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快速起效勃起的功能障碍药物STENDRA(AVANAFIL)TABLET ORAL获FDA批准上市
STENDRA is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction ( 1) DOSAGE AND ADMINISTRATION The starting dose is 100 mg taken as early as approximately 15 minutes before sexual activity, on an as needed basis. ( 2.1) Take STENDRA no more than once a day ( 2.1) Based on efficacy and/or tolerability, the dose may be increased to 200 mg taken as early as approximately 15 minutes before sexual activity, or decreased to 50 mg taken approximately 30 minutes before sexual activity. Use the lowest dose that provides benefit ( 2.1) STENDRA may be taken with or without food ( 2.2) Do not use STENDRA with strong CYP3A4 inhibitors ( 2.3) If taking a moderate CYP3A4 inhibitor, the dose should be no more than 50 mg in a 24-hour period ( 2.3) In patients on stable alpha-blocker therapy, the recommended starting dose of STENDRA is 50 mg ( 2.3) DOSAGE FORMS AND STRENGTHS Tablets: 50 mg, 100 mg, 200 mg ( 3) CONTRAINDICATIONS Administration of STENDRA to patients using any form of organic nitrate is contraindicated ( 4.1) Hypersensitivity to any component of the STENDRA tablet ( 4.2) Administration with guanylate cyclase (GC) stimulators, such as riociguat ( 4.3) WARNINGS AND PRECAUTIONS Patients should not use STENDRA if sexual activity is inadvisable due to cardiovascular status or any other reason ( 5.1) Use of STENDRA with alpha-blockers, other antihypertensives, or substantial amounts of alcohol (greater than 3 units) may lead to hypotension ( 2.3, 5.6, 5.7) Patients should seek emergency treatment if an erection lasts greater than 4 hours ( 5.3) Patients should stop STENDRA and seek medical care if a sudden loss of vision occurs in one or both eyes, which could be a sign of Non Arteritic Ischemic Optic Neuropathy (NAION). STENDRA should be used with caution, and only when the anticipated benefits outweigh the risks, in patients with a history of NAION. Patients with a "crowded" optic disc may also be at an increased risk of NAION ( 5.4, 6.2) Patients should stop taking STENDRA and seek prompt medical attention in the event of sudden decrease or loss of hearing ( 5.5) ADVERSE REACTIONS Most common adverse reactions (greater than or equal to 2%) include headache, flushing, nasal congestion, nasopharyngitis, and back pain ( 6.1) To report SUSPECTED ADVERSE REACTIONS, contact 1-877-663-0412 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS STENDRA can potentiate the hypotensive effect of nitrates, alpha-blockers, antihypertensives, and alcohol ( 7.1) CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, erythromycin) increase STENDRA exposure ( 7.2) USE IN SPECIFIC POPULATIONS Do not use in patients with severe renal impairment ( 8.6) Do not use in patients with severe hepatic impairment ( 8.7) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 9/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE STENDRA is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction. 2 DOSAGE AND ADMINISTRATION 2.1 Erectile Dysfunction The recommended starting dose is 100 mg. STENDRA should be taken orally as needed as early as approximately 15 minutes before sexual activity. Based on individual efficacy and tolerability, the dose may be increased to 200 mg taken as early as approximately 15 minutes before sexual activity, or decreased to 50 mg taken approximately 30 minutes before sexual activity. The lowest dose that provides benefit should be used. Based on individual efficacy and tolerability, the dose may be increased to 200 mg taken as early as approximately 15 minutes before sexual activity, or decreased to 50 mg taken approximately 30 minutes before sexual activity. The lowest dose that provides benefit should be used. The maximum recommended dosing frequency is once per day. Sexual stimulation is required for a response to treatment.The maximum recommended dosing frequency is once per day. Sexual stimulation is required for a response to treatment. 2.2 Use with Food STENDRA may be taken with or without food. 2.3 Concomitant Medications Nitrates Concomitant use of nitrates in any form is contraindicated [see Contraindications (4.1)]. Alpha-Blockers If STENDRA is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating treatment with STENDRA, and STENDRA should be initiated at the 50 mg dose [see Warnings and Precautions (5.6), Drug Interactions (7.1), and Clinical Pharmacology (12.2)]. CYP3A4 Inhibitors For patients taking concomitant strong CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, and telithromycin), do not use STENDRA [see Warnings and Precautions (5.2) and Drug Interactions (7.2)]. For patients taking concomitant moderate CYP3A4 inhibitors (including erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the maximum recommended dose of STENDRA is 50 mg, not to exceed once every 24 hours [see Warnings and Precautions (5.2) and Drug Interactions (7.2)]. 