Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: MENARINI INTERNATIONAL OPERATIONS LUXEMBOURG S.A., 1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg
Pharmacotherapeutic group: Urologicals; Drugs used in erectile dysfunction
ATC code: G04BE10
Avanafil is a highly selective and potent, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5. When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by avanafil produces increased levels of cGMP in the corpus cavernosum of the penis. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Avanafil has no effect in the absence of sexual stimulation.
Studies in vitro have shown that avanafil is highly selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (>100-fold for PDE6; >1,000-fold for PDE4, PDE8 and PDE10; >5,000-fold for PDE2 and PDE7; >10,000-fold for PDE1, PDE3, PDE9, and PDE11). Avanafil is >100-fold more potent for PDE5 than PDE6, which is found in the retina and is responsible for phototransduction. The approximately 20,000-fold selectivity for PDE5 versus PDE3, and enzyme found in heart and blood vessels, is important because PDE3 is involved in control of cardiac contractility.
In a penile plethysmography (RigiScan) study, avanafil 200 mg produced erections considered sufficient for penetration (60% rigidity by RigiScan) in some men as early as 20 minutes after dosing and overall response of these subjects to avanafil was statistically significant, compared to placebo, in the 20-40 minute time interval.
In clinical trials, avanafil was assessed for its effect on the ability of men with erectile dysfunction (ED) to achieve and maintain an erection sufficient for satisfactory sexual activity. Avanafil was evaluated in 4 randomized, double-blind, placebo-controlled, parallel group trials of up to 3 months in duration in the general population with ED, in patients with Type 1 or Type 2 diabetes and ED, and in patients with ED following bilateral nerve-sparing radical prostatectomy. The fourth study investigated the onset of action of avanafil at two doses (100 and 200 mg) in terms of per-subject proportion of sexual attempts resulting in satisfactory completion of sexual intercourse. A total of 1774 patients received avanafil, which was taken as needed at doses of 50 mg (one study), 100 mg and 200 mg (four studies), respectively. Patients were instructed to take 1 dose of study medicinal product approximately 30 minutes prior to initiation of sexual activity. In the fourth study patients were encouraged to attempt sexual intercourse approximately 15 minutes post-dosing, to assess the onset of the erectogenic effect of avanafil, taken on an as needed basis, at 100 and 200 mg dose.
In addition, a subset of patients was enrolled into an open-label extension trial with 493 patients receiving avanafil for at least 6 months and 153 patients for at least 12 months. Patients were initially assigned to avanafil 100 mg and at any point during the trial, they could request to have their dose of avanafil increased to 200 mg or decreased to 50 mg based on their individual response to treatment.
In all trials, statistically significant improvement in all primary efficacy measures were observed for all three doses of avanafil compared to placebo. These differences were maintained with long term treatment (as per studies in the general ED population, in diabetics with EDand in men with ED following bilateral nerve-sparing radical prostatectomy and in the open-label extension trial).
In the general population with ED, the mean percentage of attempts resulting in successful intercourse was approximately 47%, 58%, and 59% for the 50 mg, 100 mg, and 200 mg avanafil groups, respectively, as compared with approximately 28% for placebo.
In men with either Type 1 or Type 2 diabetes mellitus, the mean percentage of attempts resulting in successful intercourse was approximately 34% and 40% for the 100 mg and 200 mg avanafil groups, respectively, compared to approximately 21% for the placebo group.
In men with ED following bilateral nerve-sparing radical prostatectomy, the mean percentage of attempts resulting in successful intercourse was approximately 23% and 26% for the 100 mg and 200 mg avanafil groups, respectively, compared to approximately 9% for placebo.
In the Time to onset study, avanafil demonstrated statistically significant improvement in the primary efficacy variable (average per subject proportion of successful responses by time after dose administration, to the Sexual Encounter Profile 3-SEP3) as compared with placebo, resulting in successful intercourse in 24.71% of the attempts for the 100 mg dose and 28.18% for the 200 mg dose at approximately 15 minutes after dosing compared to 13.78% for placebo.
Across all of the pivotal trials of avanafil, the percentage of successful intercourse attempts was significantly higher for all doses of avanafil compared to placebo for attempts at all post-dosing time intervals examined.
