Date of approval.
Date of revision.
Sildenafil Citrate Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Sildenafil Citrate Tablets
English name: Sildenafil Citrate Tablets
Hanyu Pinyin: Juyuansuan Xidinafei Pian
Ingredients
The main ingredient of this product is sildenafil citrate.
Chemical name: 1-{4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1hydro-pyrazolo[4,3d]pyrimidin-5-yl)benzenesulfonyl}-4-methylpiperazine citrate.
Chemical structure formula.
Molecular formula: C22H30N6O4S-C6H8O7
Molecular weight: 666.70
Characteristic】.
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
Sildenafil is indicated for the treatment of erectile dysfunction.
Specification
According to C22H30N6O4S (1) 25mg (2) 50mg (3) 100mg
Dosage]
For most patients, the recommended dose is 50 mg, to be taken as needed about 1 hour before sexual activity; however, it can be taken at any time between 0.5 and 4 hours before sexual activity. The dose may be increased to 100 mg (maximum recommended dose) or decreased to 25 mg based on efficacy and tolerability, and may be taken up to once daily. The recommended dose of sildenafil is not effective in the absence of sexual stimulation.
The following factors are associated with increased plasma sildenafil levels (AUC): age 65 years or older (40% increase), hepatic impairment (e.g., cirrhosis, 80% increase), severe renal impairment (creatinine clearance <30 mL/min, 100% increase), concomitant use of potent cytochrome P4503A4 inhibitors [ketoconazole, itraconazole (200% increase), erythromycin (182% increase), saquinavir 182%), and saquinavir (210% increase)]. Because higher plasma levels may increase both efficacy and the incidence of adverse events, a starting dose of 25 mg is appropriate for these patients.
A study in healthy subjects free of HIV infection showed that ritonavir resulted in a significant increase in sildenafil blood levels (11-fold increase in AUC, see [Drug Interactions]). In view of this, it is recommended that patients taking concomitant ritonavir not exceed a maximum dose of 25 mg per 48-hour period.
Sildenafil potentiates the antihypertensive effect of nitrate; therefore, sildenafil is contraindicated in patients taking any dose of nitric oxide donor and nitrate.
When a combination of sildenafil and an alpha-blocker is required, the patient has been treated with an alpha-blocker to achieve a steady state prior to sildenafil therapy and sildenafil should be started at the lowest dose (see [Drug Interactions]).
[Adverse Reactions].
The following are discussed in more detail in other sections of the instruction manual.
– Cardiovascular [see Warnings – Cardiovascular
– Prolonged erection and abnormal penile erection [see Warnings – Prolonged erection and abnormal penile erection].
– Effects on the eyes [see Information for Patients – Effects on the Eyes
– Hearing loss [see Information for Patients-Loss of Hearing
– Hypotension in combination with alpha-blockers or anti-hypertensives [see Precautions – Hypotension in combination with alpha-blockers or anti-hypertensives
– Adverse reactions due to combination with ritonavir [see WARNINGS – Adverse Reactions Due to Combination with Ritonavir].
– Combination with other PDE5 inhibitors or other erectile dysfunction treatments [see Precautions – Combination with other PDE5 inhibitors or other erectile dysfunction treatments
– Effects on bleeding [see PRECAUTIONS – Effects on Bleeding].
– Patient counseling recommendations regarding sexually transmitted diseases [see Patient Information – Patient Counseling Recommendations Regarding Sexually Transmitted Diseases].
The most common adverse reactions reported in clinical trials (>2%) included headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness, and rash.
Premarketing Experience.
Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in clinical trials for one drug cannot be directly compared with the incidence of adverse reactions observed in clinical trials for another drug, nor does it reflect the incidence observed in clinical practice.
In clinical trials worldwide, more than 3700 patients (aged 19 to 87 years) took sildenafil. More than 550 of these patients were treated for more than one year.
In placebo-controlled clinical trials, there was no significant difference in the rate of discontinuation due to adverse reactions in the trial group (2.5%) compared to the placebo group (2.3%). Adverse reactions were generally transient and mostly mild to moderate in nature.
In all forms of clinical trials, adverse events reported by patients in the trial groups were generally similar. In fixed-dose trials, the occurrence of some adverse events increased with increasing dose. Often, flexible dose trials better reflect the recommended dose usage of the drug, and the nature of adverse events seen in the trials is similar to that of fixed dose trials.
In fixed-dose trials, the incidence of some adverse reactions increases with increasing dose. The flexible dose test better reflects the recommended dose usage of the drug, and the nature of the adverse events seen in the test is similar to that of the fixed dose test. When doses were taken above the recommended dose range, adverse reactions were similar to those described in Table 1 below, but generally occurred more frequently.
Table 1. Fixed-dose phase II/III clinical trials in which
Adverse reactions reported by ≥2% of patients and more in the trial group than in the placebo group
Adverse reactions 25 mg
(n=312) 50mg
(n=511) 100mg
(n=506) Placebo group
(n=607) Headache 16%21%28%7% flushing 10%19%18%2% dyspepsia 3%9%17%2% visual abnormalities* 1%2%11%1% nasal congestion 4%4%9%2% back pain 3%4%4%2% myalgia 2%2%4%1% nausea 2%3%3%1% dizziness 3%4%3%2% rash 1%2%3%1%* visual abnormalities: mild to moderate, transient, manifesting primarily as pale vision, but also enhanced sensitivity to light or blurred vision.
In flexible-dose, placebo-controlled, 2-26-week clinical trials, the following adverse reactions were reported in patients who took the product as recommended (on-demand) and took sildenafil at least once a week.
Table 2. On-demand, flexible-dose phase II/III clinical trials in which
Adverse reactions reported by ≥2% of patients and more in the trial group than in the placebo group
Adverse reactions Percentage of patients reporting adverse events Trial group (N = 734) Placebo (N = 725) Headache 16% 4% Flushing 10% 1% Dyspepsia 7% 2% Nasal congestion 4% 2% Visual abnormalities* 3% 0% Back pain 2% Dizziness 2% 1% Rash 2% 1% * Visual abnormalities: mild and transient, mainly manifesting as blurred vision, but also increased sensitivity to light or visual blurring. In these trials, only one patient discontinued the drug due to visual abnormalities.
The following adverse reactions occurred at the same rate in the trial group as in the placebo group, although the incidence >2%. They were: respiratory tract infection, back pain, flu symptoms and arthralgia.
