Sildenafil, also known as sildenafil citrate, is a Western medicine. The common dosage form is tablets. It is a phosphodiesterase type 5 inhibitor. It is used to treat erectile dysfunction.
Element
The main ingredient of this product is sildenafil citrate.
Characteristics
Sildenafil citrate tablets: film-coated tablets, white to off-white after removing the coating.
Indications
This product is suitable for the treatment of erectile dysfunction.
Specification
Sildenafil citrate tablets: 50mg.
Dosage
The usage and dosage of this product in different dosage forms and specifications may vary. Please read the specific drug instructions for use, or follow the doctor’s advice.
Sildenafil citrate tablets:
1. For most patients, the recommended dose is 50 mg, taken as needed about 1 hour before sexual activity; but it can be taken at any time within 0.5-4 hours before sexual activity. Based on efficacy and tolerance, the dose can be increased to 100 mg (maximum recommended dose) or reduced to 25 mg. Take at most once a day. The recommended dose of sildenafil is ineffective in the absence of sexual stimulation.
2. The following factors are associated with increased plasma sildenafil levels (AUC): age over 65 years (increased by 40%), liver damage (such as cirrhosis, increased by 80%), severe renal impairment (creatinine clearance <30 ml/min, increased by 100%), and concurrent use of strong CYP3A4 inhibitors. Since higher plasma levels may increase both efficacy and the incidence of adverse events, the starting dose for these patients is preferably 25 mg.
3. A study conducted in healthy subjects without HIV infection showed that Ritonavir can significantly increase the blood level of sildenafil. In view of this, it is recommended that patients taking Ritonavir at the same time should not take more than 25 mg of the drug within every 48 hours.
4. Sildenafil can enhance the antihypertensive effect of nitrates. Therefore, patients taking any dosage form of nitric oxide donors and nitrates should not take sildenafil.
5. When sildenafil needs to be used in combination with α-receptor blockers, the patient should have achieved a stable state with α-receptor blocker treatment before sildenafil treatment, and sildenafil should be started at the lowest dose.
Adverse Reactions
1. Pre-market experience:
(1) In clinical trials worldwide, more than 3,700 patients (aged 19-87 years) took sildenafil. More than 550 of them were treated for more than one year. In placebo-controlled clinical trials, there was no significant difference in the discontinuation rate due to adverse reactions in the trial group (2.5%) compared with the placebo group (2.3%). Adverse reactions are generally transient and mostly mild to moderate in nature. In fixed-dose trials, the incidence of some adverse reactions increased with increasing doses. Flexible-dose trials better reflect the recommended dosage of the drug, and the nature of the adverse reactions seen in the trials is similar to that in fixed-dose trials.
(2) When the dosage is higher than the recommended dosage range, please refer to the instructions for adverse reactions.
(3) The following are adverse events with an incidence of less than 2% in controlled clinical trials. It is not certain whether their occurrence is caused by sildenafil. Events that may be related to medication are included here, but minor events and inaccurate reports are omitted.
① Systemic reactions: facial edema, photosensitivity reaction, shock, fatigue, pain, chills, accidental falls, abdominal pain, allergic reaction, chest pain, accidental injury.
②Cardiovascular system: angina pectoris, atrioventricular block, migraine, syncope, tachycardia, palpitations, hypotension, orthostatic hypotension, myocardial ischemia, cerebral thrombosis, cardiac arrest, heart failure, abnormal electrocardiogram, cardiomyopathy.
③Digestive 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 and muscular system: arthritis, joint disease, myalgia, tendon rupture, tenosynovitis, bone pain, muscle weakness, and synovitis.
⑦ Nervous system: ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, dizziness, depression, insomnia, drowsiness, abnormal dreams, slow reflexes, and dull sensation.
⑧ Respiratory system: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, excessive sputum, and cough.
⑨Skin and its appendages: urticaria, herpes simplex, itching, sweating, skin ulcers, contact dermatitis, and exfoliative dermatitis.
⑩ Special senses: sudden hearing loss or impairment, pupil dilation, conjunctivitis, photophobia, tinnitus, eye pain, ear pain, eye hemorrhage, cataracts, dry eyes.
⑪ Urogenital system: cystitis, frequent urination at night, urinary incontinence, abnormal ejaculation, genital edema and lack of orgasm, and breast enlargement.
