Date of approval.
Date of revision.
Vardenafil Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of your physician.
Warning: This product is available in 10mg and 20mg sizes and is not intended for patients using doses of 5mg. This product should not be broken open and taken.
Drug Name
Generic Name: Vardenafil Hydrochloride Tablets
English name: Vardenafil Hydrochloride Tablets
Hanyu Pinyin: Yansuan Fadinafei Pian
Ingredients
Active ingredient: Vardenafil Hydrochloride
Chemical name: 2-[2-ethoxy-5-(4-ethyl-piperazine-1-sulfonamido)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f]-[1,2,4]triazol-4-one monohydrochloride trihydrate
Chemical structure formula.
Molecular formula: C23H32N6O4S-HCl-3H2O
Molecular weight: 579.1
【Properties】.
This product is a light yellow to dark yellow film-coated tablet, which appears white after removing the film coating.
Indications
Treatment of male penile erectile dysfunction.
Specification
According to C23H32N6O4S (1) 10mg (2) 20mg
Dosage and Administration
Usage: Take orally
Recommended Dose.
The recommended starting dose is 10mg, to be taken approximately 25-60 minutes prior to intercourse. In clinical trials, 4~5 hours before intercourse, it still showed efficacy. The maximum recommended dose frequency is once a day. Vardenafil can be taken with food or alone. Sexual stimulation is required as an instinctive response for treatment.
Dose Range.
The dose may be increased to 20 mg or decreased to 5 mg depending on potency and tolerability. the maximum recommended dose is 20 mg per day.
Hepatic Impairment.
No dose adjustment is required in patients with mild hepatic impairment (Child-PughA); in patients with moderate hepatic impairment (Child-PughB), a starting dose of 5 mg is recommended due to reduced clearance of vardenafil, followed by a gradual increase to 10 mg based on tolerability and efficacy; the pharmacokinetics of vardenafil in patients with severe hepatic impairment (Child-PughC) studies have not been conducted.
Renal impairment.
No dose adjustment is required in patients with mild, moderate, or severe renal impairment. Pharmacokinetic studies of vardenafil in dialysis patients have not been performed.
Concomitant Dosing.
Concomitant administration of vardenafil and alpha-blockers may result in symptomatic hypotension in some patients. Combinations should only be used if the patient is stable on alpha-blocker therapy. For patients who are stable on alpha-blocker therapy, vardenafil should be administered at the lowest recommended starting dose of 5 mg and tamsulosin may be taken at any time. When vardenafil is used in combination with other alpha-blockers, there should be a dosing interval. For patients who are already taking the optimal dose of vardenafil, alpha-blockers should be administered starting at the lowest dose. For patients taking PDE5 inhibitors (including vardenafil), an increase in the dose of alpha-blockers may cause a further decrease in blood pressure.
Dose adjustment of vardenafil may be required in patients taking certain CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, indinavir, and erythromycin).
The maximum dose of vardenafil should not exceed 5 mg when erythromycin is also used.
When taking ketoconazole and itraconazole, the maximum dose of vardenafil should not exceed 5 mg. When the dose of ketoconazole and itraconazole exceeds 200 mg, vardenafil should not be taken.
Avoid concomitant administration of the potent CYP3A4 inhibitors indinavir and ritonavir.
[Adverse Reactions].
List of adverse reactions.
The table below summarizes the frequency of ADRs reported in the application of vardenafil hydrochloride tablets. Within each frequency grouping, ADRs are listed in descending order of severity. These frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), occasional (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000).
Adverse reactions that were identified only during post-marketing surveillance and whose frequency could not be estimated are listed under “unknown”.
Adverse drug reactions reported in patients in all clinical trials worldwide, including those reported as drug-related or rare but considered serious in ≥ 0.1% of patients.