In the fixed-dose trial, dyspepsia (17%) and visual abnormalities (11%) were more common in the 100 mg dose group than in the lower dose group. Above the recommended dose range, the presentation of adverse events was similar to the previous, but reported with increased frequency.
The following are adverse events that occurred at an incidence <2% in controlled clinical trials. It is not certain whether their occurrence was due to sildenafil. Those events that may be related to dosing are included here, but minor events and inaccurate reports have been omitted.
Systemic reactions: facial edema, photosensitivity reaction, shock, malaise, pain, chills, accidental falls, abdominal pain, allergic reactions, chest pain, accidental injury.
Cardiovascular system: angina pectoris, atrioventricular block, migraine, syncope, tachycardia, palpitations, hypotension, postural hypotension, myocardial ischemia, cerebral thrombosis, cardiac arrest, heart failure, electrocardiogram abnormalities, cardiomyopathy.
Digestive system: vomiting, tongue inflammation, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, dry mouth, abnormal liver function, rectal bleeding, gingivitis.
Blood and lymphatic system: anemia and leukopenia.
Metabolic and nutritional: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemic reaction, hypernatremia.
Skeletal muscular system: arthritis, arthropathy, myalgia, tendon rupture, tenosynovitis, bone pain, muscle weakness, synovitis.
Neurological system: ataxia, hypertonia, neuralgia, neuropathy, sensory abnormalities, tremor, vertigo, depression, insomnia, drowsiness, dream abnormalities, diminished reflexes, sensory retardation.
Respiratory system: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, phlegm, cough.
Skin and its appendages: urticaria, herpes simplex, pruritus, sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.
Special senses: sudden hearing loss or loss, dilated pupils, conjunctivitis, photophobia, tinnitus, ocular pain, earache, ocular hemorrhage, cataract, dry eyes.
Genitourinary system: cystitis, nocturia, dysuria, urinary incontinence, abnormal ejaculation, genital edema and lack of orgasm, enlarged mammary glands.
An analysis based on the safety database of controlled clinical trials showed no significant difference in adverse reactions in patients taking sildenafil with or without concomitant antihypertensive medication. This was a retrospective analysis and was not sufficient to detect any pre-specified differences in adverse reactions.
Postmarketing experience.
The following adverse reactions were identified during the use of sildenafil after marketing approval. Because these adverse reactions were spontaneously reported from an uncertain population size, it is difficult to reliably estimate the incidence of these adverse reactions and the causal relationship with drug exposure. These events were selected for inclusion either based on their severity, frequency of reporting, lack of a clear reason for selection, or a combination of these factors.
Cardiovascular and Cerebrovascular System The following serious cardiovascular, cerebrovascular, and vascular adverse events with a temporal association with sildenafil administration have been reported postmarketing: myocardial infarction, sudden cardiac death, ventricular arrhythmias, cerebral hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhage, and pulmonary hemorrhage. The majority, though not all, of these patients had pre-existing cardiovascular risk factors. Many of the reported events occurred during or just after sexual activity; some occurred shortly after sildenafil administration before sexual activity. Other reported events occurred a few hours or even days after taking the drug or sexual activity. It is not possible to determine whether these events were directly related to sildenafil or to sexual activity, pre-existing cardiovascular disease, a combination of these factors, or other factors (see “WARNINGS” for important cardiovascular information).
In an analysis of a double-blind placebo-controlled clinical trial, over 700 individuals/year in the placebo group and over 1300 individuals/year in the sildenafil group were observed. The analysis showed no difference in the incidence of myocardial infarction (MI) or cardiovascular mortality in the sildenafil group compared to the placebo group. The incidence of myocardial infarction in men in the sildenafil and placebo groups was 1.1 cases per 100 persons/year. The mortality rate of cardiovascular events in men in the sildenafil and placebo groups was 0.3 cases per 100 persons/year.
Hematologic and lymphatic system: Vascular obstruction crisis: In a small study of patients with early terminated, pulmonary arterial hypertension (PAH) secondary to sickle cell disease using REVATIO (sildenafil citrate injection), the occurrence of vascular obstruction crisis requiring hospitalization was more commonly reported after patients used sildenafil than in the placebo group. The clinical relevance of vascular obstruction crisis to men with ED treated with sildenafil citrate tablets is unknown.
Special sensations.
Hearing: There have been individual case reports of sudden post-marketing hearing loss or hypoacusis that have been temporally correlated with the use of PDE5 inhibitors, including sildenafil citrate tablets. In some of these patients, there may be underlying disease or other factors that cause ear-related adverse events, and follow-up information is limited in many cases. It is not possible to determine whether sudden hearing loss or loss is directly related to the use of sildenafil citrate tablets, whether it is related to a patient’s pre-existing risk factors for hearing loss, or whether a combination of these two factors or other causes exist (see the “[Precautions]/Information for Patients” section).
Other Events
Other adverse reactions reported post-marketing that have been temporally associated with the administration of sildenafil but were not seen in premarketing studies are
Neurologic: seizures, seizure recurrence, anxiety, transient generalized amnesia.
Respiratory: epistaxis.
Genitourinary: prolonged erection, abnormal erection (see “WARNINGS”) and hematuria.
Vision: diplopia, transient visual loss or loss of vision, red eye or eye congestion, burning sensation in the eye, swelling and pressure in the eye, increased intraocular pressure, retinal vasculopathy or hemorrhage, vitreous detachment, peri-macular edema, etc.
There have been rare reports of non-arteritic anterior ischemic optic neuropathy (NAION) associated with time of administration in post-marketing applications of PDE5 inhibitors, including sildenafil citrate tablets, a condition that can cause vision loss, including permanent loss, in most, but not all, of these patients who have an underlying anatomic or vascular basis or risk for developing NAION factors, including but not limited to: low cup-to-disc ratio, age over 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. (See the “Precautions”/Information for Patients” section).
Hematolymphatic system: The clinical relevance of vascular obstruction crisis to men with ED treated with sildenafil citrate tablets is not known.
