the room would…
Truly amazing experience, breakfast was amazing, very friendly staff. Loved this place…
Wyman Bed & Breakfast
- Classic Double Room, 1 Queen Bed, Non Smoking
- Family Double Room, Multiple Beds, Non Smoking
- Classic Suite, Non Smoking
- Small economical bunk bed room
More great choices
What's around Wyman Bed & Breakfast
- In Jamaica Plain
- Longwood Medical Area - 22 min walk
- Dana-Farber Cancer Institute - 28 min walk
- Boston Museum of Fine Arts - 31 min walk
- Beth Israel Deaconess Medical Center - 33 min walk
- Northeastern University - 37 min walk
- Fenway Park - 38 min walk
- Boston Symphony Hall - 43 min walk
Getting around
- Boston, MA (BOS-Logan Intl.) - 12 min drive
- Portsmouth, NH (PSM-Portsmouth Intl.) - 71 min drive
- Norwood, MA (OWD-Norwood Memorial) - 21 min drive
- Bedford, MA (BED-Laurence G. Hanscom Field) - 27 min drive
- Beverly, MA (BVY-Beverly Municipal) - 38 min drive
- Lawrence, MA (LWM-Lawrence Municipal) - 41 min drive
- Boston Ruggles Station - 3 min drive
- Boston Forest Hills Station - 4 min drive
- Boston Uphams Corner Station - 5 min drive
- Stony Brook Station - 8 min walk
- Jackson Square Station - 9 min walk
- Back of the Hill Station - 17 min walk
At a glance
Key facts
- 11 rooms
- 24-hour check-in
- Check-out time is 11:00 AM
Required at check-in
- Credit card or cash deposit required
- Government-issued photo ID required
- Minimum check-in age is 18
Travelling with others
- Pets not allowed
- Free WiFi in public areas
- Free WiFi in rooms
- Free self parking
Payment types at the property
Other information
- Smoke-free property
At the property
- Free cooked-to-order breakfast daily
- Coffee/tea in a common area
- Microwave in a common area
- Laundry facilities
- Luggage storage
- English
In the room
- Air conditioning
- Premium bedding
- Individually decorated
- Individually furnished
- Free toiletries
- Netflix
- Digital TV channels
- Free WiFi
- Housekeeping - once per stay
Recommended hotels
Wyman Bed & Breakfast's small print
Also known as
- Wyman Bed & Breakfast Boston
- Wyman Boston
- Wyman Bed Breakfast
- Wyman Bed & Breakfast Boston
- Wyman Bed & Breakfast Guesthouse
- Wyman Bed & Breakfast Guesthouse Boston
Noise-free guestrooms cannot be guaranteed.
We have included all charges provided to us by this property. However, charges can vary, for example, based on length of stay or the unit you book.
Recent reviews
Very Good 8.2 From 150 reviews
Not suited for business groups like ours. The rooms were of very differing size and quality. A common area where you could sit, was definitely missing! Would not recommend to business groups.
Misrepresented. More like a boarding house than b& b. Proprietors never introduced themselves or really welcomed us. Not expecting "communal" breakfast with 12 STOOLS like a kindergarten class around one table in the kitchen. Washer/dryer running in kitchen while having breakfast. Asked for eggs 1stday. No only pancakes. Made with chocolate chips without asking. Husband allergic. Remade plain. No muffins or typical B & B options. Communal tub of yogurt/ peanut butter out of the jars. Absolutely no finesse. Never made our bed or refreshed towels when staying 2 nights.No actual dining room with option to join group or not. Nightmare tv. Kept saying you've timed out & enter code. Basically no cable...just Roku. No parlour/living room. In your room or out. All this for $500+. R u kidding me. Would never return or recommend.
It was an enjoyable stay. The place was clean and located within easy walking distance of the T. Teresa and Isaac were nice hosts, but a bit quiet and reserved. They were very helpful if anything was needed.
Friendly, accessible hosts, very cool neighborhood, easy access to public transportation, and excellent price point - highly recommended!
It was wonderful, only downfall for us was that is was farther than we thought it was away from where we needed to be. We walked to it the first day to drop our baggage off. Our mistake, we then learned the bus routes to get us back and forth the following. The owners and staff were wonderful and it was nice to meet other guests. Room clean and fresh and comfortable.
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We provide a full music recording and production system using vintage equipment to the location you choose.We provide you with the set-up engineer to get you recording. You can hire by the day, week or month and we have engineers on call to provide you with additional technical support.You get to record in the location you love, in your own time, without the studio costs but with the security of support from one of the countries most highly regarded set-up engineers.
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Welcome to WeddingMart
WeddingMart has grown exponentially over the years to become the UK's leading wholesaler of decorations and supplies to the Wedding, Hospitality and Events industries.
We deliver style and quality at low prices to thousands of customers across the UK, from self employed wedding planners to large public sector organisations and famous-name businesses.
Buy With Confidence
Importing goods directly from overseas can be fraught with difficulties and uncertainties - including unclear product, shipping and import costs, long 3-4 month delivery times, customer service in a foreign language, no chance of returning unsuitable goods and no means of reclaiming payments if goods don't arrive.
WeddingMart enables you to benefit from our global supply chain with all the security of buying from a UK supplier.
Our Head Office and Distribution Centre is located in Birmingham, at the heart of the UK's road and rail networks. Here we maintain stocks from our carefully selected suppliers, so that you benefit from high product availability and short lead times - with express next day delivery available for orders placed before 1pm Monday to Thursday.
You'll also benefit from WeddingMart's UK-based customer service team, ultra-secure website and 30 day returns policy.
Exclusive Style, Quality & Low Prices
We're confident that you won't find better style or quality at WeddingMart's low prices anywhere else - because most of our product range is manufactured exclusively for WeddingMart to our exacting specification. Our supplier relationships and buying power ensure that we're able to consistently offer high quality at low prices.
Legal Information
WeddingMart is a trading name of EVEREST (UK) LTD.
Company Reg No:GB 08066896
VAT No: GB 167911092


text: Death_Hunter Report post Posted March 12, 2018 Hello, I just got my character to 20 Will when it was 18 will before. I noticed that before (at 18 will) I got +10 attack and defense xp, when I got it up to 20 I saw that I was getting +9 attack and defense xp. So I was thinking why did it go down? If rationality was higher then it should give more xp? Beavers Normal A/D xp given: +5 attack +5 defense At Rationality 11 Beavers A/D xp given: +10 attack +10 defense At Rationality 12 Beavers A/D xp given: +9 attack +9 defense *** THIS WAS NOT TESTED ON ANY SPECIAL DAY BUT MAGIC DAY AND NORMAL DAY SO A/D HAD NO BOOST*** Also I have godless perk so there is no gods effects applied (godless since I made character) Share this post Link to post Share on other sites