(4) Analysis of the controlled clinical trial safety database showed no significant difference in adverse reactions between patients taking sildenafil and those taking antihypertensive drugs at the same time. This was a retrospective analysis and was not adequate to detect any differences in pre-specified adverse reactions.
2. Post-marketing experience:
(1) Cardiovascular and cerebrovascular system: The following serious cardiovascular, cerebrovascular and vascular adverse events with a temporal relationship to the use of sildenafil have been 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 the above patients already had cardiovascular risk factors. Many of the reported events occurred during or just after sexual activity; some occurred shortly after taking sildenafil but before engaging in sexual activity. Other reported events occurred hours or even days after taking the drug or engaging in sexual activity. For these events, it is not yet clear whether they are directly related to sildenafil, or are related to sexual activity, existing cardiovascular disease, the combined effects of the above factors, or other factors.
(2) Blood and Lymphatic System: Vascular Occlusive Crisis: In a small, prematurely terminated study of REVATIO (sildenafil citrate injection) in patients with sickle cell disease secondary to pulmonary arterial hypertension (PAH), reports of vaso-occlusive crises requiring hospitalization were more common in patients taking sildenafil than in the placebo group. The clinical relevance of vaso-occlusive crisis to men with ED treated with sildenafil citrate tablets is unclear.
(3) Nervous system: epileptic seizures, epileptic recurrence, anxiety, transient global amnesia.
(4) Respiratory system: epistaxis.
(5) Special senses:
① Hearing: There have been individual case reports of sudden hearing loss or loss after the product was marketed, which are temporally related to the use of PDE5 inhibitors (including this product). Some of these patients may have underlying diseases or other factors that cause otological adverse events, and follow-up information for many cases is limited. It is not possible to determine 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, and it is also impossible to determine the combined effect of the above two factors or the existence of other causes.
② Vision: diplopia, transient visual loss or decreased vision, red eyes or eye congestion, eye burning sensation, eye swelling and pressure, increased intraocular pressure, retinal vascular lesions or hemorrhage, vitreous detachment, perimacular edema, etc.
③ In the post-marketing application of PDE5 inhibitors, including sildenafil citrate tablets, there have been rare reports of non-arteritic anterior ischemic optic neuropathy (NAION) related to the duration of medication. NAION is a disease that can cause vision loss, including permanent loss. In most but not all cases, these patients have underlying anatomical or vascular foundations or risk factors for NAION, including but not limited to: low cup-to-disc ratio, age over 50 years old, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It cannot be determined whether these events are directly related to the use of PDE5 inhibitors; or related to the patient’s underlying vascular risk factors or anatomical defects; or the combined effect of the two; or caused by other factors.
Taboo
1. Due to the known effect of this product on the nitric oxide/cGMP pathway, sildenafil can enhance the antihypertensive effect of nitrates. Therefore, patients taking any dosage form of nitrates, whether taking them regularly or intermittently, are contraindicated.
2. It is not clear when patients can safely take nitrates (if necessary) after taking sildenafil.
Although sildenafil blood levels are much lower than peak levels 24 hours after administration, it is not known whether nitrates can be safely taken at this time.
3. This product is contraindicated for patients who are known to be allergic to any ingredient in it.
4. Warning:
(1) Sexual activity is potentially dangerous to the heart in patients with existing cardiovascular disease. Therefore, patients whose cardiovascular status is not suitable for sexual activity should generally not use drugs for the treatment of erectile dysfunction, including sildenafil.
(2) Because sildenafil causes systemic vasodilation, the blood pressure of healthy volunteers in the supine position decreases temporarily (average maximum decrease of 8.4/5.5 mmHg). Usually, in most patients, this effect can be ignored, but doctors should still carefully consider whether this vasodilation effect will cause adverse consequences to patients with cardiovascular disease before prescribing, especially during sexual activity.
(3) Patients with the following underlying diseases may be particularly sensitive to the effects of vasodilators, including sildenafil, including left ventricular outflow tract obstruction (such as aortic stenosis, idiopathic hypertrophic subaortic stenosis) and diseases associated with severe impairment of autonomic control of blood pressure.
(4) Currently, there is no clinical controlled trial data on the safety and efficacy of sildenafil in the following populations. For such patients, prescriptions should be made with caution:
① Patients who have had myocardial infarction, shock or life-threatening arrhythmia in the last 6 months.
