(This term is approved by the National Administration of Traditional Chinese Medicine)
Sildenafil (Viagra) is used to treat erectile dysfunction (impotence; inability to get or keep an erection) in men. Sildenafil (Revatio) is used to improve the ability to exercise in adults with pulmonary arterial hypertension (PAH; high blood pressure in the vessels carrying blood to the lungs, causing shortness of breath, dizziness, and tiredness). Children should not usually take sildenafil, but in some cases, a doctor may decide that sildenafil (Revatio) is the best medication to treat a child’s condition. Sildenafil is in a class of medications called phosphodiesterase (PDE) inhibitors. Sildenafil treats erectile dysfunction by increasing blood flow to the penis during sexual stimulation. This increased blood flow can cause an erection. Sildenafil treats PAH by relaxing the blood vessels in the lungs to allow blood to flow easily.
If you are taking sildenafil to treat erectile dysfunction, you should know that it does not cure erectile dysfunction or increase sexual desire. Sildenafil does not prevent pregnancy or the spread of sexually transmitted diseases such as human immunodeficiency virus (HIV).
|Phosphodiesterase type 5 inhibitors
The main ingredient of this product is Sildenafil Citrate.
This product is suitable for the treatment of erectile dysfunction.
Sildenafil citrate tablets: 50mg.
Different dosage forms and specifications of this product may vary, please read the specific drug instructions or follow the doctor’s advice.
Sildenafil citrate tablets:
- For most patients, the recommended dose is 50mg, taken as needed about 1 hour before sexual activity; However, it can be taken at any time within 0.5-4 hours before sexual activity. Depending on efficacy and tolerability, the dose can be increased to 100mg (maximum recommended dose) or reduced to 25mg. Maximum one dose per day. In the absence of sexual stimulation, the recommended dose of sildenafil does not work.
- The following factors were associated with increased plasma sildenafil levels (AUC): age over 65 years (40% increase), liver damage (e.g. cirrhosis, 80% increase), severe kidney damage (creatinine clearance & LT; 30 ml/min, an increase of 100%) and a potent CYP3A4 inhibitor. Since high plasma levels may increase both efficacy and the incidence of adverse events, 25mg is an appropriate initial dose for these patients.
- Ritonavir significantly increased sildenafil blood levels in a study of healthy subjects without HIV infection. For this reason, patients taking Ritonavir at the same time are advised not to take more than 25mg of Ritonavir every 48 hours.
- Sildenafil can enhance the antihypertensive effect of nitrates, so it is forbidden to take sildenafil in patients taking nitric oxide donors and nitrates in any dosage form.
- When sildenafil is used in combination with alpha-blockers, the patient has reached a stable state with alpha-blockers prior to sildenafil treatment, and you should start with the lowest dose.
- Sildenafil was administered to more than 3,700 patients (ages 19-87) in a worldwide clinical trial. More than 550 of the patients had been treated for more than a year. In placebo-controlled clinical trials, there was no significant difference in the rate of drug withdrawal due to adverse events in the experimental group (2.5%) compared with the placebo group (2.3%). Adverse reactions are generally short and mild to moderate in nature. In fixed-dose trials, the incidence of some adverse events increased as the dose increased. The nature of adverse reactions observed in flexible-dose trials is similar to that seen in fixed-dose trials.
- When the dose is higher than the recommended dose range, the adverse reactions are described in the instructions.
- The following are the incidence rates in controlled clinical trials. 2% adverse events. It is not certain whether sildenafil is responsible for its occurrence. Incidents that may be related to medication are included, but minor incidents and inaccurate reporting are omitted.
① Systemic reaction: facial edema, photosensitivity, shock, fatigue, pain, chills, accidental fall, abdominal pain, allergic reaction, chest pain, accidental injury.
② Cardiovascular system: angina pectoris, atrioventricular block, migraine, syncope, tachycardia, palpitations, hypotension, postural hypotension, myocardial ischemia, cerebral thrombosis, cardiac arrest, heart failure, ECG abnormalities, cardiomyopathy.
③ Digestive system: vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, dry mouth, abnormal liver function, rectal bleeding, gingivitis.
④Blood and lymphatic system: anemia and leukopenia.
⑤ Metabolism and nutrition: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.