3 DOSAGE FORMS AND STRENGTHS STENDRA (avanafil) is supplied as oval, pale yellow tablets containing 50 mg, 100 mg, or 200 mg avanafil debossed with dosage strength. 4 CONTRAINDICATIONS 4.1 Nitrates Administration of STENDRA with any form of organic nitrates, either regularly and/or intermittently, is contraindicated. Consistent with its known effects on the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway, STENDRA has been shown to potentiate the hypotensive effects of nitrates. In a patient who has taken STENDRA, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 12 hours should elapse after the last dose of STENDRA before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring [see Contraindications (4.1), Dosage and Administration (2.3), and Clinical Pharmacology (12.2)] . 4.2 Hypersensitivity Reactions STENDRA is contraindicated in patients with a known hypersensitivity to any component of the tablet. Hypersensitivity reactions have been reported, including pruritis and eyelid swelling. 4.3 Concomitant Guanylate Cyclase (GC) Stimulators Do not use STENDRA in patients who are using a GC stimulator, such as riociguat. PDE 5 inhibitors, includingStendra may potentiate the hypotensive effects of GC stimulators 5 WARNINGS AND PRECAUTIONS Evaluation of erectile dysfunction (ED) should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options. Before prescribing STENDRA, it is important to note the following: 5.1 Cardiovascular Risks There is a potential for cardiac risk during sexual activity in patients with pre-existing cardiovascular disease. Therefore, treatments for ED, including STENDRA, should not be used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status. Patients with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure can be particularly sensitive to the actions of vasodilators, including STENDRA. The following groups of patients were not included in clinical safety and efficacy trials for STENDRA, and therefore until further information is available, STENDRA is not recommended for the following groups: Patients who have suffered a myocardial infarction, stroke, life-threatening arrhythmia, or coronary revascularization within the last 6 months; Patients with resting hypotension (blood pressure less than 90/50 mmHg) or hypertension (blood pressure greater than 170/100 mmHg); Patients with unstable angina, angina with sexual intercourse, or New York Heart Association Class 2 or greater congestive heart failure. As with other PDE5 inhibitors STENDRA has systemic vasodilatory properties and may augment the blood pressure-lowering effect of other anti-hypertensive medications. STENDRA 200 mg resulted in transient decreases in sitting blood pressure in healthy volunteers of 8.0 mmHg systolic and 3.3 mmHg diastolic [see Clinical Pharmacology (12.2)] , with the maximum decrease observed at 1 hour after dosing. While this normally would be expected to be of little consequence in most patients, prior to prescribing STENDRA, physicians should carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity. 5.2 Concomitant Use of CYP3A4 Inhibitors STENDRA metabolism is principally mediated by the CYP450 isoform 3A4 (CYP3A4). Inhibitors of CYP3A4 may reduce STENDRA clearance and increase plasma concentrations of avanafil. For patients taking concomitant strong CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, and telithromycin), do not use STENDRA [see Drug Interactions (7.2)]. For patients taking concomitant moderate CYP3A4 inhibitors (including erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the maximum recommended dose of STENDRA is 50 mg, not to exceed once every 24 hours [see Drug Interactions (7.2)]. 5.3 Prolonged Erection Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported with other PDE5 inhibitors. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If not treated immediately, penile tissue damage and permanent loss of potency could result. STENDRA should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia). 5.4 Effects on Eye Physicians should advise patients to stop use of all PDE5 inhibitors, including STENDRA, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision including permanent loss of vision that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged ≥ 50. An observational study evaluated whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION. The results suggest an approximate 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. From this information, it is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [ ]. