Chemical formula: C₂₂H₃₀N₆O₄S Molecular mass: 474.576 g/mol PubChem compound: 5212
Sildenafil interacts in the following cases:
Caution is advised when sildenafil is administered to patients taking an alpha-blocker as the co-administration may lead to symptomatic hypotension in susceptible individuals. 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.
In three specific drug-drug interaction studies, the alpha-blocker doxazosin (4mg and 8mg) and sildenafil (25mg, 50mg, or 100mg) 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.
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) 125mg twice daily with sildenafil 80mg 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 20mg three times a day when added to a stable dose of bosentan (62.5mg–125mg twice a day) indicated a decrease in sildenafil exposure with bosentan co-administration, similar to that observed in healthy volunteers.
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.
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 80mg three times a day compared to the exposure at a dose of 20mg 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).
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.
The most potent of the CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected to have effects similar to ritonavir in co-administration with sildenafil.
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.
A downward dose adjustment to 20mg once daily is recommended in case of co-administration with more potent CYP3A4 inhibitors clarithromycin, telithromycin and nefazodone.
Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500mg twice daily) with sildenafil (100mg 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.
Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance <30 mL/min) a 25 mg dose should be considered. Based on efficacy and tolerability, the dose may be increased step-wise to 50 mg up to 100 mg as necessary.
In 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.
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.
Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis) a 25 mg dose should be considered. Based on efficacy and tolerability, the dose may be increased step-wise to 50 mg up to 100 mg as necessary.
Amprenavir may increase the efficacy and toxicity of sildenafil.
Atazanavir may increase the efficacy and toxicity of sildenafil.
In a study of healthy volunteers sildenafil at steady state (80mg three times a day) resulted in a 50% increase in bosentan AUC (125mg twice daily). A population pharmacokinetic analysis of data from a study of adult PAH patients on background bosentan therapy (62.5mg-125mg twice a day) indicated an increase (20% (95% CI: 9.8-30.8)) of bosentan AUC with co-administration of steady-state sildenafil (20mg three times a day) of a smaller magnitude than seen in healthy volunteers when co-administered with 80mg sildenafil three times a day.
Cimetidine (800mg), a cytochrome P450 inhibitor and a non-specific CYP3A4 inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil (50mg) to healthy volunteers. No dose adjustment is required.
Ciprofloxacin may increase sildenafil levels in blood serum.
When a single 100mg dose of sildenafil was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500mg twice daily for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC).
In general, any dose adjustment should be administered only after a careful benefit-risk assessment. A downward dose adjustment to 20mg twice daily should be considered when sildenafil is co-administered to patients already receiving CYP3A4 inhibitors like erythromycin or saquinavir.
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.
Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state (1,200mg three times a day) with sildenafil (100mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics.
In general, any dose adjustment should be administered only after a careful benefit-risk assessment. A downward dose adjustment to 20mg twice daily should be considered when sildenafil is co-administered to patients already receiving CYP3A4 inhibitors like erythromycin or saquinavir.
Cases 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. In the event of any sudden visual defect, the treatment should be stopped immediately and alternative treatment should be considered.
Sildenafil 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 sildenafil than those receiving placebo leading to the premature termination of this study.
Sildenafil 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.
The 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.
No 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.
There 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.
Due to lack of data, sildenafil should not be used in pregnant women unless strictly necessary.
There 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.
Due to lack of data on effects of sildenafil in pregnant women, sildenafil is not recommended for women of childbearing potential unless also using appropriate contraceptive measures.
Non-clinical data revealed no special hazard for humans based on conventional studies of fertility.
There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil in healthy volunteers.
No relevant adverse effects were found in reproduction studies in rats and rabbits following oral administration of sildenafil.
Sildenafil has moderate influence on the ability to drive and use machines.
As dizziness and altered vision were reported in clinical trials with sildenafil, patients should be aware of how they might be affected by sildenafil, before driving or using machines.
Adverse reactions that resulted from intravenous sildenafil use are similar to those associated with oral sildenafil use. Since there are limited data for intravenous sildenafil use and since pharmacokinetic models predict that 20 mg oral and 10 mg intravenous formulations will yield similar plasma exposures, the safety information for intravenous sildenafil is supported by that of oral sildenafil.
A 10 mg dose of sildenafil solution for injection is predicted to provide total exposure of free sildenafil and its N-desmethyl metabolite and their combined pharmacological effects comparable to those of a 20 mg oral dose.
Study A1481262 was a single centre, single dose, open label study to assess the safety, tolerability and pharmacokinetics of a single intravenous dose of sildenafil (10 mg) administered as a bolus injection to patients with Pulmonary Arterial Hypertension (PAH) who were already receiving and stable on oral sildenafil 20 mg three times per day.
A total of 10 PAH subjects enrolled and completed the study. The mean postural changes in systolic and diastolic blood pressure over time were small (<10 mmHg) and returned towards baseline beyond 2 hours. No symptoms of hypotension were associated with these changes. The mean changes in heart rate were clinically insignificant. Two subjects experienced a total of 3 adverse reactions (flushing, flatulence and hot flush). There was one serious adverse reaction in a subject with severe ischaemic cardiomyopathy who experienced ventricular fibrillation and death 6 days post study. It was judged to be unrelated to the study medicinal product.
In the pivotal placebo-controlled study of sildenafil 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 oral sildenafil 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 sildenafil 80 mg TID.
In a placebo-controlled study of sildenafil as an adjunct to intravenous epoprostenol in pulmonary arterial hypertension, a total of 134 patients were treated with oral sildenafil (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 drug 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 events 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 sildenafil 80 mg TID.
In the two-placebo controlled oral sildenafil studies adverse events were generally mild to moderate in severity. The most commonly reported adverse reactions that occurred (greater or equal to 10%) on sildenafil compared to placebo were headache, flushing, dyspepsia, diarrhoea and pain in extremity.
Adverse reactions which occurred in >1% of sildenafil-treated patients and were more frequent (>1% difference) on sildenafil in the pivotal study or in the sildenafil combined data set of both the placebo-controlled studies in pulmonary arterial hypertension, at oral doses of 20, 40 or 80 mg TID are listed 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, undesirable effects are presented in order of decreasing seriousness.
Reports from post-marketing experience are included in italics.
Common: cellulitis, influenza, bronchitis, sinusitis, rhinitis, gastroenteritis
Common: anaemia
Common: fluid retention
Common: insomnia, anxiety
Very common: headache
Common: migraine, tremor, paraesthesia, burning sensation, hypoaesthesia
Common: retinal haemorrhage, visual impairment, vision blurred, photophobia, chromatopsia, cyanopsia, eye irritation, ocular hyperaemia
Uncommon: visual acuity reduced, diplopia, abnormal sensation in eye
Not known: Non-arteritic anterior ischaemic optic neuropathy (NAION), Retinal vascular occlusion, Visual field defect*
Common: vertigo
Not known: sudden hearing loss
Very common: flushing
Not Known: hypotension
Common: epistaxis, cough, nasal congestion
Very common: diarrhoea, dyspepsia
Common: gastritis, gastrooesophageal reflux disease, haemorrhoids, abdominal distension, dry mouth
Common: alopecia, erythema, night sweats
Not known: rash
Very common: pain in extremity
Common: myalgia, back pain
Uncommon: haematuria
Uncommon: penile haemorrhage, haematospermia, gynaecomastia
Not known: priapism, erection increased
Common: pyrexia
* These adverse events/reactions have been reported in patients taking sildenafil in the treatment of male erectile dysfunction (MED).
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