Table 3 Adverse reactions (ADRs) by systemic organ (SOC) and CIOMS frequency, with ADRs in decreasing order of medical severity within each CIOMS frequency and SOC classification
System Organ Classification Very common (≥1/10) Common (greater than or equal to 1/100 to <1/10) Rare (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Infection and Infestation Rhinitis Immune System Abnormalities Hypersensitivity Reactions Neurologic Abnormalities Headache Dizziness Drowsiness Seizures*, Seizure Recurrence*, Syncope Eye Abnormalities Blurred vision, visual abnormalities, blue vision ocular pain, photophobia, flash hallucinations, chromatic vision, ocular congestion, visual illumination ocular edema, ocular swelling, ocular dryness, ocular fatigue, iridophthalmia, xerophthalmia, ocular abnormalities, conjunctival congestion, ocular irritation, ocular sensory abnormalities, eyelid edema cardiac abnormalities tachycardia, palpitations vascular abnormalities hot flashes, flushing hypotension respiratory, thoracic, and mediastinal abnormalities nasal congestion epistaxis, sinus congestion throat tightness Nasal dryness, nasal edema Gastrointestinal abnormalities Nausea, dyspepsia GERD, vomiting, epigastric pain, dry mouth Decreased oral sensation Skin and subcutaneous tissue abnormalities Rash Musculoskeletal and connective tissue abnormalities Myalgia Limb pain Reproductive system and breast abnormalities Abnormal erections*
Prolonged erection time General abnormalities and administration site conditions Heat sensation irritability check Accelerated heart rate *ADR monitored after marketing.
[Contraindicated].
Nitrates: Due to the known effects of sildenafil citrate tablets on the nitric oxide/cGMP pathway (see [Pharmacology and Toxicology]), sildenafil may enhance the antihypertensive effects of nitrates. Therefore, it is contraindicated in patients taking nitric oxide donors (e.g., any form of organic nitrates or organic nitrites), either regularly or intermittently.
Combination of PDE5 inhibitors (including sildenafil) with guanylate cyclase agonists (e.g., liothyronine) is contraindicated because it may cause symptomatic hypotension.
It is not known when it is safe for patients to take nitrates (if needed) after sildenafil. Based on pharmacokinetic data in healthy volunteers, plasma sildenafil concentrations after 24 hours of a single oral dose of 100 mg are approximately 2 ng/ml (peak blood concentration of approximately 440 ng/ml) (see [Pharmacokinetics]). Plasma sildenafil concentrations after 24 hours are 3 to 8 times higher than in healthy volunteers: age 65 years or older, hepatic impairment (e.g., cirrhosis), severe renal impairment (creatinine clearance below 30 ml/min), and concomitant use of strong inhibitors of cytochrome P4503A4 such as erythromycin. Although sildenafil blood levels 24 hours after dosing are well below peak concentrations, it is not known whether nitrates can be safely administered at this time.
It is contraindicated in patients with known hypersensitivity to any of the components of this product.
Warnings
Cardiovascular: Sexual activity is potentially dangerous to the heart of patients with pre-existing cardiovascular disease. Therefore, medications for erectile dysfunction, including sildenafil, should generally not be used in patients whose cardiovascular status makes them unfit for sexual activity.
A transient decrease in supine blood pressure (mean maximum decrease of 8.4/5.5 mmHg) occurs in healthy volunteers due to vasodilation of the body circulation by sildenafil (see [Pharmacologic Toxicology]). Usually, in most patients, the results of such effects can be discounted, but physicians should still carefully consider whether such vasodilatory effects may have adverse consequences in patients with concomitant cardiovascular disease, especially during sexual activity, before prescribing.
Patients with the following underlying conditions may be particularly sensitive to the effects of vasodilators, including sildenafil – including left ventricular outflow tract obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and conditions associated with severe impairment of autonomic control of blood pressure. Such patients should be administered with caution.
There is no information from controlled clinical trials on the safety and efficacy of sildenafil in the following populations. Caution should be exercised in prescribing to such patients.
Patients who have had a myocardial infarction, shock, or life-threatening arrhythmia within the last 6 months.
Patients with resting state hypotension (blood pressure below 90/50mmHg) or hypertension (blood pressure above 170/110mmHg).
Patients with heart failure or unstable angina pectoris in coronary artery disease
Patients with pigmentary uveitis (a minority of patients with this condition have a genetic abnormality of retinal phosphodiesterase).
Patients with sickle cell anemia or related anemia.
Prolonged erection time and abnormal penile erection: A small number of reports of prolonged erection time (more than 4 hours) and abnormal erection (painful erection more than 6 hours) have been reported after foreign approval of sildenafil citrate tablets for marketing. Patients should seek immediate medical attention if an erection lasts longer than 4 hours. If abnormal erections are not treated immediately, penile tissue may be damaged and permanent loss of erectile function may result. Sildenafil should be used with caution in patients with anatomical abnormalities of the penis (e.g., penile deviation, cavernous fibrosis, Peyronie’s disease) and diseases that predispose to abnormal penile erections (e.g., sickle cell anemia, multiple myeloma, leukemia). However, there are no controlled clinical data on the safety or efficacy of this product in patients with sickle cell anemia or related anemia.
Adverse effects due to combination with ritonavir: Concomitant administration of the protease inhibitor ritonavir significantly increased the blood concentration of sildenafil (11-fold increase in AUC). Sildenafil should be used with caution in patients taking ritonavir. Information on the effects of high blood levels of sildenafil in subjects is limited, with only visual abnormalities known to be more common at higher doses. Some healthy subjects taking high doses of sildenafil (200-800 mg) have reported decreased blood pressure, syncope, and prolonged erection time. To reduce the likelihood of adverse events in patients taking ritonavir, it is recommended that the dose of sildenafil be reduced.
Precautions]
General matters The diagnosis of erectile dysfunction should be accompanied by identification of the underlying cause and a thorough medical examination to determine the appropriate treatment plan.
Before administering sildenafil to patients, some important issues should be noted as follows.
Hypotension in combination with alpha-blockers or anti-hypertensive drugs
Alpha blockers: Caution should be exercised when combining PDE5 (phosphodiesterase type 5) inhibitors with alpha blockers, which are both vasodilators and have blood pressure-lowering effects. When vasodilators are combined, cumulative effects on blood pressure can be expected. In some patients, the combination of these two classes of drugs can significantly lower blood pressure, resulting in symptoms of hypotension (e.g., dizziness, lightheadedness, fainting) (see [Drug Interactions]).
The following should also be noted.
-Patients should have reached a stable state of alpha-blocker therapy before receiving sildenafil. Patients treated with alpha blockers alone for hemodynamic instability are at increased risk of hypotensive symptoms with the combination of PDE5 inhibitors.
– PDE5 inhibitors should be started at the lowest dose in patients who have reached steady state on alpha blocker therapy.
– For patients already taking the ideal dose of a PDE5 inhibitor, treatment with an alpha blocker should be started at the lowest dose. Concomitant administration of PDE5 inhibitors may further lower blood pressure as the dose of alpha blockers is gradually increased.