⑥Skeletal muscle system: arthritis, joint disease, myalgia, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.
⑦ Nervous system: ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, lethargy, abnormal dreams, reflexes, sensory retardation.
⑧ Respiratory system: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, phlegm, cough.
⑨ Skin and its appendages: urticaria, herpes simplex, pruritus, sweating, skin ulcers, contact dermatitis, exudative dermatitis.
⑩ Special sensations: sudden hearing loss or loss, dilated pupils, conjunctivitis, photophobia, tinnitus, eye pain, ear pain, eye bleeding, cataract, dry eye.
⑪Genitourinary system: cystitis, nocturia, frequent urination, urinary incontinence, abnormal ejaculation, genital edema and lack of orgasm, and breast enlargement.
- Analysis of the safety database of controlled clinical trials showed no significant difference in adverse reactions between patients taking sildenafil and those taking antihypertensive drugs. This was a retrospective analysis and was not sufficient to detect any prespecified adverse effect differences.
Experience after listing:
- Cardiovascular and cerebrovascular system: the following serious cardiovascular, cerebrovascular and vascular adverse events associated with the use of sildenafil were reported after marketing: myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebral hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhage, and pulmonary hemorrhage. Most, though not all, of these patients, have pre-existing cardiovascular risk factors. Many of the reported incidents occurred during or just after sexual activity; Individual occurrence occurs shortly after taking sildenafil before sexual activity. Other reported incidents occurred hours or even days after taking medication or sexual activity. It has not been determined whether these events were directly related to sildenafil, sexual activity, pre-existing cardiovascular disease, a combination of these factors, or other factors.
- The blood and lymph systems: crisis: blocked blood vessels in early termination, pulmonary arterial hypertension (PAH) secondary patients with sickle cell disease use REVATIO (sildenafil citrate injection) in the small study, patients with sildenafil, the blood vessel blocking crisis need to be hospitalized report is more common than the placebo group. The clinical relevance of vascular occlusion crisis to ED in men treated with sildenafil citrate tablets is unclear.
- Nervous system: epileptic seizure, epileptic relapse, anxiety, transient global amnesia.
- Respiratory system: epistaxis.
- Special feeling:
① Hearing: individual cases of sudden hearing loss or loss have been reported after marketing, which is time-related to the use of PDE5 inhibitors (including this product). Some of these patients may have underlying diseases or other factors that cause ear-related adverse events, and follow-up information is limited in many cases. It cannot be determined whether the sudden hearing loss or loss is directly related to the use of this product, whether it is related to the patient’s existing risk factors for hearing loss, nor can it be determined whether the combined effect of the above two factors or the existence of other causes.
② Vision: diplopia, transient visual loss or vision loss, red-eye or eye congestion, eye burning, eye swelling, and pressure, increased intraocular pressure, retinal vasculopathy or bleeding, vitreous detachment, periocular edema, etc.
③ In the post-marketing use of PDE5 inhibitors including sildenafil citrate tablets, there were rare reports of time-dependent nonarterial anterior ischemic optic neuropathy (NAION). NAION) is a kind of can cause vision loss including permanent loss of disease in most but not all cases, these patients have the potential of NAION anatomy or blood vessels or the basis of risk factors, including but not limited to: lower plates, older than 50 years of age, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. It cannot be determined whether these events are directly related to the use of PDE5 inhibitors; related to the patient’s basic vascular risk factors or anatomical defects; Or a combination of the two; Or it could be something else.
- Sildenafil enhances the hypotensive effect of nitrates due to its known effect on the nitric oxide /cGMP pathway. Therefore, patients taking nitrates of any dosage form, whether regular or intermittent use, are contraindicated.
- It is not clear when patients can safely take nitrates after sildenafil if needed.
- It is not known whether nitrates can be safely administered at this time, although the blood concentration of sildenafil 24 hours after administration is well below peak levels.
- This product is contraindicated in patients who are known to be allergic to any of the ingredients.
(1) Sexual activity is potentially dangerous to the heart of patients with existing cardiovascular disease. Therefore, erectile dysfunction medications, including sildenafil, should generally not be used in patients whose cardiovascular status is unsuitable for sexual activity.