② Patients with resting hypotension (blood pressure below 90/50 mmHg) or hypertension (blood pressure above 170/110 mmHg).
③ Patients with unstable angina due to heart failure or coronary heart disease.
④ Patients with retinitis pigmentosa (a small number of patients with this disease have hereditary abnormalities of retinal phosphodiesterase).
⑤ Patients with sickle cell anemia or related anemia.
(5) After the product was approved for marketing abroad, there were a few reports of prolonged erections (more than 4 hours) and abnormal erections (painful erections lasting more than 6 hours). If the erection lasts for more than 4 hours, the patient should seek medical attention immediately. If the abnormal erection is not treated immediately, the penile tissue may be damaged and may lead to permanent loss of erectile function.
(6) Taking the protease inhibitor Ritonavir at the same time will significantly increase the blood concentration of sildenafil (AUC increased by 11 times). Patients taking Ritonavir should use sildenafil with caution. There is very limited information on the effects of high blood concentrations of sildenafil on subjects. It is only known that visual abnormalities are more common at high doses. Some healthy subjects taking high doses of sildenafil (200-800 mg) reported decreased blood pressure, syncope, and prolonged erection. In order to reduce the possibility of adverse events in patients taking Ritonavir, it is recommended to reduce their sildenafil dosage.
Precautions
1. General matters: When diagnosing erectile dysfunction, its underlying cause should be identified, and appropriate treatment plans should be determined after a comprehensive medical examination. Before giving sildenafil to patients, the following important issues should be noted:
(1) PDE5 (phosphodiesterase type 5) inhibitors should be used with caution when used in combination with alpha-blockers. PDE5 inhibitors (including this product) and alpha-blockers are both vasodilators and have the effect of lowering blood pressure. When vasodilators are used in combination, it can be expected that the effects on blood pressure may be cumulative. In some patients, the combination of these two types of drugs can significantly lower blood pressure and cause symptoms of hypotension (such as dizziness, lightheadedness, and fainting).
(2) Patients should have reached a stable state of α-blocker treatment before receiving sildenafil treatment. Patients who take α-blockers alone to treat hemodynamic instability have an increased risk of developing hypotension symptoms after taking PDE5 inhibitors in combination.
(3) For patients who have reached a stable state after receiving α-blocker treatment, PDE5 inhibitors should be started at the lowest dose.
(4) For patients who are already taking an ideal dose of PDE5 inhibitors, α-blocker treatment should start at the lowest dose. Taking PDE5 inhibitors at the same time may further lower blood pressure as the dose of α-blockers is gradually increased.
(5) The safety of combined use of PDE5 inhibitors and α-blockers may be affected by other factors, including insufficient intravascular volume and other antihypertensive drugs.
(6) Sildenafil causes systemic vasodilation and may enhance the antihypertensive effect of other antihypertensive drugs.
(7) The main clinical trials included patients who were taking multiple antihypertensive drugs at the same time. Another independent drug interaction study showed that when hypertensive patients taking 5 mg or 10 mg of amlodipine were given 100 mg of this product, the systolic and diastolic blood pressures were further reduced by an average of 8 mmHg and 7 mmHg.
(8) When patients with benign prostatic hyperplasia (BPH) took the α-blocker doxazosin (4 mg) and sildenafil (25 mg) simultaneously, supine systolic and diastolic blood pressures were further reduced by an average of 7 mmHg each. If a higher dose of sildenafil and doxazosin (4 mg) were taken simultaneously, some patients were reported to experience symptoms of orthostatic hypotension within 1-4 hours after taking the medication.
Patients receiving sildenafil concurrently with sildenafil therapy may cause hypotension in some patients.
If it exceeds 25 mg, it should not be taken within 4 hours of taking alpha-blockers.
(9) It is currently unknown whether sildenafil is safe for patients with bleeding disorders and active peptic ulcers.
(10) Sildenafil should be used with caution in patients with the following diseases: penile anatomical deformity (such as penile deviation, cavernous fibrosis, Peyronie’s disease), diseases that are prone to cause abnormal penile erection (such as sickle cell anemia, multiple myeloma, leukemia). The safety and effectiveness of other treatments for erectile dysfunction combined with this product have not been studied. Therefore, combined use is not recommended.