– The safety of combining PDE5 inhibitors with alpha blockers may be affected by other factors, including intravascular volume insufficiency and other antihypertensive drugs.
Antihypertensive drugs: Sildenafil causes vasodilation in the body circulation and may enhance the antihypertensive effect of other antihypertensive drugs.
Patients taking multiple antihypertensive drugs concomitantly were included in the main clinical trial. Another independent drug interaction study showed a further reduction in systolic and diastolic blood pressure by an average of 8 mmHg and 7 mmHg in hypertensive patients taking 5 mg or 10 mg amlodipine plus a 100 mg dose of sildenafil citrate tablets (see [Drug Interactions]).
In three drug interaction studies in which patients with benign prostatic hyperplasia (BPH) treated to steady state with doxazosin were concurrently administered the alpha blockers doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 mg), further reductions in supine blood pressure were observed in these study populations by a mean of 7/7 mmHg, 9/5 mmHg, and 8 /If higher doses of sildenafil and doxazosin (4 mg) were administered concomitantly, postural hypotension symptoms, including dizziness and lightheadedness, without syncope, were reported in individual patients within 1 to 4 hours of administration. Concomitant administration of sildenafil to patients given alpha-blocker therapy may cause symptoms of hypotension in some patients. Therefore, sildenafil doses that exceed 25 mg should not be taken within 4 hours of alpha-blocker administration. Safety database analysis showed no difference in side effects in patients taking sildenafil with or without antihypertensive drugs.
Post-marketing experience with prolonged erection and abnormal erections associated with sildenafil has been reported. Patients should be seen immediately if an erection lasts longer than 4 hours. If abnormal erections are not addressed immediately, penile tissue may be damaged and permanent loss of erectile function may result. Combination with Other PDE5 Inhibitors or Other Erectile Dysfunction Treatments: The safety and efficacy of combining other PDE5 inhibitors, or other sildenafil-containing drugs for pulmonary arterial hypertension (PAH) (Revatio), or other treatments for erectile dysfunction with this product has not been studied. Such combinations may further lower blood pressure. Therefore, combination use is not recommended.
Effects on bleeding: Post-marketing bleeding events have been reported in patients who have taken sildenafil citrate tablets. A causal relationship between this product and these events has not been established. Sildenafil citrate tablets had no effect on the duration of bleeding in humans, either alone or in combination with aspirin. However, in in vitro experiments, sildenafil citrate tablets potentiated the antiplatelet coagulation effect of sodium nitroprusside, a nitric oxide donor, in humans. In addition, the combination of heparin and sildenafil had a superimposed effect on the prolongation of bleeding time in rabbits under anesthesia, but no similar human studies have been performed. The safety of sildenafil citrate tablets in patients with bleeding disorders and in patients with active peptic ulcers is unknown.
Information for Patients
Physicians should explain to patients that concomitant administration of sildenafil with nitrate is prohibited (regardless of whether the latter is administered regularly or intermittently).
Physicians should inform patients about the potential for sildenafil to potentiate the antihypertensive effects of alpha-blockers and other antihypertensive drugs. Concomitant administration of sildenafil and an alpha blocker may cause hypotension in some patients. When a combination of sildenafil and an alpha blocker is needed, the patient should have reached a stable state on alpha blocker therapy before sildenafil treatment and sildenafil should be started at the lowest dose.
The physician should explain to the patient the potential cardiac risks of sexual activity in the presence of pre-existing cardiovascular risk factors. If symptoms such as angina, dizziness, or nausea occur at the beginning of sexual activity, sexual activity must be discontinued and these conditions discussed with the physician.
Effects on the eyes: Patients should be advised by their physician to discontinue all phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil citrate tablets, immediately and consult with their physician if they experience sudden loss of vision in one or both eyes. This condition may be a manifestation of non-arteritic anterior ischemic optic neuropathy (NAION), a condition that can cause vision loss including permanent loss, and rare reports of NAION associated with time of administration have been reported in all post-marketing applications of PDE5 inhibitors. An observational case-crossover study assessed the risk of NAION when using PDE5 inhibitor analogs just prior to the onset of NAION (within 5 half-lives) by comparing it to the use of PDE5 inhibitors over a prior period of time. The results showed an approximately 2-fold increased risk of NAION with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported consistent results with a risk estimate of 2.27 (95% CI 0.99, 5.20). other risk factors for NAION (e.g., optic disc “crowding”) may be involved in NAION occurring in these studies. rare post-marketing reports and correlations between PDE5 inhibitor use and NAION in observational studies have not confirmed a causal relationship between PDE5 inhibitor use and NAION. use and a causal relationship with NAION (see [Adverse Reactions]/Postmarketing Experience section). Published literature indicates that the annual incidence of NAION in the general population is 2.5 to 11.8 cases per 100,000 men (≥50 years of age). In case of sudden vision loss, patients should be advised to stop taking sildenafil and consult a physician immediately. For patients with potential risk factors for NAION, physicians should consider whether they may be adversely affected by the use of PDE5 inhibitors. Individuals who have already had NAION are at increased risk of NAION recurrence. Physicians should inform patients who have had monocular NAION that they are at increased risk of reoccurring NAION regardless of whether vasodilators such as PDE5 inhibitors may adversely affect them. In these patients, PDE5 inhibitors (including sildenafil) should be used with caution only if the expected benefit exceeds the risk. Patients with optic disc “crowding” are also considered to be at higher risk of NAION than the general population, but the evidence is not yet sufficient to support screening potential users of PDE5 inhibitors (including this product) for this rare disease.
There are no controlled clinical data on the safety or efficacy of this product in patients with retinitis pigmentosa, a small proportion of whom have retinal phosphodiesterase genetic disorders.
It cannot be determined whether these events are directly related to the application of PDE5 inhibitors or to other factors. Physicians should inform patients who have experienced monocular NAION that they are at increased risk of reoccurring NAION regardless of whether vasodilators such as PDE5 inhibitors may have adverse effects on them (see section “Adverse Reactions”/Postmarketing Experience/Special Feelings”).
Hearing loss: Patients should be advised by their physicians to stop taking PDE5 inhibitors (including this product) and seek medical attention as soon as possible if sudden hearing loss or loss occurs. Such events can be accompanied by tinnitus and dizziness and have been reported to be time-related to the use of PDE5 inhibitors, including sildenafil citrate tablets. However, it is uncertain whether such events are directly related to the use of PDE5 inhibitors or other factors (see [Adverse Reactions]/Premarketing Experience section and Postmarketing Experience section).