Systemic
Very common Common Occasional Rare Infectious and Infectious Diseases Conjunctivitis Immune System Disorders Allergic Edema and Angioedema Allergic Reactions Psychiatric Disorders Sleep Disorders Various Neurological Disorders
Headache Dizziness Dullness of sensation
Abnormal sensations
Drowsiness Syncope
Amnesia
Convulsive seizures Eye organ disorders Visual disturbances
Ocular congestion
Visual color distortion
Eye pain and eye discomfort
Photophobia Increased intraocular pressure Ear and vagus disorders Tinnitus
Vertigo Heart disorders Palpitations
Tachycardia Angina pectoris
Myocardial infarction
Ventricular tachyarrhythmias Vascular and lymphatic disorders Vascular dilation Hypotension Respiratory, thoracic and mediastinal disorders Nasal congestion Dyspnea
Sinus congestion Gastrointestinal system disorders Indigestion
Nausea
Gastrointestinal pain and abdominal pain
Dry mouth
Diarrhea
Gastroesophageal reflux disease
Gastritis
Vomiting Liver and biliary system disorders Elevated transaminases Skin and subcutaneous tissue disorders Erythema
Rash Various musculoskeletal and connective tissue disorders Back pain
Elevated creatine phosphokinase
Increased muscle tone, spasticity
Myalgia Reproductive and breast disorders Erectile enhancement Abnormal penile erection Systemic disorders and various reactions at the drug administration site Discomfort Chest pain Description of individual adverse reactions
Myocardial infarction (MI): The occurrence of myocardial infarction (MI) has been reported with vardenafil for sexual activity, but it was not possible to determine whether the myocardial infarction was directly related to vardenafil, or progressive activity, or to the patient’s underlying cardiovascular disease, or to a combination of these factors.
Non-arteritic anterior ischemic optic neuropathy: The development of non-arteritic anterior ischemic optic neuropathy (NAION), which may be associated with vardenafil, has been reported in a very small number of patients following the marketing of PDE5 inhibitors, including vardenafil hydrochloride tablets, and can lead to vision loss or even permanent blindness. Most, but not all, of these patients have anatomic or vascular risk factors that predispose them to NAION, including: small cup-to-disc ratio (small optic papilla), age over 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. Whether these events are associated with the use of PDE5 inhibitors or the patient’s underlying vascular risk factors or anatomical defects, or a combination of these factors, or other factors directly, is uncertain.
Visual impairment: Very few patients have been reported to experience visual impairment, including blindness (temporary or permanent), that may be associated with the marketed use of PDE5 inhibitors, including vardenafil hydrochloride tablets. Whether these events are directly related to the use of PDE5 inhibitors, the patient’s underlying vascular risk factors or anatomic defects, or a combination of these factors, or other factors is uncertain.
Two case-crossover observational studies evaluated the risk of NAION after taking drugs such as PDE5 inhibitors. The results suggested an approximately 2-fold increase in the risk of NAION. However, a causal relationship between the use of PDE5 inhibitors and NAION has not been confirmed. (See [Caution])
Sudden deafness or hearing loss: Sudden deafness or hearing loss has been reported in a small number of patients after the marketed use of PDE5 inhibitors (including vardenafil hydrochloride tablets) and in clinical trials. Whether these events are directly related to the use of vardenafil hydrochloride tablets, the patient’s underlying risk factors for hearing loss, or a combination of these factors, or other factors is uncertain.
Contraindications
Contraindicated in patients with hypersensitivity to any of the components of this product.
PDE5 inhibitors may enhance the antihypertensive effect of nitrates by the same mechanism of action as PDE inhibitors in the NO/cGMP pathway. Therefore, concomitant use of vardenafil is contraindicated in patients taking nitrates or nitric oxide donor therapy. (See [Drug Interactions])
Concomitant use with the HIV protein kinase inhibitors indinavir or ritonavir and vardenafil is prohibited because they are potent CYP3A4 inhibitors. (See [DOSAGE AND ADMINISTRATION] and [DRUG INTERACTIONS])
Vardenafil is contraindicated in patients with loss of vision due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether the condition is associated with prior exposure to alkaline phosphodiesterase 5 (PDE5) inhibitors.