(11) Whether used alone or in combination with aspirin, this product has no effect on human bleeding time. In in vitro experiments, this product enhances the anti-aggregation effect of sodium nitroprusside (a nitric oxide donor) on human platelets. In anesthetized rabbits, the combination of heparin and sildenafil has an additive effect on the prolongation of bleeding time, but similar human studies have not been conducted.
2. Patient Information:
(1) Physicians should explain to patients that sildenafil should not be taken simultaneously with nitrates (regardless of whether the latter are taken regularly or intermittently). (2) Physicians should inform patients that sildenafil has the potential to enhance the antihypertensive effect of α-blockers and other antihypertensive drugs. Taking sildenafil and α-blockers simultaneously may cause hypotension symptoms in some patients. When sildenafil and α-blockers need to be used together, the patient should have reached a stable state of α-blocker treatment before sildenafil treatment, and sildenafil should be started at the lowest dose.
(3) Doctors should explain to patients that sexual activity has potential risks to the heart when cardiovascular risk factors are present. If patients experience symptoms such as angina, dizziness, or nausea at the beginning of sexual activity, they should stop the activity and discuss these situations with their doctor.
(4) Doctors should inform patients that if they experience sudden vision loss in one or both eyes, they should immediately stop taking all phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil citrate tablets, and consult a doctor. This situation may be a manifestation of non-arteritic anterior ischemic optic neuropathy (NAION), a disease that can cause vision loss, including permanent loss. Rare reports of NAION related to medication time have been reported in all post-marketing applications of PDE5 inhibitors. It cannot be determined whether these events are directly related to the use of PDE5 inhibitors or related to other factors. Doctors should inform patients who have experienced unilateral NAION that their risk of NAION occurring again is increased regardless of whether vasodilator drugs such as PDE5 inhibitors have adverse effects on them.
(5) Doctors should inform patients that if hearing loss or impairment occurs suddenly, they should stop taking PDE5 inhibitors (including this product) and seek medical attention as soon as possible. Such events may be accompanied by tinnitus and dizziness, which have been reported to be temporally related to the use of PDE5 inhibitors (including this product). However, it is not certain whether such events are directly related to the use of PDE5 inhibitors or other factors.
(6) Doctors should warn patients: After the product was approved for marketing abroad, there were a small number of reports of prolonged erections (more than 4 hours) and abnormal erections (painful erections lasting more than 6 hours). If the erection lasts for more than 4 hours, the patient should seek medical attention immediately. If the abnormal erection is not treated immediately, the penile tissue may be damaged and may lead to permanent loss of erectile function.
(7) Doctors 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 does not protect against sexually transmitted diseases. Patients should be informed of measures to prevent sexually transmitted diseases (including human immunodeficiency virus, HIV) as appropriate.
3. Use in pregnant and lactating women: Sildenafil is not suitable for women.
4. Use in children: Sildenafil is not suitable for newborns and children.
5. Medication for the elderly: The clearance rate of sildenafil in healthy elderly volunteers (≥65 years old) is reduced. Considering that higher blood drug concentrations may increase both efficacy and the occurrence of adverse events, the starting dose is preferably 25 mg.
6. Drug overdose:
(1) When healthy volunteers were given a single dose of up to 800 mg, adverse events were similar to those at lower doses, but the incidence and severity were increased.
(2) When drug overdose occurs, routine supportive therapy should be taken as needed. Because sildenafil has a high binding rate to plasma proteins and is not cleared from the urine, renal dialysis will not increase the clearance rate.
Drug interactions
1. Effects of other drugs on sildenafil:
(1) In vitro experiments: This product is metabolized mainly through cytochrome P4503A4 (main pathway) and 2C9 (minor pathway). Therefore, inhibitors of these isozymes will reduce the clearance of sildenafil, while inducers of these isozymes will increase the clearance of sildenafil.
(2) In vivo study: When healthy volunteers took 50 mg of this product and 800 mg of cimetidine (a nonspecific cytochrome P450 inhibitor) simultaneously, the plasma sildenafil concentration increased by 56%.
(3) When a single dose of sildenafil 100 mg was co-administered with erythromycin, a specific inhibitor of cytochrome P4503A4 (500 mg twice a day for 5 days to reach steady state), the area under the concentration-time curve (AUC) of sildenafil increased by 182%. In addition, in a study conducted in healthy male volunteers, when the HIV protease inhibitor saquinavir (another CYP4503A4 inhibitor) reached steady state (1200 mg three times a day), taking a single dose of 100 mg of sildenafil increased the Cmax of the latter by 140% and the AUC by 210%.