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged ≥ 50. An observational study evaluated whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION. The results suggest an approximate 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. From this information, it is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [ see Adverse Reactions (6.2)]. Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including STENDRA, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with "crowded" optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including STENDRA, for this uncommon condition. Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including STENDRA, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with "crowded" optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including STENDRA, for this uncommon condition. 5.5 Sudden Hearing Loss Use of PDE5 inhibitors has been associated with sudden decrease or loss of hearing, which may be accompanied by tinnitus or dizziness. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions (6)] . Patients experiencing these symptoms should be advised to stop taking STENDRA and seek prompt medical attention. 5.6 Alpha-Blockers and Other Antihypertensives Physicians should discuss with patients the potential for STENDRA to augment the blood pressure-lowering effect of alpha-blockers and other antihypertensive medications [see Drug Interactions (7.1) and Clinical Pharmacology (12.2)]. Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. Phosphodiesterase type 5 inhibitors, including STENDRA, and alpha-adrenergic blocking agents are both vasodilators with blood pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting). Consideration should be given to the following: Patients should be stable on alpha-blocker therapy prior to initiating treatment with a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors. In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose (STENDRA 50 mg). In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor. Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs [see Dosage and Administration (2) and Drug Interactions (7.1)]. 5.7 Alcohol Patients should be made aware that both alcohol and PDE5 inhibitors including STENDRA act as vasodilators. When vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., greater than 3 units) in combination with STENDRA may increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache [see Drug Interactions (7.1) and Clinical Pharmacology (12.2)] . 5.8 Combination with Other PDE5 Inhibitors or Erectile Dysfunction Therapies The safety and efficacy of combinations of STENDRA with other treatments for ED has not been studied. Therefore, the use of such combinations is not recommended. 5.9 Effects on Bleeding The safety of STENDRA is unknown in patients with bleeding disorders and patients with active peptic ulceration. In vitro studies with human platelets indicate that STENDRA potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide [NO] donor). 5.10 Counseling Patients about Sexually Transmitted Diseases The use of STENDRA offers no protection against sexually transmitted diseases. Counseling patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV), should be considered. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. STENDRA was administered to 2215 men during clinical trials. In trials of STENDRA for use as needed, a total of 493 patients were exposed for greater than or equal to 6 months, and 153 patients were treated for greater than or equal to 12 months. In three randomized, double-blind, placebo-controlled trials lasting up to 3 months in duration, the mean age of patients was 56.4 years (range from 23 to 88 years). 83.9% of patients were White, 13.8% were Black, 1.4% Asian, and < 1% Hispanic. 41.1% were current or previous smokers. 30.6% had diabetes mellitus. The discontinuation rate due to adverse reactions for patients treated with STENDRA 50 mg, 100 mg, or 200 mg was 1.4%, 2.0%, and 2.0%, respectively, compared to 1.7% for placebo-treated patients. Table 1 presents the adverse reactions reported when STENDRA was taken as recommended (on an as-needed basis) from these 3 clinical trials. Table 1: Adverse Reactions Reported by Greater Than or Equal to 2% of Patients Treated with STENDRA From 3 Placebo-Controlled Clinical Trials Lasting 3 Months for STENDRA Use as Needed