(2) A temporary reduction in supine blood pressure (mean maximum reduction of 8.4/5.5mmHg) was observed in healthy volunteers due to sildenafil dilating the systemic circulation. Although this effect is generally negligible in most patients, physicians should carefully consider whether the vasodilation effect has adverse consequences in patients with cardiovascular disease, especially during sexual activity, before prescribing it.
(3) Patients with underlying conditions such as left ventricular outflow tract obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and with severe impairment of autonomic blood pressure control may be particularly sensitive to the effects of vasodilators, including sildenafil.
(4) Currently, there are no controlled clinical trials on the safety and efficacy of sildenafil in the following populations. For these patients, the prescription should be cautious:
① Patients who have had a myocardial infarction, shock, or life-threatening arrhythmias within the last 6 months.
② Patients with resting hypotension (blood pressure below 90/50mmHg) or hypertension (blood pressure above 170/110mmHg).
③ Patients with heart failure or unstable angina pectoris of coronary heart disease.
④ Patients with retinitis pigmentosa (a small number of patients with this disease have genetic abnormalities of retinal phosphodiesterase).
⑤ Patients with sickle cell anemia or related anemia.
(5) After the approval of this product on the market abroad, there are a few reports of prolonged erection time (more than 4 hours) and abnormal erection (more than 6 hours of painful erection). If the erection lasts more than 4 hours, the patient should see a doctor immediately. If erections are not addressed immediately, penile tissue may be damaged and permanent erectile dysfunction may result.
(6) Concomitant use of the protease inhibitor Ritonavir significantly increased sildenafil plasma concentration (AUC increased 11-fold). Sildenafil should be used with caution in patients taking Ritonavir. There is limited information on the effects of sildenafil at high blood concentrations on subjects, except that visual abnormalities are more common at high doses. Some healthy subjects taking high doses of sildenafil (200 to 800mg) reported decreased blood pressure, fainting, and prolonged erections. To reduce the likelihood of adverse events in patients taking Ritonavir, the dosage of sildenafil is recommended.
Matters needing attention
Diagnosis of erectile dysfunction should be clear at the same time its potential causes, after a comprehensive medical examination to determine the appropriate treatment plan. Before sildenafil is administered to patients, the following important issues should be noted:
(1) Caution should be exercised when PDE5 (type 5 phosphodiesterase) inhibitors are combined with α -blockers. PDE5 inhibitors (including this product) and α -blockers are vasodilators and lower blood pressure. When vasodilators are combined, the effect on blood pressure can be expected to be cumulative. In some patients, the combination of the two drugs can significantly lower blood pressure, leading to symptoms of hypotension (such as dizziness, dizziness, and fainting).
(2) The patient should have reached a stable state of α blocker therapy before receiving sildenafil treatment. Patients taking alpha-blockers alone for hemodynamic instability have an increased risk of hypotension symptoms after concomitant use of PDE5 inhibitors.
(3) PDE5 inhibitors should be taken starting at the lowest dose in patients who have reached a stable state on α -blocker therapy.
(4) Alpha-blocker therapy should be initiated at the lowest dose for patients already receiving an ideal PDE5 inhibitor. Concomitant use of a PDE5 inhibitor may further lower blood pressure as the alpha-blocker dose increases.
(5) The safety of the combination of PDE5 inhibitors and alpha-blockers may be affected by other factors, including intravascular hypovolemia and other antihypertensive agents.
(6) Sildenafil dilates blood vessels in the systemic circulation, which may enhance the antihypertensive effect of other antihypertensive drugs.
(7) Patients taking multiple antihypertensive drugs at the same time were included in major clinical trials. In a separate drug interaction study, patients with hypertension taking either 5mg or 10mg of amlodipine with additional doses of 100mg of amlodipine had further reductions of 8mmHg and 7mmHg on average in systolic and diastolic blood pressure.
(8) Patients with benign prostatic hyperplasia (BPH) who took the α -blockers doxazosin (4mg) and sildenafil (25mg) at the same time had a further mean reduction of 7mmHg in both decubed systolic and diastolic blood pressure. Postural hypotension symptoms have been reported in individual patients with a higher dose of sildenafil combined with doxazosin (4mg) within 1 to 4 hours of administration. Sildenafil concomitant therapy with alpha-blockers may cause hypotensive symptoms in some patients. Therefore, sildenafil doses of more than 25mg should not be taken within 4 hours of taking an alpha-blocker.