Drugs for erectile dysfunction should generally not be used in men who are unfit for sexual activity (e.g., patients with severe cardiovascular dysfunction: e.g., unstable angina pectoris or severe heart failure)
Vardenafil has not been studied in the safety of vardenafil in the following patients, unless further information is available, vardenafil is contraindicated in
Patients with severe hepatic impairment (Child-PughC),
End-stage renal disease requiring dialysis,
Hypotension (blood pressure <90/50 mmHg),
History of recent stroke or heart attack (within 6 months),
Unstable angina, familial degenerative eye disease such as retinitis pigmentosa.
Concomitant use of strong P450 (CYP) 3A4 inhibitors (ketoconazole and itraconazole (oral dosage form)) is contraindicated in elderly patients over 75 years of age.
Combination of PDE-5 inhibitors, including vardenafil, with guanylate cyclase stimulating agents (e.g., liothyronine) is prohibited due to the potential for symptomatic hypotension.
Precautions]
Because sexual activity carries a degree of cardiac risk, physicians should first consider the cardiovascular status of the patient before taking any treatment for erectile dysfunction. Vardenafil’s vasodilatory properties may lead to a temporary mild decrease in blood pressure. Patients with left ventricular outflow disorders, such as aortic stenosis and idiopathic hypertrophic subaortic stenosis, may be sensitive to vasodilators, including PDE5 inhibitors.
Caution is needed when treating patients with anatomical abnormalities of the penis (e.g., horn formation, cavernous fibrosis, Peyronie’s disease), or with erections that do not subside (e.g., sickle cell disease, multiple myeloma, and leukemia).
The safety and efficacy of vardenafil have not been studied in combination with other treatments for erectile dysfunction, and therefore the combination is not recommended.
The safety of vardenafil has not been studied and vardenafil is not recommended for patients with severe hepatic impairment, end-stage renal disease requiring dialysis, hypotension (resting systolic blood pressure <90 mmHg), recent stroke or myocardial infarction (within 6 months), unstable angina, and familial degenerative eye disease such as retinitis pigmentosa.
Effect on QT interval
Medications for erectile dysfunction are usually not available for patients with underlying cardiovascular problems for which intercourse is not recommended.
A study of the effect of vardenafil on the QT interval in 59 healthy male subjects showed that therapeutic doses (10 mg) and overdoses (80 mg) of vardenafil resulted in a prolongation of the QTc interval. A post-marketing study showed a cumulative effect on the QT interval when vardenafil was combined with another drug that affects the QT interval compared to each drug alone (see “Pharmacologic Effects”). Therefore, this should be taken into account in the clinical use of vardenafil in patients with a history of QT interval prolongation or on QT interval-prolonging drugs. Vardenafil should be avoided in patients with congenital QT interval prolongation or in patients taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic drugs.
Effects on vision
Transient blindness and non-arteritic anterior ischemic optic neuropathy (NAION) have been reported in association with the administration of PDE5 inhibitors, including vardenafil hydrochloride tablets.
Analysis of observational data showed an increased risk of acute NAION in ED patients taking PDE5 inhibitors such as vardenafil, tadalafil, and sildenafil (see [Adverse Reactions]). Because this risk may be associated with all patients taking vardenafil hydrochloride tablets, patients should be advised to stop taking vardenafil hydrochloride tablets in the event of sudden blindness and to seek immediate medical attention (see [ADVERSE REACTIONS]).
Combined use with CYP3A4 inhibitors
Concomitant use of the intermediate or potent CYP3A4 inhibitors ketoconazole, itraconazole, erythromycin, clarithromycin, indinavir, and ritonavir will significantly increase the blood levels of vardenafil.