In an open-label, long-term extension study of two of these randomized, double-blind, placebo-controlled trials, the total duration of treatment was up to 52 weeks. Among the 712 patients who participated in this open-label extension study, the mean age of the population was 56.4 years (range from 23 to 88 years). The discontinuation rate due to adverse reactions for patients treated with STENDRA (50 mg, 100 mg, or 200 mg) was 2.8%. In this extension trial, all eligible patients were initially assigned to STENDRA 100 mg. At any point during the trial, patients could request to have their dose of STENDRA increased to 200 mg or decreased to 50 mg based on their individual response to treatment. In total, 536 (approximately 75%) patients increased their dose to 200 mg and 5 (less than 1%) patients reduced their dose to 50 mg. Table 2 presents the adverse reactions reported when STENDRA was taken as recommended (on an as-needed basis) in this open-label extension trial. Table 2: Adverse Reactions Reported by Greater Than or Equal to 2% of Patients Treated With STENDRA in an Open-Label Extension Trial
The following events occurred in less than 1% of patients in the three placebo-controlled 3-month clinical trials and/or the open-label, long-term extension study lasting 12 months. A causal relationship to STENDRA is uncertain. Excluded from this list are those events that were minor, those with no plausible relation to drug use, and reports too imprecise to be meaningful. Body as a whole — edema peripheral, fatigue Cardiovascular — angina, unstable angina, deep vein thrombosis, palpitations Digestive — gastritis, gastroesophageal reflux disease, hypoglycemia, blood glucose increased, alanine aminotransferase increased, oropharyngeal pain, stomach discomfort, vomiting Musculoskeletal — muscle spasms, musculoskeletal pain, myalgia, pain in extremity Nervous — depression, insomnia, somnolence, vertigo Respiratory — cough, dyspnea exertional, epistaxis, wheezing Skin and Appendages – pruritus Urogenital – balanitis, erection increased, hematuria, nephrolithiasis, pollakiuria, urinary tract infection In an additional randomized, double-blind, placebo-controlled study lasting up to 3 months in 298 men who had undergone bilateral nerve-sparing radical prostatectomy for prostate cancer, the mean age of patients was 58.4 years (range 40 – 70). Table 3 presents the adverse reactions reported in this study. Table 3: Adverse Reactions Reported by Greater than or Equal to 2% of Patients Treated with STENDRA in a Placebo-Controlled Clinical Trial Lasting 3 Months in Patients Who Underwent Bilateral Nerve-Sparing Radical Prostatectomy
Table 4: Adverse Reactions Reported by ≥ 2% of Patients Treated with STENDRA in a Placebo-Controlled Clinical Trial Lasting 2 Months to Determine the Time to Onset of Effect (Study 3)
6.2 Postmarketing Experience Ophthalmologic: Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors [see Warnings and Precautions (5.4) and Patient Counseling Information (17.6)]. 7 DRUG INTERACTIONS 7.1 Potential for Pharmacodynamic Interactions with STENDRA Nitrates Administration of STENDRA to patients who are using any form of organic nitrate is contraindicated. In a clinical pharmacology trial, STENDRA was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken STENDRA, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 12 hours should elapse after the last dose of STENDRA before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring [see Contraindications (4.1), Dosage and Administration (2.3), and Clinical Pharmacology (12.2)] . Alpha-Blockers Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including STENDRA, and alpha-adrenergic blocking agents are both vasodilators with blood pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting) [see Warnings and Precautions (5.6), Dosage and Administration (2.3), and Clinical Pharmacology (12.2)]. Antihypertensives PDE5 inhibitors, including STENDRA, are mild systemic vasodilators. A clinical pharmacology trial was conducted to assess the effect of STENDRA on the potentiation of the blood pressure-lowering effects of selected antihypertensive medications (amlodipine and enalapril). Additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single 200 mg dose of STENDRA with these agents compared with placebo [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.2)]. Alcohol Both alcohol and PDE5 inhibitors, including STENDRA, act as vasodilators. When vasodilators are taken in combination, blood pressure-lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., greater than 3 units) in combination with STENDRA can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache [see Drug Interactions (7.1) and Clinical Pharmacology (12.2)] . 