Physicians should warn patients that there have been a small number of reports of prolonged erections (longer than 4 hours) and abnormal erections (painful erections longer than 6 hours) following foreign approval of sildenafil citrate tablets for marketing. Patients should seek immediate medical attention if an erection lasts longer than 4 hours. If abnormal erections are not treated immediately, penile tissue may be damaged and permanent loss of erectile function may result.
Patients should be advised 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 has not been studied.
Patient counseling advice regarding sexually transmitted diseases: Sildenafil is not protective against sexually transmitted diseases. Patients should be advised on measures to prevent sexually transmitted diseases (including human immunodeficiency virus, HIV) as appropriate.
Effects on the ability to drive and use machines
Because dizziness and visual changes have been reported in clinical studies of sildenafil, patients should be informed of their possible reactions to sildenafil before driving and operating machinery. The effect of sildenafil on the ability to drive and use machines has not been studied.
For Pregnant and Lactating Women
Pregnant women
Sildenafil is not indicated for use in women.
There are no data available on the use of sildenafil in pregnant women to detect a risk of adverse developmental outcomes associated with the drug. Animal reproduction studies with sildenafil have shown no adverse developmental outcomes during organogenesis in rats and rabbits receiving doses 16 and 32 times the maximum recommended human dose (MRHD, 100 mg/day, based on mg/m2), respectively.
Lactating women
Sildenafil is not indicated for use in women.
Limited data suggest that sildenafil, as well as its active metabolites, are secreted into human breast milk. No information is available on the effect of such breast milk on children and on the effect of sildenafil on breast milk production.
[For Children] Sildenafil is not indicated for use in newborns and children.
Geriatric Use]
Sildenafil clearance is reduced in healthy elderly volunteers (≥65 years of age) (see “[Pharmacokinetics]: Pharmacokinetics in Special Populations”). Given that higher blood levels may increase both efficacy and adverse events, a starting dose of 25 mg is appropriate (see [Dosage]).
Drug Interactions
Effects of other drugs on sildenafil
In vitro experiments: Sildenafil citrate tablets are metabolized mainly through cytochrome P450 (CYP) 3A4 (primary pathway) and 2C9 (secondary pathway). Therefore, inhibitors of these isoenzymes decrease the clearance of sildenafil, while inducers of these isoenzymes increase the clearance of sildenafil. Potent inhibitors of erythromycin or CYP3A4 (e.g., saquinavir, ketoconazole, itraconazole) and non-specific inhibitors of CYP, such as cimetidine, are associated with increased sildenafil plasma levels when combined with sildenafil.
In vivo test: concomitant administration of sildenafil citrate tablets 50 mg and cimetidine (a non-specific cytochrome P450 inhibitor) 800 mg to healthy volunteers resulted in a 56% increase in plasma sildenafil concentrations.
When a single dose of sildenafil 100 mg was combined with erythromycin, an intermediate inhibitor of CYP3A4 (500 mg twice a day for 5 days to reach steady state), the area under the drug-time curve (AUC) of sildenafil was increased by 182%. In addition, in a study in healthy male volunteers, when the HIV protease inhibitor saquinavir (another CYP4503A4 inhibitor) was at steady-state (1200 mg three times a day), a single dose of 100 mg sildenafil increased the Cmax of the latter by 140% and the AUC by 210%. Sildenafil did not affect the pharmacokinetics of saquinavir. These effects may be greater with more potent CYP4503A4 inhibitors such as ketoconazole and itraconazole. Population pharmacokinetic data from clinical trials also suggest that clearance of sildenafil is reduced when combined with CYP4503A4 inhibitors such as ketoconazole, erythromycin, and cimetidine (see [DOSAGE]).
In another study in healthy male volunteers, when the HIV protease inhibitor ritonavir (a potent inhibitor of CYP450) was at steady state (500 mg twice a day), a single dose of 100 mg sildenafil increased the Cmax of the latter by 300% (4-fold) and the AUC by 1000% (11-fold). This is consistent with the significant effect of ritonavir on many CYP450 substrates. Sildenafil citrate tablets do not affect the pharmacokinetics of ritonavir (see [DOSAGE]).
Although the interaction of sildenafil in combination with other protease inhibitors has not been studied, it is predicted that the combination will increase the plasma concentration levels of sildenafil.
A study in male healthy volunteers found that when a steady-state dose of sildenafil (80 mg three times daily) was combined with a steady-state dose of the endothelin receptor antagonist bosentan (125 mg twice daily, a moderately potent inducer of CYP3A4 , CYP2C9, and possibly cytochrome P4502C19), sildenafil AUC decreased 63% and sildenafil Cmax decreased by 55%. Sildenafil increased the AUC of bosentan by 50% and Cmax by 42%. Concomitant administration of a potent CYP3A4 inducer such as rifampin would be predicted to cause an even greater decrease in plasma sildenafil levels.
Single-dose antacids (magnesium hydroxide/aluminium hydroxide) had no effect on the bioavailability of sildenafil citrate tablets.
In healthy male volunteers, there is no evidence that azithromycin (500 mg daily for 3 days) affects the AUC, Cmax, Tmax, clearance rate constant, or half-life of sildenafil or its major circulating metabolites.
Pharmacokinetic data from patients in clinical trials indicate that CYP4502C9 inhibitors (e.g., tosylbutazone, warfarin), CYP4502D6 inhibitors (e.g., selective 5-hydroxytryptamine reuptake inhibitors, tricyclic antidepressants), thiazides and thiazide diuretics, angiotensin-converting enzyme inhibitors, and calcium channel blockers have no effect on sildenafil The pharmacokinetics of sildenafil were not affected. Tab diuretics and potassium-preserving diuretics increased the AUC of the active sildenafil metabolite (N-desmethyl sildenafil) by 62%, while non-selective β-blockers increased it by 102%. These effects on sildenafil metabolites do not cause clinical changes.
Effects of sildenafil on other drugs
In vitro experiments: Sildenafil citrate tablets are a weak inhibitor of cytochrome P4501A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50> 150 μM). Since the peak plasma concentration is approximately 1 μM after the recommended dose of sildenafil, sildenafil does not alter the clearance of these isoenzymatic substrates.
In vivo test: In hypertensive patients taking both sildenafil (100 mg) and amlodipine 5 mg or 10 mg, systolic blood pressure was further reduced by a mean of 8 mmHg in the supine position and diastolic blood pressure by a mean of 7 mmHg.