(9) It is unknown whether sildenafil is safe for patients with the hemorrhagic disease and active gi ulcers.
(10) Sildenafil should be used with caution in patients with anatomical malformations of the penis (e.g., penile skew, cavernous fibrosis, Peyronie’s disease) or diseases that may cause penile erection (e.g., sickle cell anemia, multiple myeloma, leukemia). The safety and efficacy of other treatments for erectile dysfunction have not been studied in combination with this product. Therefore, combined use is not recommended.
(11) Whether used alone or in combination with aspirin, this product has no effect on bleeding time. In vitro, the product enhanced the antiplatelet aggregation of sodium nitroprusside, a nitric oxide donor, in humans. The combination of heparin and sildenafil has an additive effect on the prolongation of bleeding time in rabbits under anesthesia, but no similar human studies have been conducted.
Notice to Patients:
(1) The physician should instruct the patient to contraindicate sildenafil with nitrate (whether the latter is used regularly or intermittently).
(2) Physicians should inform patients of the potential for sildenafil to enhance the antihypertensive effects of alpha-blockers and other antihypertensive drugs. Concomitant use of sildenafil and alpha-blockers may cause hypotension in some patients. When a combination of sildenafil and alpha-blocker is required, patients should have reached a stable state of alpha-blocker therapy prior to sildenafil treatment, and sildenafil should be started at the lowest dose.
(3) Physicians should explain to patients the potential risks of sexual activity to the heart in the presence of existing cardiovascular risk factors. If symptoms such as angina, dizziness, and nausea occur at the beginning of the sexual activity, stop sexual activity and discuss these with your doctor.
(4) Physicians should inform patients to immediately discontinue all type 5 phosphodiesterase (PDE5) inhibitors, including sildenafil citrate tablets, and consult their physicians in the event of a sudden loss of vision in one or both eyes. This condition may be a manifestation of nonarterial anterior ischemic optic neuropathy (NAION), a disease that can cause vision loss including permanent loss. There have been rare reports of time-dependent NAION in all postmarketing of PDE5 inhibitors. It cannot be determined whether these events are directly related to the use of PDE5 inhibitors or other factors. Physicians should inform patients who have had NAION in the past that they are at increased risk of having NAION again, regardless of whether they have been adversely affected by vasodilators such as PDE5 inhibitors.
(5) The physician should inform the patient that if sudden hearing loss or loss occurs, the patient should stop taking PDE5 inhibitors (including this product) and seek medical attention as soon as possible. Such events, which can be accompanied by tinnitus and dizziness, have been reported to be time-related to the use of PDE5 inhibitors, including this product. However, it is unclear whether such events are directly related to the use of PDE5 inhibitors or other factors.
(6) Doctors should warn patients: that there are a small number of reports of prolonged erection time (more than 4 hours) and abnormal erection (more than 6 hours of painful erection) after the product is approved for marketing abroad. If the erection lasts more than 4 hours, the patient should see a doctor immediately. If erections are not addressed immediately, penile tissue may be damaged and permanent erectile dysfunction may result.
(7) Physicians should inform patients that this product should not be used in combination with other PDE5 inhibitors. The safety and efficacy of this product in combination with other PDE5 inhibitors have not been studied.
(8) Sildenafil has no protective effect against sexually transmitted diseases. Patients should be informed of measures to prevent sexually transmitted diseases (including human immunodeficiency virus, HIV), as appropriate.
Medication for pregnant and lactating women: Sildenafil is not suitable for women.
Children’s medication: Sildenafil is not suitable for newborns and children.
Medication for the elderly: The clearance rate of sildenafil in healthy elderly volunteers (≥65 years old) was reduced. The initial dose of 25mg is appropriate, since high plasma concentration may increase both efficacy and adverse events.
- In healthy volunteers at a single dose of 800mg, adverse events were similar to those at lower doses, but with increased incidence and severity.
- When drug overdose occurs, routine supportive therapy should be taken as needed. Because sildenafil binds to plasma proteins at a high rate and is not cleared from urine, renal dialysis does not increase clearance.