7.2 Potential for Other Drugs to Affect STENDRA STENDRA is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Strong CYP3A4 Inhibitors Ketoconazole (400 mg daily), a selective and strong inhibitor of CYP3A4, increased STENDRA 50 mg single-dose systemic exposure (AUC) and maximum concentration (C max) equal to 13-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately 9 hours. Other potent inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir, and telithromycin) would be expected to have similar effects. Do not use STENDRA in patients taking strong CYP3A4 inhibitors [see Warnings and Precautions (5.2) and Dosage and Administration (2.3)] . HIV Protease inhibitor — Ritonavir (600 mg twice daily), a strong CYP3A4 inhibitor, which also inhibits CYP2C9, increased STENDRA 50 mg single-dose C max and AUC equal to approximately 2-fold and 13-fold, and prolonged the half-life of avanafil to approximately 9 hours in healthy volunteers. Do not use STENDRA in patients taking ritonavir. Moderate CYP3A4 Inhibitors Erythromycin (500 mg twice daily) increased STENDRA 200 mg single-dose C max and AUC equal to approximately 2-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately 8 hours in healthy volunteers. Moderate CYP3A4 inhibitors (e.g., erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil) would be expected to have similar effects. Consequently, the maximum recommended dose of STENDRA is 50 mg, not to exceed once every 24 hours for patients taking concomitant moderate CYP3A4 inhibitors [see Warnings and Precautions (5.2) and Drug Interactions (7.2)]. Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit juice are likely to increase avanafil exposure. Weak CYP3A4 Inhibitors No in vivo drug-drug interaction studies with weak CYP3A4 inhibitors were conducted. CYP3A4 Substrate When administered with STENDRA 200 mg, amlodipine (5 mg daily) increased the C max and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of STENDRA was prolonged to approximately 10 hrs. The C max and AUC of amlodipine decreased by approximately 9% and 4%, respectively [see Dosage and Administration (2.3)]. Cytochrome P450 Inducers The potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated. The concomitant use of STENDRA and CYP inducers is not recommended. 7.3 Potential for STENDRA to Affect Other Drugs In vitro studies Avanafil had no effect on CYP1A1/2, 2A6, 2B6, and 2E1 (IC 50 greater than 100 micromolar) and weak inhibitory effects toward other isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4). Major circulating metabolites of avanafil (M4 and M16) had no effect on CYPs 1A, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4. Avanafil and its metabolites (M4 and M16) are unlikely to cause clinically significant inhibition of CYPs 1A, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4. In vivo studies Warfarin —A single 200 mg dose of STENDRA did not alter the changes in PT or INR induced by warfarin, and did not affect collagen-induced platelet aggregation or the AUC or C max of R- or S-warfarin, a 2C9 substrate. Desipramine — A single STENDRA 200 mg dose increased AUC and C max of a single 50 mg dose of desipramine, a CYP2D6 substrate, by 5.7% and 5.2%, respectively. Omeprazole — A single STENDRA 200 mg dose increased AUC and C max of a single 40 mg dose of omeprazole, a CYP2C19 substrate, given once daily for 8 days by 5.9% and 8.6%, respectively. Rosiglitazone — A single STENDRA 200 mg dose increased AUC by 2.0% and decreased C max by 14% of a single 8 mg dose of rosiglitazone, a CYP2C8 substrate. Amlodipine — A single STENDRA 200 mg dose did not affect the pharmacokinetics of amlodipine (5 mg daily), a CYP3A4 substrate [see Dosage and Administration (2.3)]. Alcohol — A single oral dose of STENDRA 200 mg did not affect alcohol (0.5 g ethanol/kg) plasma concentrations [see Warnings and Precautions (5.7)] . 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C STENDRA is not indicated for use in women. There are no adequate and well-controlled studies of STENDRA in pregnant women. Fetal Risk Summary Based on animal data, STENDRA is predicted to have a low risk for major developmental abnormalities in humans. Animal Data In pregnant rats administered 100, 300, or 1000 mg/kg/day from gestation days 6 to 17, no evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed at exposures up to approximately 8 times the exposure at the Maximum Recommended Human Dose (MRHD) of 200 mg based on AUCs for total avanafil (protein bound plus free avanafil). At the maternally toxic dose (1000 mg/kg/day), a dose producing exposures approximately 30 times the MRHD on an AUC basis, decreased fetal body weight occurred with no signs of teratogenicity. In pregnant rabbits administered 30, 60, 120, or 240 mg/kg/day from gestation days 6 to 18, no teratogenicity was observed at exposures up to approximately 6 times the human exposure at the MRHD based on AUC. At the high dose associated with maternally-reduced body weights, increased postimplantation loss was observed consistent with increased late resorptions. In a pre- and post-natal development study in rats given 100, 300, or 600 mg/kg/day on gestation days 6 through lactation day 20, offspring growth and maturation were reduced when maternal rats were given avanafil doses greater than or equal to 300 mg/kg/day resulting in exposures greater than or equal to 17 times the human exposure. There was no effect on reproductive performance of the maternal rats or offspring, or on the behavior of the offspring at up to the highest dose tested. The no observed adverse effect level (NOAEL) for developmental toxicity (100 mg/kg/day) was approximately 2-fold greater than the systemic exposure in humans at the MRHD. 8.4 Pediatric Use STENDRA is not indicated for use in pediatric patients. Safety and efficacy in patients below the age of 18 years has not been established. 