The maximum dose of vardenafil should not exceed 5 mg when ketoconazole and itraconazole are used concomitantly, and vardenafil is prohibited when ketoconazole and itraconazole are used in amounts greater than 200 mg (see [Dosage] and [Drug Interactions]).
The maximum dose of vardenafil should not exceed 5 mg when erythromycin or clarithromycin is used concurrently.
Concomitant administration of vardenafil with the superpotent CYP3A4 inhibitors indinavir and ritonavir is prohibited (see [Dosage], [Contraindications], and [Drug Interactions]).
Combined use with alpha-blockers
Combination with alpha-blockers should only be used if the patient is stable on alpha-blocker therapy (see [Drug Interactions]). Vardenafil should be administered at the lowest recommended starting dose of 5 mg to patients who are stable on alpha-blocker therapy.
Vardenafil and tamsulosin or alfuzosin may be taken at any time. When vardenafil is used in combination with other alpha-blockers, there should be a dosing interval (see [Drug Interactions]).
For patients already taking optimal doses of vardenafil, alpha-blockers should be administered starting at the lowest dose. For patients taking PDE5 inhibitors (including vardenafil), a gradual increase in the dose of alpha-blockers may cause a further decrease in blood pressure.
Effects on bleeding
Vardenafil should not be used in patients with bleeding abnormalities or active peptic ulcers and should therefore only be used after a careful benefit-risk assessment.
Vardenafil alone or in combination with aspirin had no effect on bleeding time.
In vitro tests with human platelets have shown that vardenafil alone does not inhibit platelet agglutination induced by multiple platelet factors. A slight concentration-dependent enhancement of the anticoagulant effect of sodium nitroprusside, a nitric oxide donor, was observed with vardenafil at overdose treatment.
Vardenafil in combination with heparin had no effect on bleeding time in rats, but the interaction has not been studied in humans.
Effects on the ability to drive and operate machinery.
Before driving and operating machinery, patients should consider their own reactions to vardenafil.
Use in Pregnant and Lactating Women
No studies have been conducted and no reliable references are available.
Pediatric Use
Children (birth to 16 years): Vardenafil is not indicated for use in children.
Geriatric use
In elderly patients (≥65 years), the clearance of vardenafil is reduced and the starting dose is considered to be 5 mg.
Drug Interactions]
Nitrates, nitric oxide donors.
A study of 18 healthy subjects showed no enhanced hypotensive effect when vardenafil (10 mg) was combined with sublingual nitroglycerin (0.4 mg) over a period of time (24 hours to 1 hour) prior to sublingual administration.
The hypotensive effect of sublingual nitroglycerin (0.4 mg) was enhanced in healthy middle-aged subjects after 1 to 4 hours of vardenafil administration. This effect was not observed with vardenafil 20 mg administered 24 hours prior to nitroglycerin.
There is no data to confirm the potential hypotensive effect of combining vardenafil and nitrates in patients and the combination should be prohibited, see [Contraindication].
Nicorandil is a potassium channel opener containing a nitrate component. Because of the nitrate component, Nicorandil has potentially serious interactions with vardenafil.
CYP inhibitors.
Vardenafil is metabolized primarily through the hepatic enzyme system via cytochrome P450 (CYP) isoenzyme 3A4, with CYP3A5 and CYP2C isoenzymes playing a role in its metabolism. Therefore, inhibitors of these enzymes can reduce the clearance of vardenafil.
Cimetidine (400 mg twice a day): In healthy volunteers, the combination of vardenafil (20 mg) and the nonspecific cytochrome P450 inhibitor cimetidine did not affect the AUC and Cmax of vardenafil.
Erythromycin (500 mg three times a day): In healthy volunteers, the combination of vardenafil (5 mg) and the CYP3A4 inhibitor erythromycin increased the AUC and Cmax of vardenafil by 300% and 200%, respectively.
Ketoconazole (200 mg): In healthy volunteers, the combination of vardenafil (5 mg) and the strong CYP3A4 inhibitor ketoconazole increased the AUC and Cmax of vardenafil by 900% and 300%, respectively.