(4) Sildenafil does not affect the pharmacokinetics of saquinavir. The above effects may be greater for more potent CYP4503A4 inhibitors such as ketoconazole and itraconazole. Population data from clinical trials also showed that the clearance of sildenafil was reduced when used in combination with CYP4503A4 inhibitors (such as ketoconazole, erythromycin, and cimetidine).
(5) In another study conducted on healthy male volunteers, when the HIV protease inhibitor retonavir (a highly effective inhibitor of CYP450) reached steady state (500 mg, twice a day), a single dose of 100 mg sildenafil increased the latter’s Cmax by 300% (4 times) and AUC by 1000% (11 times). 24 hours after taking the drug, the plasma sildenafil concentration was still close to 200 ng/ml, while it was only about 5 ng/ml when sildenafil was used alone. This is consistent with the significant effect of retonavir on many CYP450 substrates. This product does not affect the pharmacokinetics of retonavir.
(6) Although the interaction between sildenafil and other protease inhibitors has not been studied, it can be predicted that co-administration will increase the plasma concentration of sildenafil.
(7) A study in healthy male volunteers found that when a steady-state dose of sildenafil (80 mg three times daily) was co-administered with a steady-state dose of the endothelin receptor antagonist bosentan (125 mg twice daily, a moderate inducer of CYP3A4, CYP2C9, and possibly also a moderate inducer of cytochrome P4502C19), the sildenafil AUC decreased by 63% and the sildenafil Cmax decreased by 55%. It is predictable that the concomitant use of a strong CYP3A4 inducer such as rifampicin would cause a greater decrease in plasma sildenafil levels.
(8) A single dose of antacid (magnesium hydroxide/aluminum hydroxide) has no effect on the bioavailability of this product.
Pharmacokinetic data of patients in clinical trials showed that CYP4502C9 inhibitors (such as tolbutamide, warfarin), CYP4502D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide drugs and thiazide diuretics, angiotensin converting enzyme inhibitors, calcium channel blockers, etc., have no effect on the pharmacokinetics of sildenafil. Loop diuretics and potassium-sparing diuretics can increase the AUC of sildenafil’s active metabolite (N-desmethylsildenafil) by 62%, while non-selective beta-blockers increase it by 102%. These effects on sildenafil metabolites will not cause clinical changes.
2. Effects of sildenafil on other drugs:
(1) In vitro experiments: This product is a weak inhibitor of cytochrome P4501A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50>150μM). Since the peak plasma concentration of sildenafil after taking the recommended dose is about 1μM, sildenafil will not change the clearance of the substrates of these isozymes.
(2) In vivo study: When hypertensive patients took sildenafil (100 mg) and amlodipine 5 mg or 10 mg simultaneously, supine systolic blood pressure was further reduced by an average of 8 mmHg and diastolic blood pressure was further reduced by an average of 7 mmHg.
(3) No significant interaction was found between tolbutamide (250 mg) and warfarin (40 mg), which are metabolized by CYP4502C9, and sildenafil.
(4) Sildenafil (50 mg) does not increase the prolonged bleeding time caused by aspirin (150 mg).
A study in healthy male volunteers showed that sildenafil (100 mg) did not affect the steady-state pharmacokinetics of the HIV protease inhibitors saquinavir and ritonavir, both of which are substrates of CYP4503A4. Steady-state doses of sildenafil (80 mg three times daily) caused a 50% increase in the AUC and a 42% increase in the Cmax of bosentan (125 mg twice daily).
3. Effect of sildenafil on blood pressure when taking nitroglycerin together: Pharmacokinetic studies of healthy volunteers taking a single oral dose of sildenafil 100 mg showed that the sildenafil content in plasma was about 2 ng/mL (peak concentration was about 440 ng/mL) after 24 hours. For patients over 65 years old, with liver damage (such as cirrhosis), severe renal damage (clearance rate <30 mL/min), and taking erythromycin or strong CYP3A4 inhibitors at the same time, the sildenafil content in plasma 24 hours after taking it was 3-8 times higher than that of healthy volunteers. Although the sildenafil content in plasma after 24 hours is much lower than the peak concentration, the safety of taking nitrates at the same time is still unknown.