8.5 Geriatric Use Of the total number of subjects in clinical studies of avanafil, approximately 23% were 65 and over. No overall differences in efficacy and safety were observed between subjects over 65 years of age compared to younger subjects; therefore no dose adjustment is warranted based on age alone. However, a greater sensitivity to medication in some older individuals should be considered [see Clinical Pharmacology (12.3)] 8.6 Renal Impairment In a clinical pharmacology trial using single 200 mg doses of STENDRA, avanafil exposure (AUC or C max) in normal subjects was comparable to patients with mild (creatinine clearance greater than or equal to 60 to less than 90 mL/min) or moderate (creatinine clearance greater than or equal to 30 to less than 60 mL/min) renal impairment. No dose adjustment is necessary for patients with mild to moderate renal impairment (creatinine clearance greater than or equal to 30 to less than 90 mL/min). The pharmacokinetics of avanafil in patients with severe renal disease or on renal dialysis has not been studied; do not use STENDRA in such patients [see Clinical Pharmacology (12.3)] 8.7 Hepatic Impairment In a clinical pharmacology trial, avanafil AUC and C max in patients with mild hepatic impairment (Child-Pugh Class A) was comparable to that in healthy subjects when a dose of 200 mg was administered. Avanafil C max was approximately 51% lower and AUC was 11% higher in patients with moderate hepatic impairment (Child Pugh Class B) compared to subjects with normal hepatic function. No dose adjustment is necessary for patients with mild to moderate hepatic impairment (Child Pugh Class A or B). The pharmacokinetics of avanafil in patients with severe hepatic disease has not been studied; do not use STENDRA in such patients [see Clinical Pharmacology (12.3)] . 10 OVERDOSAGE Single doses up to 800 mg have been given to healthy subjects, and multiple doses up to 300 mg have been given to patients. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance because avanafil is highly bound to plasma proteins and is not significantly eliminated in the urine. 11 DESCRIPTION STENDRA (avanafil) is a selective inhibitor of cGMP-specific PDE5. Avanafil is designated chemically as (S)-4-[(3-Chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]- N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide and has the following structural formula:
Avanafil occurs as white crystalline powder, molecular formula C 23H 26ClN 7O 3 and molecular weight of 483.95 and is slightly soluble in ethanol, practically insoluble in water, and soluble in 0.1 mol/L hydrochloric acid. STENDRA, for oral administration, is supplied as oval, pale yellow tablets containing 50 mg, 100 mg, or 200 mg avanafil debossed with dosage strengths. In addition to the active ingredient, avanafil, each tablet contains the following inactive ingredients: mannitol, fumaric acid, hydroxypropylcellulose, low substituted hydroxypropylcellulose, calcium carbonate, magnesium stearate, and ferric oxide yellow.
Effects of STENDRA on Blood Pressure When Administered with Alpha-Blockers A single-center, randomized, double-blinded, placebo-controlled, two-period crossover trial was conducted to investigate the potential interaction of STENDRA with alpha-blocker agents in healthy male subjects which consisted of two cohorts: Cohort A (N=24): Subjects received oral doses of doxazosin once daily in the morning at 1 mg for 1 day (Day 1), 2 mg for 2 days (Days 2 – 3), 4 mg for 4 days (Days 4 – 7), and 8 mg for 11 days (Days 8 – 18). On Days 15 and 18, the subjects also received a single oral dose of either 200 mg STENDRA or placebo, according to the treatment randomization code. The STENDRA or placebo doses were administered 1.3 hours after the doxazosin administration on Days 15 and 18. The co-administration was designed so that doxazosin (T max ~2 hours) and STENDRA (T max ~0.7 hours) would reach their peak plasma concentrations at the same time. Cohort B (N=24): Subjects received 0.4 mg daily oral doses of tamsulosin in the morning for 11 consecutive days (Days 1 – 11). On Days 8 and 11, the subjects also received a