Indinavir (800 mg three times a day): The combination of vardenafil (10 mg) and the HIV protease inhibitor indinavir resulted in a 1500% increase in vardenafil AUC and a 600% increase in Cmax. After 24 hours of coadministration, the plasma concentration of vardenafil was approximately 4% of its maximum blood concentration (Cmax).
Ritonavir (600 mg twice a day): Concomitant use of ritonavir and vardenafil 5 mg resulted in a 13-fold increase in vardenafil Cmax and a 49-fold increase in AUC 0-24. The strong CYP3A4 inhibitor ritonavir (which also inhibits CYP2C9 enzyme) blocked the transhepatic metabolism of vardenafil, and ritonavir significantly prolonged the half-life of vardenafil to 25.7 hours.
Concomitant use of the P450 (CYP)3A4 inhibitors ketoconazole, itraconazole, erythromycin, clarithromycin, indinavir, and ritonavir significantly increased vardenafil plasma levels.
Alpha-blockers.
Because alpha-blockers can significantly lower blood pressure, particularly leading to postural hypotension and syncope, the interaction of alpha-blockers and vardenafil was studied.
In both drug interaction studies, a large number of patients were reported to have hypotension (symptomatic in some cases) after the combined application of vardenafil in volunteers with normal blood pressure taking increasing doses of tamsulosin and terazosin over a period of no more than 14 days.
No clinical relevance was found for the mean maximum additional decrease in blood pressure in patients receiving long-term tamsulosin therapy with 5 mg, 10 mg, or 20 mg vardenafil. When vardenafil 5 mg was administered concurrently with tamsulosin 0.4 mg, 2 of 21 patients experienced a standing systolic blood pressure below 85 mm Hg. When vardenafil 5 mg was administered 6 hours apart from tamsulosin, 2 of 21 patients experienced a standing systolic blood pressure below 85 mm Hg.
In subjects taking terazosin, simultaneous administration of vardenafil and terazosin to achieve Cmax was more likely to trigger hypotension (standing systolic blood pressure below 85 mmHg) than when the two drugs were taken 6 hours apart to achieve Cmax separately. Because these studies were conducted in healthy volunteers given progressively increasing doses of alpha-blockers to high doses, they have limited clinical relevance.
Three drug interaction studies with vardenafil film-coated tablets were conducted in patients with benign prostatic hyperplasia (BPH) after stabilization with alpha-blocker therapy, including alfuzosin, tamsulosin, or terazosin.
When alfuzosin was administered 4 hours later, 5 mg or 10 mg of vardenafil was administered. The 4-hour dosing interval was chosen to induce the maximum possible interaction. No clinical relevance was found for the mean maximum additional decrease in blood pressure during the 10-hour interval after vardenafil administration. 2 patients (1 patient on vardenafil 5 mg film-coated tablets and 1 patient on vardenafil 10 mg film-coated tablets) had a decrease in standing systolic blood pressure >30 mmHg from baseline. no standing systolic blood pressure <. 85 mmHg was observed during the course of this study; 85 mmHg. 4 patients (1 in the placebo group, 2 in the vardenafil 5 mg film-coated group and 1 in the vardenafil 10 mg film-coated group) experienced dizziness. Based on these results, no dosing interval was required between alfuzosin and vardenafil.
In a follow-up study in patients with benign prostatic hyperplasia (BPH), vardenafil 10 mg and 20 mg were not found to have a standing systolic blood pressure below 85 mmHg when administered concomitantly with tamsulosin 0.4 mg or 0.8 mg. Based on these results, no dosing interval is required between tamsulosin and vardenafil.
When vardenafil 5 mg was administered concomitantly with terazosin 5 or 10 mg, one of 21 patients developed symptoms of postural hypotension. No symptoms of hypotension were observed when vardenafil 5 mg was administered 6 hours apart from terazosin. Therefore, the results of the above studies should be considered together to determine the dosing interval. There was no syncope in this study or in earlier trials of alfuzosin or terazosin.