4. Effect of sildenafil on blood pressure when taking alpha-blockers at the same time: Three double-blind, placebo-controlled, randomized, double-crossover trials evaluated the interaction between sildenafil and doxazosin, an alpha-adrenergic blocker.
5. Effect of sildenafil on blood pressure when taken simultaneously with antihypertensive drugs: Oral administration of sildenafil 100 mg together with amlodipine 5 mg or 10 mg can reduce supine systolic and diastolic blood pressure by an average of 8 mmHg and 7 mmHg in hypertensive patients.
6. Effect of sildenafil on blood pressure when taken with alcohol: 50mg sildenafil does not affect the hypotensive effect of alcohol (0.5/kg) on healthy volunteers (average maximum blood alcohol content is 0.08%). When alcohol is used alone, the maximum reduction in systolic blood pressure is 17.4mmHg, while when used in combination with sildenafil, the maximum reduction is 18.5mmHg. When alcohol is used alone, the maximum reduction in diastolic blood pressure is 11.1mmHg, while when used in combination with sildenafil, the maximum reduction is 17.2mmHg. No reports of postural dizziness or orthostatic hypotension were found. This experiment did not examine the maximum recommended dose of sildenafil of 100mg.
Pharmacological Action
This product is an oral medication for the treatment of erectile dysfunction. It is the citrate of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE 5 ).
1. Mechanism of action:
(1) The physiological mechanism of penile erection involves the release of nitric oxide (NO) in the corpus cavernosum of the penis during sexual stimulation. NO activates guanylate cyclase, leading to an increase in cyclic guanosine monophosphate (cGMP) levels, which relaxes the smooth muscles in the corpus cavernosum and allows blood to flow in. Sildenafil has no direct relaxant effect on the isolated human corpus cavernosum, but it can enhance the effect of nitric oxide (NO) by inhibiting type 5 phosphodiesterase (PDE 5 ) that breaks down cGMP in the corpus cavernosum. When sexual stimulation causes local NO release, sildenafil inhibits PDE 5 to increase cGMP levels in the corpus cavernosum, relax smooth muscles, and allow blood to flow into the corpus cavernosum. In the absence of sexual stimulation, the recommended dose of sildenafil has no effect.
(2) In vitro experiments show that sildenafil is selective for PDE 5. Its effect on PDE 5 is much stronger than that on other known phosphodiesterases ( 10 times that on PDE 6 , more than 80 times that on PDE 1 , and more than 700 times that on PDE 2 , PDE 3 , PDE 4 , PDE 7 , PDE 8 , PDE 9 , PDE 10 , and PDE 11 ). Sildenafil’s selectivity for PDE 5 is about 4000 times that for PDE 3 , which is important because the latter is related to the control of myocardial contractility. Sildenafil’s effect on PDE 5 is about 10 times that on PDE 6. PDE 6 is an enzyme present in the retina. Sildenafil’s relatively low selectivity for PDE 6 is the reason why it causes color vision abnormalities at high doses or high plasma concentrations.
(3) In addition to human corpus cavernosum smooth muscle, PDE 5 is also found in platelets, blood vessels and visceral smooth muscle, skeletal muscle, brain, heart, liver, kidney, lung, spleen, prostate, bladder, testicle, and seminal vesicle . Sildenafil’s inhibition of PDE 5 in these tissues may be the basis for its enhancement of nitric oxide’s antiplatelet aggregation effect (in vitro experiments), inhibition of platelet thrombosis (in vivo experiments), and relaxation of peripheral arteries and veins (in vivo experiments).
2. Effect of sildenafil on erectile response: In 8 double-blind, placebo-controlled crossover trials on patients with organic or psychological erectile dysfunction, erectile hardness and duration were measured by a durometer and it was found that after taking sildenafil, erections caused by sexual stimulation were improved compared with the placebo group. Most trials evaluated the efficacy of sildenafil about 60 minutes after taking the drug. The durometer measurement found that the erectile response generally increased with the increase of sildenafil dose and plasma concentration. A test to determine the duration of drug effect showed that the effect could last up to 4 hours, but the reaction was weaker than at 2 hours.