single oral dose of either 200 mg STENDRA or placebo, according to the treatment randomization code. The STENDRA or placebo doses were administered 3.3 hours after the tamsulosin administration on Days 8 and 11. The co-administration was designed so that tamsulosin (T max ~4 hours) and STENDRA (T max ~0.7 hours) would reach their peak plasma concentrations at the same time. Supine and sitting BP and pulse rate measurements were recorded before and after STENDRA or placebo dosing. A total of seven subjects in Cohort A (doxazosin) experienced potentially clinically important absolute values or changes from baseline in standing SBP or DBP. Three subjects experienced standing SBP values less than 85 mmHg. One subject experienced a decrease from baseline in standing SBP greater than 30 mmHg following STENDRA. Two subjects experienced standing DBP values less than 45 mmHg following STENDRA. Four subjects experienced decreases from baseline in standing DBP greater than 20 mmHg following STENDRA. One subject experienced such decreases following placebo. There were no severe adverse events related to hypotension reported during the trial. There were no cases of syncope. A total of five subjects in Cohort B (tamsulosin) experienced potentially clinically important absolute values or changes from baseline in standing SBP or DBP. Two subjects experienced standing SBP values less than 85 mmHg following STENDRA. One subject experienced a decrease from baseline in standing SBP greater than 30 mmHg following STENDRA. Two subjects experienced standing DBP values less than 45 mmHg following STENDRA. Four subjects experienced decreases from baseline in standing DBP greater than 20 mmHg following STENDRA; one subject experienced such decreases following placebo. There were no severe adverse events related to hypotension reported during the trial. There were no cases of syncope. Table 6 presents the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure results for the 24 subjects who received STENDRA 200 mg and matching placebo. Table 6: Placebo-Subtracted Mean (95% CI) Maximum Decreases from Baseline in Standing and Supine Systolic Blood Pressure (mmHg) with 200 mg STENDRA
Figure 2: Mean (SD) Change From Baseline in Standing Systolic Blood Pressure Over Time Following Administration of a Single Dose 200 mg Dose of STENDRA with Doxazosin
comparison to placebo for change from baseline Results in the ED Population with Diabetes Mellitus (Study 2) STENDRA was evaluated in ED patients (n=390) with type 1 or type 2 diabetes mellitus in a randomized, double-blind, parallel, placebo-controlled fixed dose trial of 3 months in duration. The mean age was 58 years (range 30 to 78 years). The population was 80.5% White, 17.2% Black, 1.5% Asian, and 0.8% of other races. The mean duration of ED was approximately 6 years. In this trial, STENDRA at doses of 100 mg and 200 mg demonstrated statistically significant improvement in all 3 primary efficacy variables as measured by the erectile function domain of the IIEF questionnaire; SEP2 and SEP3 (see Table 8). Table 8: Mean Change From Baseline for Primary Efficacy Variables in ED Population with Diabetes Mellitus (Study 2)
comparison to placebo for change from baseline Time to Onset of Effect (Study 3) STENDRA was evaluated in 440 subjects with ED including diabetics (16.4%) and subjects with severe ED (41.4%) in a randomized, double-blind, parallel, placebo-controlled study of 2 months duration. The mean age was 58.2 years (range 24 to 86 years). The population was 75.7% White, 21.4% Black, 1.6% Asian, and 1.4% of other races. Subjects were encouraged to attempt intercourse approximately 15 minutes after dosing and used a stopwatch for measurement of time to onset of effect, defined as the time to the first occurrence of an erection sufficient for sexual intercourse. STENDRA 100 mg and 200 mg demonstrated statistically significant improvements relative to placebo in the primary efficacy variable, percentage of all attempts resulting in an erection sufficient for penetration at approximately 15 minutes after dosing followed by successful intercourse (SEP3) (see Table 9). Table 9: Percentage of All Attempts Resulting in an Erection Sufficient for Penetration at Approximately 15 Minutes After Dosing Followed by Successful Intercourse (SEP3) During the 8-Week Treatment Period in the Time to Onset of Effect (Study 3)
16 HOW SUPPLIED/STORAGE AND HANDLING STENDRA (avanafil) is supplied as oval, pale yellow tablets containing 50 mg, 100 mg, or 200 mg avanafil debossed with dosage strengths.
Protect from light [see USP Controlled Room Temperature]. 完整资料附件：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f5172788-e1ab-45f9-99fa-878ee42cf91d | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