No significant interactions were found with sildenafil for toluenosulfonylurea (250 mg) and warfarin (40 mg), which are metabolized by CYP4502C9.
Sildenafil (50 mg) did not increase the prolonged bleeding time due to aspirin (150 mg).
Effect of sildenafil on blood pressure when taken with alcohol
Sildenafil (50 mg) did not enhance the hypotensive effect of alcohol (0.5 g/kg) at a mean maximum plasma alcohol concentration of 0.08% in healthy volunteers. The maximum reduction in systolic blood pressure was 17.4 mmHg with alcohol alone and 18.5 mmHg with concomitant sildenafil. diastolic blood pressure was 11.1 mmHg with alcohol alone and 17.2 mmHg with concomitant sildenafil. no postural dizziness or postural hypotension was reported. The trial did not evaluate the maximum recommended dose of 100 mg of sildenafil.
A study in healthy male volunteers showed that sildenafil (100 mg) did not affect the pharmacokinetics at steady state 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 AUC and a 42% increase in Cmax for bosentan (125 mg twice daily).
Effect of sildenafil on blood pressure when combined with nitroglycerin
Pharmacokinetic testing of a single oral dose of sildenafil 100 mg in healthy volunteers showed a plasma sildenafil level of approximately 2 ng/mL after 24 h (peak concentration of approximately 440 ng/mL). In patients older than 65 years, with hepatic impairment (e.g., cirrhosis), severe renal impairment (clearance <30 mL/min), and taking concomitant erythromycin or strong CYP3A4 inhibitors, plasma levels of sildenafil after 24 h were 3-8 times higher than in healthy volunteers. Although plasma levels of sildenafil after 24 h were well below peak concentrations, the safety of concomitant nitrates is not known.
Effect of sildenafil on blood pressure with concomitant administration of alpha-blockers
In three drug interaction studies in which patients with benign prostatic hyperplasia (BPH) treated with doxazosin to steady state received concomitant administration of the alpha blockers doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 mg), further reductions in supine blood pressure were observed in these study populations by a mean of 7/7 mmHg, 9/5 mmHg, and 8 /If higher doses of sildenafil and doxazosin (4 mg) were administered concomitantly, postural hypotension symptoms, including dizziness and lightheadedness, without syncope, were reported in individual patients within 1 to 4 hours of administration. Concomitant administration of sildenafil to patients treated with alpha-blockers may cause symptoms of hypotension in some patients. Therefore, sildenafil doses above 25 mg should not be taken within 4 hours of an alpha-blocker. Analysis of the safety database showed no difference in side effects in patients taking sildenafil with or without antihypertensive drugs.
Three double-blind, placebo-controlled, randomized, double-crossover trials evaluated the interaction of sildenafil with doxazosin, an alpha-adrenergic blocker.
Study 1: Sildenafil and Doxazosin
A two-cycle crossover single-dose trial of 100 mg oral sildenafil or placebo enrolled four healthy men with benign prostatic hyperplasia. Subjects took doxazosin for at least 14 consecutive days, followed by 100 mg of sildenafil or placebo. After combining the data from these 4 subjects (see table below), the dose of sildenafil was reduced to 25 mg. 17 subjects then took 25 mg of sildenafil or placebo with doxazosin 4 mg (15 subjects) or 8 mg (2 subjects). The mean age of the subjects was 66.5 years.
The mean maximum reduction in baseline (95% CI) systolic blood pressure net of placebo for the 17 subjects taking 25 mg of sildenafil or placebo was as follows.
Mean maximum reduction in systolic blood pressure after placebo at baseline (mm Hg) Sildenafil citrate tablets
25 mg flat 7.4 (-0.9, 15.7) upright 6.0 (-0.8, 12.8) The mean change in upright systolic blood pressure relative to baseline for subjects taking either 25 mg sildenafil or placebo plus doxazosin is shown in Figure 1.
Figure 1 Change in baseline values of mean upright systolic blood pressure
Blood pressure was measured before or 15 min, 30 min, 45 min, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 h after administration of sildenafil or placebo. Extremes were defined as having one or more time points of upright systolic blood pressure <85 mmHg or a decrease in upright systolic blood pressure from baseline >30 mmHg. None of the subjects taking 25 mg of sildenafil had upright systolic blood pressure below 85 mmHg. No blood pressure-related serious adverse events were reported in this group.
In the four subjects taking 100 mg of sildenafil in the first part of the trial, there was one blood pressure-related serious adverse event (postural hypotension that developed 35 minutes after dosing and persisted for 8 hours) and two mild adverse events that may have been related to blood pressure (dizziness, headache, and fatigue 1 hour after dosing and dizziness, lightheadedness, and nausea 4 hours after dosing). No syncope was reported. the mean maximum baseline reductions in prone and upright systolic blood pressure were 14.8 mmHg and 21.5 mmHg, respectively, in four subjects. two had upright systolic blood pressure < 85 mmHg, one had low baseline upright systolic blood pressure, and the other had baseline upright hypotension.
Study 2: Sildenafil and Doxazosin
A two-cycle crossover single-dose trial of 50 mg oral sildenafil or placebo enrolled 20 healthy men with benign prostatic hyperplasia. Subjects took doxazosin for at least 14 consecutive days followed by either 50 mg of sildenafil or placebo. The doxazosin dose was 4 mg (17) or 8 mg (3). The mean age of the subjects was 63.9 years.
Twenty subjects took 50 mg of sildenafil, but only 19 took placebo. The trial was terminated due to a hypotensive adverse event in one patient, who was taking minoxidil, a potent vasodilator, during the trial.
The mean maximum reduction in baseline (95% CI) systolic blood pressure net of placebo for the 19 subjects taking sildenafil or placebo was as follows.
Mean maximum reduction in systolic blood pressure after placebo at baseline (mm Hg) Sildenafil citrate tablets 25 mg (95% CI) flat lying 9.08 (5.48, 12.68) upright 11.62 (7.34, 15.90) The mean change in upright systolic blood pressure relative to baseline for subjects taking either 50 mg sildenafil or placebo plus doxazosin is shown in Figure 2.
Figure 2 Change in baseline values of mean upright systolic blood pressure
The time points for blood pressure measurements were consistent with the first trial of doxazosin. Two subjects had an upright systolic blood pressure <85 mmHg. Moderate adverse events were reported in these 2 subjects, with hypotension occurring 1 hour after administration of 50 mg sildenafil and resolving at approximately 7.5 hours. The baseline reduction in upright systolic blood pressure was > 30 mmHg in 1 subject on 50 mg sildenafil and in the other subject on either 50 mg sildenafil or placebo. no serious adverse events potentially related to blood pressure were reported. No syncope was reported.