3. Effect of sildenafil on blood pressure: A single oral dose of 100 mg of sildenafil in healthy male volunteers resulted in a decrease in sitting blood pressure (average maximum decrease of 8.3/5.3 mmHg). The blood pressure drop was most obvious 1-2 hours after taking the drug, and there was no difference from the placebo group 8 hours after taking the drug. The effects of 25 mg, 50 mg or 100 mg of sildenafil on blood pressure were similar, so this effect was unrelated to drug dose and blood drug concentration. This effect was greater in patients taking nitrates at the same time.
4. Effects of sildenafil on cardiac parameters:
(1) No clinically significant electrocardiographic changes occurred in normal male volunteers after taking a single oral dose of 100 mg of this product.
(2) Related studies provide data on the effects of sildenafil on cardiac output. In a small-scale, open, uncontrolled preliminary trial, 8 patients with stable ischemic heart disease were intravenously injected with a total of 40 mg of sildenafil in 4 doses under Swan-Ganz catheter monitoring. The results of the trial are shown in Table 3. At rest, the patients’ systolic and diastolic blood pressure decreased by 7% and 10%, respectively, compared with baseline. The resting right atrial pressure, pulmonary artery pressure, pulmonary artery wedge pressure and cardiac output decreased by an average of 28%, 28%, 20% and 7%, respectively. Although the blood concentration at this intravenous dose is 2-5 times higher than the average peak blood concentration of a single oral dose of 100 mg sildenafil in healthy male volunteers, the hemodynamic response during exercise in the above patients still exists.
(3) In a double-blind trial, 144 patients with erectile dysfunction and exercise-limiting chronic angina who were not receiving long-term oral nitrate therapy were randomly given a single dose of placebo or 100 mg of sildenafil 1 hour before exercise testing. The primary endpoint was the duration of limiting angina in the evaluable population. The mean duration of limiting angina (adjusted by baseline) in the sildenafil group (N=70) and the placebo group was 423.6 seconds and 403.7 seconds, respectively. This result demonstrated that the effect of sildenafil on the primary endpoint was statistically not inferior to that of placebo.
5. Effect of sildenafil on vision: After a single oral dose of 100mg and 200mg of the drug, Farnsworth-Munsell-100 color test revealed transient blue/green color discrimination abnormalities, which occurred in a dose-related manner; the peak effect time was close to the peak blood concentration time. This phenomenon is consistent with the drug’s inhibitory effect on PDE 6. PDE 6 is involved in light conduction in the retina. Studies have shown that when taking the drug at 2 times the maximum recommended dose, this product has no effect on vision, intraocular pressure, and optic disc size.
6. Effect of sildenafil on sperm: Oral administration of 100 mg of sildenafil to healthy volunteers had no effect on sperm mortality and morphology.
Toxicological effects
1. Genotoxicity: Sildenafil was negative in the following tests: in vitro mutagenicity test on bacteria and Chinese hamster ovary cells, in vitro genetic toxicity test on human lymphocytes, and in vivo mouse micronucleus test.
2. Reproductive toxicity:
(1) No reproductive toxicity was observed in female rats given 60 mg/kg body weight/day of sildenafil for 36 days and male rats given 102 days of sildenafil (the AUC value achieved at this dose is more than 25 times the AUC of human males). After a single oral dose of 100 mg of sildenafil was administered to healthy volunteers, sperm motility and morphology were not affected.
(2) During the organogenesis period, rats and rabbits received up to 200 mg/kg body weight/day of sildenafil, and no evidence of teratogenicity, embryotoxicity or fetotoxicity was found. This dose, calculated on a mg/m2 basis, is equivalent to 20 times and 40 times the MRHD of a 50kg subject, respectively. In the prenatal and postnatal developmental studies in rats, the safe dose (NOAEL) was 30 mg/kg body weight/day after 36 days of administration.
(3) The AUC of non-pregnant rats at this dose is approximately 20 times the AUC of humans. There are no adequate and strictly controlled trials of sildenafil in pregnant women.
3. Carcinogenicity: When male and female rats were given sildenafil for 24 months, the total volume under the drug-time curve (AUCs) of unbound sildenafil and its main metabolites in the body reached 29 and 42 times the maximum recommended human dose (MRHD) of 100 mg for males, respectively, and no carcinogenicity was observed. When mice were given sildenafil for 18-21 months, no carcinogenicity was observed when the dose was as high as 10 mg/kg/body weight/day (maximum tolerated dose (MTD)), which is about 0.6 times the MRHD calculated in mg/ m2 .