Combination of medications should only be used if the patient is stable on alpha-blocker therapy (see [Drug Interactions]). Vardenafil should be administered at the lowest recommended starting dose of 5 mg to patients who are stable on alpha-blocker therapy and may be administered concomitantly with tamsulosin or alfuzosin at any time. When vardenafil is used in combination with other alpha-blockers, there should be a dosing interval. (See [Precautions])
For patients already taking optimal doses of vardenafil, alpha-blockers should be administered starting with the lowest dose. In patients taking PDE5 inhibitors (including vardenafil), a gradual increase in the dose of alpha-blockers may cause a further decrease in the patient’s blood pressure.
Other.
There are no data on pharmacokinetic interactions associated with the use of vardenafil (20 mg) in combination with digoxin (0.375 mg) when steady state is achieved, every other day, for more than 14 days.
Single-dose antacids (magnesium hydroxide/aluminium hydroxide) did not affect the AUC or maximum blood concentration (Cmax) of vardenafil.
The combination of the H2-receptor antagonist ranitidine (150 mg twice a day) did not affect the bioavailability of vardenafil (20 mg).
Vardenafil (10 mg and 20 mg) did not affect bleeding time when used alone or in combination with low-dose aspirin (2 x 81 mg tablets).
Vardenafil 20 mg did not enhance the hypotensive effect of alcohol (0.5 g/kg by body weight). The pharmacokinetics of its vardenafil were not altered.
Population pharmacokinetic data from phase III clinical trials showed no significant effect of aspirin, ACE-inhibitors, beta-blockers, weak CYP3A4-inhibitors, diuretics and therapeutic agents used for diabetes (sulfonylureas and metformin) on the pharmacokinetics of vardenafil.
The relative bioavailability of glibenclamide was not affected when vardenafil (20 mg) was combined with glibenclamide (3.5 mg). There was no evidence that the combined application of glibenclamide affected the pharmacokinetics of vardenafil.
No pharmacological (prothrombin time and coagulation factors II, VII and X) interactions were observed when vardenafil (20 mg) was used in combination with warfarin (25 mg). The combination of warfarin did not affect the pharmacokinetics of vardenafil.
No pharmacokinetic interactions associated with the combination of vardenafil (20 mg) and nifedipine (30 or 60 mg) were observed, and no pharmacodynamic interactions occurred. Compared with placebo, vardenafil resulted in additional blood pressure reductions, with mean reductions in supine systolic and diastolic blood pressure of 5.9 mmHg and 5.2 mmHg, respectively.
Liocecal
Preclinical studies have shown severe reductions in blood pressure when PDE5 inhibitors are used in combination with riociguat. Riosiphon showed an increased blood pressure lowering effect of PDE5 inhibitors. However, there is no valid clinical evidence of a role for the combination in this population. The combination of Riosiphon with PDE5 inhibitors, including vardenafil, is prohibited.
Drug overdose]
The highest test dose up to and including 120 mg per day was used in single-dose subject studies. The highest test dose (80 mg daily) was well tolerated without any serious adverse drug reactions. The same results were confirmed in another clinical trial in which 40 mg of vardenafil (once daily) was administered for 4 weeks.
When vardenafil was administered at a dose of 40 mg twice daily, several cases of more severe back pain were observed, however no muscular or neurotoxic effects were confirmed.
In case of overdose, symptomatic treatment measures should be given as needed. Because vardenafil is highly bound to plasma proteins and is not primarily cleared by urine, renal dialysis does not enhance its clearance in vivo.