Study 3: Sildenafil and Doxazosin
A three-cycle crossover single-dose trial of 100 mg oral sildenafil or placebo enrolled 20 healthy men with benign prostatic hyperplasia. For the first cycle of the trial, subjects took doxazosin (open-label) for at least 14 consecutive days, followed by a single dose of 50 mg of sildenafil along with doxazosin. The trial was terminated if the subject failed to complete the first dose cycle. The first dose cycle was skipped if the subject successfully completed the previous doxazosin interaction test without significant hemodynamic adverse events. Doxazosin was administered for at least 7 days after the first dose cycle, followed by 100 mg of sildenafil or placebo and concomitant doxazosin 4 mg (14 subjects) or 8 mg (6 subjects). The mean age of the subjects was 66.4 years.
A total of 25 subjects were screened. Two were discontinued at the first cycle of the study, one failed the dose pre-screening test, and the other developed moderate adverse event-symptomatic hypotension 30 minutes after taking 50 mg of sildenafil. Of the 20 subjects who ultimately participated in the trial, 13 successfully completed the first cycle of the trial and 7 successfully completed the previous doxazosin trial (with 50 mg of sildenafil).
The mean maximum reduction in baseline (95% CI) systolic blood pressure net of placebo for the 20 subjects taking 100 mg of sildenafil or placebo was as follows.
Mean maximum reduction in systolic blood pressure after placebo at baseline (mm Hg) Sildenafil citrate tablets
100 mg flat 7.9 (4.6, 11.1) upright 4.3 (-1.8, 10.3) The mean change in upright systolic blood pressure relative to baseline for subjects taking either 100 mg sildenafil or placebo plus doxazosin is shown in Figure 3.
Figure 3 Change in baseline values of mean upright systolic blood pressure
The time points for blood pressure measurements were consistent with the previous trials of doxazosin. Three subjects had an upright systolic blood pressure <85 mmHg. All three subjects experienced mild adverse events after 100 mg of sildenafil, with vasodilation and dizziness accompanying the decrease in upright systolic blood pressure. Baseline reductions in upright systolic blood pressure were > 30 mmHg in four subjects on 100 mg sildenafil, > 30 mmHg in one subject on placebo, and > 30 mmHg in one subject on either 100 mg sildenafil or placebo. No serious adverse events potentially related to blood pressure were reported, and one reported moderate vasodilation on both 50 and 100 mg of sildenafil. No syncope was reported.
Effect of Sildenafil on Blood Pressure When Taken Concomitantly with Antihypertensives
Sildenafil 100 mg given orally with amlodipine 5 mg or 10 mg reduced systolic and diastolic blood pressure by a mean of 8 mmHg and 7 mmHg in the prone position in hypertensive patients.
Effect of sildenafil on blood pressure when taken concomitantly with alcohol
Sildenafil 50 mg did not affect the antihypertensive effect of alcohol (0.5/kg) on healthy volunteers (mean maximum blood alcohol level of 0.08%) at a mean maximum plasma alcohol concentration of 0.08%. The maximum reduction in systolic blood pressure was 17.4 mmHg with alcohol alone and 18.5 mmHg with sildenafil. the maximum reduction in diastolic blood pressure was 11.1 mmHg with alcohol alone and 17.2 mmHg with sildenafil. no postural dizziness or upright hypotension was reported. The trial did not examine the maximum recommended dose of 100 mg of sildenafil.
[Drug Overdose].
Single doses up to 800 mg in healthy volunteers resulted in adverse events similar to those at lower doses, but with an increased incidence and severity.
When an overdose occurs, conventional supportive therapy should be administered as needed. Because sildenafil is highly bound to plasma proteins and is not cleared from the urine, renal dialysis does not increase the clearance rate.
Pharmacology and Toxicology
Pharmacological effects
Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).
During sexual stimulation, the physiological mechanism of penile erection includes the release of nitric oxide (NO) from the penile corpus cavernosum, which activates guanylate cyclase and leads to increased cGMP levels, resulting in smooth muscle relaxation and blood flow in the corpus cavernosum. Sildenafil enhances the effect of NO by inhibiting PDE5, which breaks down cGMP in the corpus cavernosum, and therefore has no direct relaxing effect on the isolated human corpus cavernosum. When local NO release is induced by sexual stimulation, sildenafil inhibition of PDE5 increases the level of cGMP in the cavernous body, relaxing the smooth muscle and allowing blood to flow into the cavernous body. In the absence of sexual stimulation, the recommended dose of sildenafil is not effective.
In vitro tests have shown that sildenafil is selective for PDE5. It is much more potent against PDE5 than against other known phosphodiesterases (10 times more potent than against PDE6, more than 80 times more potent than against PDE1, and more than 700 times more potent than against PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). Sildenafil is approximately 4000 times more selective for PDE5 than for PDE3, which is involved in the regulation of myocardial contractility. The effect of sildenafil on PDE5 is only 10 times greater than that on PDE6, an enzyme present in the retina and involved in the photoconversion pathway of the retina. The relatively low selectivity of sildenafil for PDE6 is the reason for its abnormal color vision at high doses or high plasma concentrations.
In addition to human cavernous smooth muscle, PDE5 is also present in platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicles. The inhibition of PDE5 in these tissues by sildenafil may underlie its potentiation of the anti-platelet aggregation effect of nitric oxide (in vitro assay), inhibition of platelet thrombosis, and diastole of peripheral arterioles (in vivo assay).
Toxicological studies
Genotoxicity: Bacterial revertant mutation test, Chinese hamster ovary cell mutagenesis test, human peripheral blood lymphocyte chromosome aberration test, and in vivo bone marrow micronucleus test in mice were all negative.
Reproductive toxicity: No reproductive toxicity was observed in male and female rats given sildenafil 60 mg/kg/day for 36 and 102 consecutive days, respectively (the AUC of male rats at this dose was approximately 25 times more than the AUC of males in clinical practice). Sperm motility and morphology were not affected following a single oral dose of sildenafil 100 mg in healthy volunteers. Embryo-fetal developmental toxicity tests showed no teratogenicity, embryotoxicity or fetal toxicity in rats and rabbits given sildenafil at 200 mg/kg/day (approximately 16 and 32 times the maximum recommended human dose (MRHD) in 50 kg subjects, respectively, converted to body surface area). In a perinatal toxicity test in rats, the dose level at which no clinical adverse effects were observed (NOAEL) was 30 mg/kg/day (approximately 2 times the MRHD of a 50 kg subject converted to body surface area) when administered for 36 consecutive days.