Effects of other drugs on sildenafil
(1) In vitro test: cytochrome P4503A4 (main pathway) and 2C9 (secondary pathway) were used to metabolize the product. Therefore, inhibitors of these isoenzymes decrease sildenafil clearance, while inducers of these isoenzymes increase sildenafil clearance.
(2) in vivo: in healthy volunteers taking 50mg of this product together with 800mg of cimetidine (a nonspecific cytochrome P450 inhibitor) resulted in a 56% increase in plasma sildenafil concentration.
(3) When a single dose of sildenafil 100mg was combined with erythromycin, a specific inhibitor of cytochrome P4503A4 (500mg twice daily for 5 days), the area under the curve (AUC) of sildenafil increased by 182%. Furthermore, in a study of healthy male volunteers, a single dose of 100mg sildenafil increased Cmax by 140% and AUC by 210% when the HIV protease inhibitor saquinavir (another CYP4503A4 inhibitor) reached homeostasis (1200mg three times a day).
(4) Sildenafil did not affect the pharmacokinetics of saquinavir. More potent CYP4503A4 inhibitors, such as ketoconazole and itraconazole, may have even greater effects. Population data from clinical trials also suggest that sildenafil clearance rates are reduced when used in combination with CYP4503A4 inhibitors such as ketoconazole, erythromycin, and cimetidine.
(5) in another study of healthy male volunteers, a single dose of 100mg of sildenafil increased Cmax by 300% (4-fold) and AUC by 1000% (11-fold) when the HIV protease inhibitor ritonavir (a highly potent inhibitor of CYP450) reached homeostasis (500mg twice daily). After 24 h of administration, the plasma sildenafil concentration was still close to 200ng/ml, compared with about 5ng/ml for sildenafil alone. This is consistent with the significant effects of Ritonavir on many CYP450 substrates. This product does not affect the pharmacokinetics of ritonavir.
(6) Although the interaction of sildenafil with other protease inhibitors was not studied, it was predicted that the combination would increase the plasma concentration levels of sildenafil.
(7) a study of healthy male volunteers found that the combination of a steady-state dose of sildenafil (80mg three times daily) and a steady-state dose of the endothelin receptor antagonist bosentan (125mg twice daily, a moderate inducer of CYP3A4 and CYP2C9) Sildenafil AUC decreased by 63% and sildenafil Cmax decreased by 55% when treated with cytochrome P4502C19. Concomitant administration of a potent CYP3A4 inducer such as rifampicin can be predicted to cause more declines in plasma sildenafil levels.
(8) A single dose of antacid (magnesium hydroxide/aluminum hydroxide) had no effect on the bioavailability of the product. Pharmacokinetic data of patients in clinical trials showed that CYP4502C9 inhibitors (such as N-(p-Toluenesulfonyl)urea and warfarin), CYP4502D6 inhibitors (such as selective serotonin reuptake inhibitors, and tricyclic antidepressants), thiazide drugs and thiazide diuretics, angiotensin-converting enzyme inhibitors, calcium channel blockers, etc., The pharmacokinetics of sildenafil were not affected. Loop diuretics and potassium-preserving diuretics increased the AUC of sildenafil’s inactive metabolite (N-dimethyl sildenafil) by 62% compared with 102% with non-selective β -blockers. These effects on sildenafil metabolites do not cause clinical changes.
Effects of sildenafil on other drugs
(1) In vitro test: this product is a cytochrome P4501A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50& GT; 150μM). Since the plasma peak concentration of sildenafil at the recommended dose is approximately 1μM, sildenafil does not alter the clearance of these isoenzyme substrates.
(2) In vivo trials: patients with hypertension who took sildenafil (100mg) and amlodipine 5mg or 10mg at the same time had a further mean reduction of 8mmHg in systolic blood pressure and 7mmHg diastolic blood pressure in the supine position.
(3) There was no significant interaction between N-(p-Toluenesulfonyl)urea (250mg) and warfarin (40mg) metabolized by CYP4502C9 and sildenafil.
(4) sildenafil (50mg) did not increase the bleeding time induced by aspirin (150mg).