Pharmacology and Toxicology
Pharmacological effects
Penile erection is a hemodynamic process involving relaxation of vascular smooth muscle in the penile corpus cavernosum and its associated small arteries. During sexual stimulation, neuronal endings and endothelial cells in the penile corpus cavernosum release nitric oxide (NO), which activates guanylate cyclase in smooth muscle cells, resulting in an increase in intracellular cyclic guanosine monophosphate (cGMP) levels, which ultimately leads to smooth muscle relaxation and increased blood flow in the penis. The rate of cGMP degradation is jointly regulated.
Vardenafil increases cGMP content by inhibiting PDE5 activity, thereby enhancing male erectile function. Since the release of local NO requires sexual stimulation, PDE5 inhibitors do not improve erectile function in the absence of sexual stimulation.
In vitro results show that vardenafil is a selective PDE5 inhibitor, with a much higher inhibitory effect on PDE5 than on other PDEs (15 times higher than PDE6, 130 times higher than PDE1, 300 times higher than PDE11, and 1000 times higher than PDE2, 3, 4, 7, 8, 9, 10)
Toxicological studies
Genotoxicity.
The results of in vitro Ames test, Chinese hamster V79 cell forward mutation test, in vitro chromosome aberration test and in vivo micronucleus test in mice were all negative.
Reproductive toxicity.
No significant effects on fertility were observed in male and female rats administered continuously from 14 days before mating to day 7 of gestation and 4 weeks before mating at doses up to 100 mg/kg/day, respectively. In a similar 1-month toxicity test in rats, the in vivo exposure (AUC) of vardenafil free drug at the same dose (100 mg/kg) was 200 times higher than the human clinical human maximum recommended dose (MRHD ).
No teratogenicity or embryonic or fetal toxicity was observed in pregnant rats and rabbits given vardenafil at doses up to 18 mg/kg/day during organogenesis. The AUC of vardenafil free drug and its major metabolites at this dose was approximately 100 times (rats) and 29 times (rabbits) that of human MRHD 20 mg.
In a perinatal toxicity test in rats, the NOAEL dose for maternal toxicity was 8 mg/kg/day. delayed offspring development was seen in rats exposed to vardenafil at 1 and 8 mg/kg, but no maternal effects were seen, analyzed for vasodilation and/or drug secretion into the milk. The number of live fetuses was reduced in rats at a dose of 60 mg/kg/day. Based on the results of the perinatal toxicity test in rats, the offspring developmental toxicity NOAEL dose was less than 1 mg/kg/day, and the AUC of vardenafil free drug and its major metabolites in rats at this dose was approximately equivalent to a human MRHD exposure of 20 mg.
Carcinogenicity.
No carcinogenicity was observed in rats and mice administered for 24 consecutive months. The AUCs of vardenafil free and its major metabolites in the carcinogenicity test were approximately 400 and 170 times those of human MRHD 20 mg in male and female rats, and approximately 21 and 37 times those of human MRHD in male and female mice.
[Pharmacokinetics].
Absorption.
Vardenafil is rapidly absorbed after oral administration, reaching maximum blood concentration (Cmax) in as early as 15 minutes under fasted condition, with a time to peak (Tmax) of 90 % from 30 to 120 minutes (mean 60 minutes).
The mean absolute bioavailability of oral vardenafil is approximately 15% due to the significant first-pass effect.
In the recommended dose range of 5-20 mg, the increase in AUC (area under the drug concentration-time curve) and Cmax after oral vardenafil was almost proportional to the increase in dose.
When vardenafil was ingested concomitantly with a high-fat diet (57% lipid content), the absorption of vardenafil was reduced, Tmax was prolonged by 60 minutes, and Cmax values were reduced by an average of 20%, but AUC was not affected. The pharmacokinetic parameters (Cmax, Tmax and AUC) were not affected when vardenafil was consumed with a regular diet (30% lipid content).
Therefore, vardenafil can be taken with food or alone.
Distribution.
Vardenafil achieves a mean volume of distribution of 208 L at steady state, indicating distribution in tissues.
Vardenafil and its main active metabolite M1 are highly bound to human plasma proteins (approximately 95%) and this binding is independent of the total drug concentration and is reversible.