Pharmacokinetics
This product is rapidly absorbed after oral administration, with an absolute bioavailability of approximately 41% (25-63%). Its pharmacokinetic parameters are proportional to the dose within the recommended dose range. Elimination is mainly through liver metabolism (cytochrome P450 isoenzyme 3A4 pathway), generating an active metabolite with properties similar to sildenafil. When potent inhibitors of cytochrome P450 isoenzyme 3A4 (CYP4503A4) (such as erythromycin, ketoconazole, itraconazole) and nonspecific inhibitors of cytochrome P450 (CYP450) such as cimetidine are used in combination with sildenafil, it may lead to an increase in sildenafil plasma levels.
The elimination half-life of sildenafil and its metabolites is approximately 4 hours.
1. Absorption and distribution: This product is absorbed rapidly. The peak plasma concentration (Cmax) is reached 30 to 120 minutes (median 60 minutes) after oral administration on an empty stomach. When taken with a high-fat diet, the absorption rate is reduced, the peak time (Tmax) is delayed by an average of 60 minutes, and the Cmax decreases by an average of 29%. The average steady-state distribution volume (Vss) of sildenafil is 105 liters, indicating that it is distributed in tissues. About 96% of sildenafil and its main circulating metabolites (N-demethylated products) are bound to plasma proteins. The protein binding rate is unrelated to the total drug concentration. According to the results of semen examination of healthy volunteers 90 minutes after taking the drug, it can be inferred that the amount of sildenafil in the semen of patients after taking the drug is less than 0.001% of the dose.
2. Metabolism and excretion:
(1) Sildenafil is mainly cleared by the liver’s microsomal enzymes cytochrome P4503A4 (primary pathway) and cytochrome P4502C9 (secondary pathway). The main circulating metabolite is the N-desmethylated form of sildenafil, which will be further metabolized. The N-desmethylated metabolite has a similar PDE selectivity to sildenafil, and in vitro, its effect on PDE5 is about 50% of that of sildenafil. The plasma concentration of this metabolite is about 40% of that of sildenafil, so about 20% of the pharmacological effects of sildenafil come from its metabolites.
(2) After oral or intravenous administration, sildenafil is excreted mainly in the form of metabolites from the feces (about 80% of the oral dose), and a small part is excreted from the urine (about 13% of the oral dose). The pharmacokinetic parameter values of patients obtained through population pharmacokinetic studies are similar to those of healthy volunteers.
3. Pharmacokinetics in special populations
(1) Elderly: The clearance of sildenafil in healthy elderly volunteers (≥65 years old) was reduced, and the area under the concentration-time curve (AUC) of sildenafil and its active N-desmethyl metabolite was approximately 84% and 107% higher than that of young healthy volunteers (18-45 years old), respectively. Taking into account the effect of age differences on plasma protein binding, the AUC of free (not bound to plasma proteins) sildenafil and its active N-desmethyl metabolite increased by 45% and 57%, respectively.
(2) Renal insufficiency: The pharmacokinetics of a single oral dose of sildenafil 50 mg did not change in volunteers with mild (creatinine clearance = 50-80 ml/min) and moderate (creatinine clearance = 30-49 ml/min) renal impairment. In volunteers with severe renal impairment (creatinine clearance 30 ml/min), the clearance of sildenafil was reduced, and the area under the concentration-time curve (AUC) and Cmax were almost doubled compared with volunteers of the same age group without renal impairment. In addition, compared with subjects with normal renal function, the AUC and Cmax of sildenafil N-desmethyl metabolites were significantly increased in subjects with severe renal impairment, increasing by 200% and 79%, respectively.
(3) Hepatic impairment: The clearance of sildenafil was reduced in volunteers with cirrhosis (Child-Pugh grade A and B), and the AUC and Cmax increased by 84% and 47%, respectively, compared with volunteers of the same age group without liver damage. The pharmacokinetics of sildenafil in patients with severe liver damage (Child-Pugh grade C) have not been studied.
Therefore, patients over 65 years old, with liver damage and severe renal damage will have elevated plasma sildenafil levels. The starting dose for these patients is preferably 25 mg.
Storage method
Sealed, store in a cool, dry place.
Validity
36 months
Implementation Standards
Sildenafil citrate tablets: National Food and Drug Administration National Drug Standard YBH00722017.