A study of healthy male volunteers showed that sildenafil (100mg) did not affect the steady-state pharmacokinetics of HIV protease inhibitors saquinavir and ritonavir, both of which are substrates for CYP4503A4. A steady-state dose of sildenafil (80mg thrice daily) resulted in a 50% increase in AUC and a 42% increase in Cmax for bosentan (125mg twice daily).
Effect of sildenafil on blood pressure in combination with nitroglycerin
A pharmacokinetic test of a single oral dose of sildenafil 100mg in healthy volunteers showed that the plasma content of sildenafil was about 2ng/mL after 24h (peak concentration was about 440ng/mL). For those older than 65 years, liver damage (e.g. cirrhosis), severe kidney damage (clearance rate < 30mL/min), the plasma levels of sildenafil were 3-8 times higher in patients taking erythromycin or CYP3A4 suppressor at 24h than in healthy volunteers. Although plasma levels of sildenafil at 24h were well below peak concentrations, the safety of concomitant administration of nitrates is unknown.
Effects of sildenafil on blood pressure in concomitant α -blockers
Three double-blind, placebo-controlled, randomized, double-crossover trials evaluated the interaction of sildenafil with doxazosin, an alpha-adrenergic blocker.
Effect of sildenafil on blood pressure when taken together with antihypertensive drugs
Sildenafil 100mg and amlodipine 5mg or 10mg orally reduced the systolic and diastolic blood pressure in the recumbent position by 8mmHg and 7mmHg on average in hypertensive patients.
Effect of sildenafil on blood pressure when taken in combination with alcohol
50mg of sildenafil did not affect the hypotensive effect of alcohol (0.5/kg) on healthy volunteers with a mean maximum blood alcohol content of 0.08%. The maximum reduction in systolic blood pressure was 17.4mmHg when alcohol was used alone and 18.5mmHg when combined with sildenafil. Diastolic blood pressure decreased by a maximum of 11.1mmHg when alcohol was used alone and 17.2mmHg when combined with sildenafil. No postural dizziness or orthostatic hypotension was reported. The trial did not examine the maximum recommended dose of sildenafil of 100mg.
This product is an oral medication for the treatment of erectile dysfunction. It is the citrate of sildenafil, a selective inhibitor of acycloguanosine (cGMP) -specific phosphodiesterase type 5 (PDE5).
Mechanism of action
(1) The physiological mechanism of penile erection involves the release of nitric oxide (NO) in the penile sponge during sexual stimulation. NO activates guanosine cyclase, which leads to increased levels of cyclic guanosine phosphate (cGMP), relaxation of smooth muscle in sponges, and blood inflow. Sildenafil has NO direct relaxation effect on isolated human sponges but can enhance the effect of nitric oxide (NO) by inhibiting the cGMP decomposition type 5 phosphodiesterase (PDE5) in the sponge. Sildenafil inhibition of PDE5 increases the level of cGMP in sponges relaxes smooth muscle and allows blood to flow into sponges when NO is released locally due to sexual stimulation. In the absence of sexual stimulation, the recommended dose of sildenafil does not work.
(2) In vitro experiments showed that sildenafil was selective for PDE5. Its effect on PDE5 is much stronger than that on other known phosphodiesterases (10 times that on PDE6, more than 80 times that on PDE1, and more than 700 times that on PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, PDE11). Sildenafil is about 4000 times more selective for PDE5 than PDE3, which is of great significance because the latter is related to the control of myocardial contractility. Sildenafil is about 10 times more potent on PDE5 than PDE6. PDE6 is an enzyme found in the retina. Sildenafil’s relatively low selectivity to PDE6 is responsible for its abnormal color vision at high doses or plasma concentrations.
(3) PDE5 is also found in platelets, vascular and visceral smooth muscle, skeletal muscle, brain, heart, liver, kidney, lung, spleen, prostate, bladder, testis, and seminal vesicles in addition to human spongiform smooth muscle. Sildenafil’s inhibition of PDE5 in these tissues may be the basis for its enhancement of the antiplatelet aggregation of nitric oxide (in vitro), inhibition of platelet thrombosis (in vivo), and relaxation of peripheral arteriovenous (in vivo).