Carcinogenicity: No carcinogenicity was observed in female and male rats given sildenafil for 24 consecutive months. The AUCs of the free drug and its major metabolites in rats at this carcinogenicity test dose were approximately 20 and 38 times higher, respectively, than those in male subjects given MRHD (100 mg/person). No carcinogenicity was observed in mice given sildenafil 10 mg/kg/day (maximum tolerated dose in mice, converted to body surface area, about 0.4 times the MRHD in 50 kg subjects) for 18-21 months.
[Pharmacokinetics].
Sildenafil citrate tablets are rapidly absorbed after oral administration, with an absolute bioavailability of about 41% (25-63%). The pharmacokinetic parameters are proportional to the dose within the recommended dose range. Elimination is mainly by hepatic metabolism (cytochrome P450 isoenzyme 3A4 pathway), producing an active metabolite with properties similar to those of sildenafil. Potent inhibitors of cytochrome P450 isoenzyme 3A4 (CYP4503A4) (e.g., erythromycin, ketoconazole, itraconazole) and nonspecific inhibitors of cytochrome P450 (CYP450) such as cimetidine may cause elevated plasma levels of sildenafil when combined with sildenafil (see [DOSAGE]). The elimination half-life of sildenafil and its metabolites is approximately 4 hours.
The mean blood concentrations following a single oral dose of sildenafil 100 mg in healthy male volunteers are shown in Figure 4.
Figure 4 Mean plasma sildenafil concentrations in healthy male volunteers
Absorption and distribution.
Sildenafil citrate tablets are rapidly absorbed. Peak plasma concentrations (Cmax ) are reached after 30 to 120 minutes (median 60 minutes) of oral administration in the fasted state. When taken with a high-fat diet, the rate of absorption was reduced, with a mean delay in time to peak (Tmax) of 60 minutes and a mean decrease in Cmax of 29%. However, the degree of absorption was not significantly affected (11% decrease in AUC). In vitro inhibition of human PDE5 enzyme activity was 50% at sildenafil concentrations of 3.5 nM. In humans, the mean maximum free plasma sildenafil concentration after a single oral dose of 100 mg sildenafil was approximately 18 ng/mL or 38 nM. The mean steady-state volume of distribution (Vss) of sildenafil was 105 liters, indicating a tissue distribution. Both sildenafil and its major circulating metabolite (N-demethylation) were approximately 96% bound to plasma proteins. The protein binding rate was independent of the total drug concentration. Based on the results of semen examination in healthy volunteers 90 minutes after dosing, it can be inferred that the amount of sildenafil in the semen after dosing is less than 0.001% of the dose.
Metabolism and excretion.
Sildenafil is primarily cleared by the microsomal enzymes cytochrome P4503A4 (primary pathway) and cytochrome P4502C9 (secondary pathway) in the liver. The major circulating metabolite is the N-demethylation of sildenafil, which will be further metabolized. the N-demethylation has a similar PDE selectivity to sildenafil, and in vitro, it is approximately 50% as potent as sildenafil for PDE5. The N-demethylation metabolite is further metabolized with a terminal half-life of approximately 4 hours.
The systemic clearance of sildenafil is 41 L/h, with a terminal half-life of 3-5 hours. Following oral or intravenous administration, sildenafil is excreted primarily as a metabolite in the feces (approximately 80% of the oral dose), with a small proportion excreted in the urine (approximately 13% of the oral dose). The values of pharmacokinetic parameters obtained from the population pharmacokinetic study were similar in patients and healthy volunteers.
Pharmacokinetics in special populations
Elderly: sildenafil clearance was reduced in healthy elderly volunteers (≥65 years) and the area under the drug-time curve (AUC) of sildenafil and its active N-desmethyl metabolite was approximately 84% and 107% higher, respectively, than in younger healthy volunteers (18 to 45 years). Taking into account the effect of age differences on plasma protein binding, the AUCs of free (unbound to plasma proteins) sildenafil and its active N-demethyl metabolite were correspondingly increased by 45% and 57%, respectively. Of all subjects in the clinical study of sildenafil citrate tablets, 18% were aged 65 years and older and 2% were aged 75 years and older. No overall differences in safety or efficacy were observed between older (age > 65 years) and younger (age < 65 years) subjects.
Renal impairment: The pharmacokinetics of a single dose of oral sildenafil 50 mg were not altered in volunteer subjects with mild (creatinine clearance = 50 to 80 ml/min) and moderate (creatinine clearance = 30 to 49 ml/min) renal impairment. In volunteer subjects with severe renal impairment (creatinine clearance £30 ml/min), the clearance of sildenafil was reduced and the area under the drug-time curve (AUC) (100%) and Cmax (88%) were almost doubled compared to volunteers in the same age group without renal impairment.
In addition, the AUC and Cmax of sildenafil N-demethyl metabolites were significantly higher in subjects with severe renal impairment, by 200% and 79%, respectively, compared to subjects with normal renal function.
Hepatic impairment: Sildenafil clearance was reduced in volunteer subjects with hepatic impairment (Child-Pugh class A and B), with an 84% and 47% increase in AUC and Cmax, respectively, compared to volunteers in the same age group without hepatic impairment. The pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh class C) have not been studied.
Therefore, age 65 years or older, hepatic impairment, and severe renal impairment result in elevated plasma sildenafil levels. A starting dose of 25 mg is appropriate for such patients (see [DOSAGE]).
Storage
Seal and store at room temperature.
Packaging
Aluminum-plastic packaging. 25mg: 5 tablets/plate x 1 plate/box; 50mg: 5 tablets/plate x 1 plate/box; 100mg: 1 tablet/plate x 1 plate/box.
Expiration date
24 months
【Execution standard
Approval number】
[Drug marketing license holder
Name: Guangzhou Long Sheng Pharmaceutical Co.
Registered Address: No. 3 Jinfengyuan Road, Science City, Guangzhou High-Tech Industrial Development Zone
Manufacturer
Company Name: Guangzhou Long Sheng Pharmaceutical Co.
Production Address: No. 3 Jinfengyuan Road, Science City, Guangzhou Hi-Tech Industrial Development Zone
Postal Code: 510670
Tel: +86-20-32086699
Product Hotline：400-6068-990
Website: http://www.regenex.com.cn