The concentration of the drug in semen after 90 minutes of vardenafil administration in healthy volunteers did not exceed 0.00012% of the administered dose.
Metabolism.
Vardenafil is metabolized primarily by the hepatic enzyme system CYP3A4 type, and to a lesser extent by CYP3A5 and CYP2C9 isoenzymes.
The elimination half-life of M1, the major circulating metabolite in humans, is approximately 3-5 hours, similar to that of the prodrug.
M1 is derived from the deethylation of the piperazine portion of vardenafil, and then M1 continues to be metabolized.
Non-glucuronide M1 in plasma accounts for approximately 26% of the prodrug component. Metabolite M1 has similar phosphodiesterase selectivity to vardenafil, and in in vitro assays, M1 inhibited PDE5 by approximately 28% of vardenafil, accounting for 7% of the potency.
Excretion.
The total clearance of vardenafil in vivo is 56 L/h, with a terminal half-life of 4-5 hours.
After oral administration, vardenafil is excreted as metabolites, mostly in the feces (91-95%) and a small proportion in the urine (2-6%).
Pharmacokinetics in special populations.
Elderly patients (≥65 years).
Hepatic clearance of vardenafil was reduced in elderly healthy volunteers compared to young and middle-aged volunteers (≤45 years of age). The AUC of older men taking vardenafil was on average 52% higher than that of young men, which was within the range of variability of the clinical trial.
There were no differences in vardenafil safety and efficacy between older and younger adults in placebo-controlled clinical trials.
Patients with hepatic impairment.
The clearance of vardenafil in patients with mild to moderate hepatic impairment (Child-Pugh A and B) was reduced in proportion to the degree of hepatic impairment.
The AUC of vardenafil was increased by 17% (1.2-fold) and Cmax by 22% in patients with mild hepatic impairment (Child-PughA) compared to healthy controls.
Patients with moderate hepatic impairment (Child-PughB) had a 160% (2.6-fold) increase in AUC and a 130% (2.3-fold) increase in Cmax for vardenafil.
The pharmacokinetics of vardenafil have not been studied in patients with severe hepatic impairment (Child-PughC).
Patients with renal impairment.
In patients with mild (creatinine clearance CLcr: 50-80 ml/min) and moderate (CLcr: 30-50 ml/min) renal impairment, vardenafil pharmacokinetics were similar to those of normal renal function controls. Mean AUC increased by 21% and mean Cmax decreased by 23% in volunteers with severe renal impairment (CLcr<30ml/min) compared to volunteers without renal impairment. There was no significant correlation between creatinine clearance (CLcr) and plasma exposure (AUC and Cmax) to vardenafil.
Pharmacokinetic studies of vardenafil have not been performed in patients with renal impairment requiring dialysis treatment.
Storage
Store at room temperature.
Packaging
Aluminum-plastic packaging (polyvinyl chloride/polyethylene/polyvinylidene chloride solid pharmaceutical composite rigid tablets, aluminum foil for pharmaceutical packaging)
10 mg: 10 tablets/plate, 1 plate/box
20 mg: 4 tablets/plate, 1 plate/box
[Expiration date
24 months
【Execution standard
Approval number】
【Drug marketing license holder
Name: Sichuan Kellen Pharmaceutical Co.
Registered address: Chengdu Xindu Satellite City Industrial Development Zone, South Second Road
Zip code: 610500
Contact: 028-86130259
Fax: 028-86139152
Website: www.kelun.com
【Manufacturer】
Company name: Sichuan Keren Pharmaceutical Co.
Production Address: Ziyang Economic and Technological Development Zone Anyue Industrial Park (Anyue County Shi Qiaopu Town)
Postal code: 642350
Telephone number: 028-86130259
After-sales consultation line: 028-82860553
Pharmacovigilance line：028-67825853
Fax number：028-86139152
Website: www.kelun.com