Effect of sildenafil on erectile response
In eight double-blind, placebo-controlled cross-trials of patients with organic or cardiac erectile dysfunction, erectile hardness and duration were measured by a drop tester and erectile response improved with sildenafil compared with placebo. Most trials assess the efficacy of sildenafil about 60 minutes after taking the drug. The erectile response generally increased with sildenafil dose and plasma concentration as measured by a durometer. A trial to determine the duration of the effect showed that it lasted up to four hours, but the response was weaker than at two hours.
Effect of sildenafil on blood pressure
A single dose of sildenafil 100mg in healthy male volunteers resulted in a reduction in sitting blood pressure (mean maximum reduction of 8.3/5.3mmHg). Blood pressure decreased most significantly at 1 to 2 hours after taking the drug, and no difference was observed at 8 hours after taking the drug. Sildenafil 25mg, 50mg, or 100mg had similar effects on blood pressure, so the effect was independent of dose and blood concentration. The effect was greater in patients who were also taking nitrates.
Effects of sildenafil on cardiac parameters
(1) No clinically significant ECG changes were observed in normal male volunteers after a single dose of oral administration of 100mg.
(2) Relevant studies provide data on the effect of sildenafil on cardiac output. In a small, open, uncontrolled pilot trial, eight patients with stable ischemic heart disease received 40mg of sildenafil intravenously in four separate doses monitored by a swan-Ganz catheter. The test results are shown in Table 3. Systolic and diastolic blood pressure at rest decreased by 7% and 10%, respectively, from baseline. Resting right atrial pressure, pulmonary artery pressure, pulmonary wedge pressure, and cardiac output decreased by 28%, 28%, 20%, and 7% on average, respectively. Although blood concentrations at this intravenous dose were 2-5 times higher than the average peak of sildenafil in healthy male volunteers with a single oral dose of 100mg, the hemodynamic response to exercise persisted in these patients.
(3) in a double-blind trial, 144 patients with erectile dysfunction and exercise-restricted chronic angina who did not receive long-term oral nitrate therapy were randomized to a single dose of placebo or 100mg sildenafil 1 hour prior to exercise. The primary endpoint was the duration of restrictive angina in an evaluable population. The mean duration of restrictive angina attacks (adjusted for baseline) in sildenafil (N=70) and placebo groups were 423.6 and 403.7 seconds, respectively. This result demonstrated that sildenafil was not statistically worse than placebo for the primary endpoint.
Effects of sildenafil on vision
After a single dose of 100mg and 200mg of sildenafil, transient blue/green color discrimination abnormalities were found by the Farnsworth-Munsell-100 tone test, and the occurrence was dose-related; The peak effect time was close to the peak time of plasma concentration. This phenomenon is consistent with the inhibition of PDE6 by the drug. PDE6 is involved in light conduction in the retina. Studies have shown no effect on visual acuity, intraocular pressure, or visual nipple size at doses twice the maximum recommended dose.
Effect of sildenafil on sperm
Oral administration of sildenafil 100mg in healthy volunteers had no effect on sperm mortality and morphology.
Sildenafil was negative in the following tests: in vitro mutagenicity test of bacteria and Chinese hamster ovary cells, in vitro human lymphocyte genotoxicity test, and in vivo mouse micronucleus test.
(1) sildenafil was administered to female rats for 36 days and male rats for 102 days, and the AUC value of sildenafil reached 60mg/kg body weight/day (more than 25 times that of human male AUC). No reproductive toxicity was observed. In healthy volunteers, a single dose of sildenafil 100mg was taken orally without affecting sperm motility and morphology.
(2) there was no evidence of teratogenicity, embryotoxicity, or fetal toxicity in rats and rabbits receiving sildenafil up to 200mg/kg BW/day during organogenesis. This dose, calculated in mg/m2, is equivalent to 20 times and 40 times MRHD in 50kg subjects, respectively. The drug was administered for 36 days at a safe dose (NOAEL) of 30mg/kg body weight/day in pre – and postnatal developmental experiments in rats.
(3) The AUC of non-pregnant rats at this dose is about 20 times that of human AUC. Sildenafil has not been adequately and rigorously controlled in pregnant women.
No carcinogenicity was observed in male and female rats after 24 months of sildenafil administration when the total volume under the curve (AUCs) of non-combined sildenafil and its main metabolites in vivo was 29 times and 42 times that in male rats after 100mg of MRHD. Sildenafil was not carcinogenic in mice at doses up to 10mg/kg/ body weight/day (maximum tolerated dose (MTD)) at mg/m2, about 0.6 times MRHD, for 18-21 months.
Oral absorption is rapid and the absolute bioavailability is approximately 41% (25-63%). Its pharmacokinetic parameters are proportional to the dose within the recommended dose range. Elimination is dominated by liver metabolism (cytochrome P450 isoenzyme 3A4 pathway), producing an active metabolite whose properties are similar to sildenafil. The combination of potent inhibitors of cytochrome P450 isoenzyme 3A4 (CYP4503A4) (e.g., erythromycin, ketoconazole, itraconazole) and nonspecific inhibitors of cytochrome P450 (CYP450), such as cimetidine and sildenafil, may lead to elevated plasma levels of sildenafil.
The elimination half-life of sildenafil and its metabolites is about 4 hours.
Absorption and distribution
This product is quickly absorbed. Peak plasma concentration (Cmax) was achieved after 30 to 120 minutes (median 60 minutes) of oral administration on an empty stomach. When taken with a high-fat diet, absorption rate decreased, peak time (Tmax) was delayed by an average of 60 minutes, and Cmax decreased by an average of 29%. The mean steady-state volume of distribution (Vss) of sildenafil was 105 l, indicating its distribution in tissues. About 96% of sildenafil and its main circulating metabolite (n-demethylated) are bound to plasma proteins. The protein binding rate was independent of the total drug concentration. According to the semen examination results of healthy volunteers after 90 minutes of medication, it can be deduced that the amount of sildenafil in the semen after the medication is less than 0.001% of the dose.
Metabolism and excretion
(1) Sildenafil is mainly cleared by the liver microsomal enzyme cytochrome P4503A4 (the main pathway) and cytochrome P4502C9 (the secondary pathway). The main circulating metabolite is the n-demethylate of sildenafil, which is further metabolized. N-demethylated metabolites have PDE selectivity similar to that of sildenafil, with approximately 50% of the activity on PDE5 in vitro. The plasma concentration of this metabolite is approximately 40% of that of sildenafil, so approximately 20% of sildenafil’s pharmacological action is due to its metabolite.
(2) After oral or intravenous administration, sildenafil is excreted mainly as metabolites from the stool (approximately 80% of the oral dose) and a small fraction from the urine (approximately 13% of the oral dose). Pharmacokinetic parameters obtained from population-based pharmacokinetic studies were similar to those obtained from healthy volunteers.
Pharmacokinetics of special populations
(1) Elderly: The clearance rate of sildenafil was reduced in healthy elderly volunteers (≥65 years old), and the area under the drug time curve (AUC) of sildenafil and its active N-demethylation metabolites was about 84% and 107% higher than that of young healthy volunteers (18-45 years old), respectively. The AUC of free (not bound to plasma protein) sildenafil and its active N-demethylated metabolites correspondingly increased by 45% and 57%, respectively, taking into account the effect of age differences on plasma protein binding.
(2) Renal insufficiency: In volunteers with mild (creatinine clearance =50-80ml/min) and moderate (creatinine clearance =30-49 mL /min) renal impairment, the pharmacokinetics of a single dose of sildenafil 50mg did not change. Volunteers with severe renal impairment (creatinine clearance of 30ml/min) had reduced clearance of sildenafil and almost double the area under the curve (AUC) and Cmax at treatment time compared with the same age group without renal impairment. In addition, the AUC and Cmax of sildenafil n-demethylation metabolites were significantly increased in subjects with severe renal impairment, by 200% and 79%, respectively, compared with subjects with normal renal function.
(3) Liver dysfunction: Sildenafil clearance was reduced in volunteers with cirrhosis (Child-Pugh grade A and B), and AUC and Cmax increased by 84% and 47%, respectively, compared with the same age group without liver damage. Sildenafil pharmacokinetics in patients with severe liver impairment (Child-Pugh grade C) have not been studied.
Thus, increased plasma sildenafil levels are associated with age 65 and older, liver function impairment, and severe renal impairment. The appropriate starting dose for these patients is 25mg.
Store tightly sealed in a cool dry place.
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