The European Medicines Agency has waived the obligation to submit the results of studies with Spedra in all subsets of the paediatric population in erectile dysfunction (see section 4.2 for information on paediatric use).
Avanafil is rapidly absorbed after oral administration, with a median Tmax of 30 to 45 minutes. Its pharmacokinetics are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly CYP3A4). The concomitant use of potent CYP3A4 inhibitors (e.g. ketoconazole and ritonavir) is associated with increased plasma exposure of avanafil (see section 4.5). Avanafil has a terminal half-life of approximately 6-17 hours.
Avanafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 0.5 to 0.75 hours of oral dosing in the fasted state. When avanafil is taken with a high fat meal, the rate of absorption is reduced with a mean delay in Tmax of 1.25 hours and a mean reduction in Cmax of 39% (200 mg). There was no effect on the extent of exposure (AUC). The small changes in avanafil Cmax are considered to be of minimal clinical significance.
Avanafil is approximately 99% bound to plasma proteins. Protein binding is independent of total active substance concentrations, age, renal and hepatic function. Avanafil was not found to accumulate in plasma when dosed 200 mg twice daily over 7 days. Based upon measurements of avanafil in semen of healthy volunteers 45-90 minutes after dosing, less than 0.0002% of the administered dose may appear in the semen of patients.
Avanafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The plasma concentrations of the major circulating metabolites, M4 and M16, are approximately 23% and 29% that of the parent compound, respectively. The M4 metabolite shows a phosphodiesterase selectivity profile similar to that of avanafil and an in vitro inhibitory potency for PDE5 18% of that of avanafil. Therefore, M4 accounts for approximately 4% of total pharmacologic activity. The M16 metabolite was inactive against PDE5.
Avanafil is extensively metabolised in humans. After oral administration, avanafil is excreted as metabolites predominantly in the faeces (approximately 63% of administered oral dose) and to a lesser extent in the urine (approximately 21% of the administered oral dose).
Older patients (65 years or over) had comparable exposure to that seen in younger patients (18-45 years). However, data on subjects older than 70 years are limited.
In subjects with mild (creatinine clearance ≥50 - <80 mL/min) and moderate (creatinine clearance ≥30 - <50 mL/min) renal impairment, the pharmacokinetics of a single 200 mg dose of avanafil were not altered. There are no data available for subjects with severe renal insufficiency or end-stage renal disease on haemodialysis.
Subjects with mild hepatic impairment (Child-Pugh A) had comparable exposure to subjects with normal hepatic function when a single dose of 200 mg avanafil was administered.
The exposure 4 hours post-dose was lower in subjects with moderate hepatic impairment (Child-Pugh B) compared to subject with normal hepatic function after 200 mg of avanafil. The maximum concentration and exposure was similar to that observed after subjects with normal hepatic function received an efficacious avanafil 100 mg dose.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.
In a rat fertility and early embryonic development trial, a decrease in fertility and sperm motility, altered estrous cycles, and an increased percentage of abnormal sperm occurred at 1000 mg/kg/day, a dose which also caused parental toxicity in the treated males and females. No effects on fertility or sperm parameters were noted at doses up to 300 mg/kg/day (in male rats 9 times human exposure based on unbound AUC at a dose of 200 mg). There were no treatment-related testicular findings in mice or rats treated with doses up to 600 or 1000 mg/kg/day for 2 years, and no testicular findings in dogs treated with avanafil for 9 months at exposures 110 times human exposure at the Maximum Recommended Human Dose (MRHD).
In pregnant rats, no evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed at doses up to 300 mg/kg/day (approximately 15 times the MRHD on a mg/m² basis in a 60 kg subject). At a maternally toxic dose of 1000 mg/kg/day (approximately 49 times the MRHD on a mg/m² basis), decreased fetal body weight occurred with no signs of teratogenicity. In pregnant rabbits, no teratogenicity, embryotoxicity or fetotoxicity was observed at doses up to 240 mg/kg/day (approximately 23 times the MRHD on a mg/m² basis. In the rabbit study, maternal toxicity was observed at 240 mg/kg/day.
In a rat pre- and post-natal development study, pups exhibited persistent decreases in body weight at 300 mg/kg/day and higher (approximately 15 times the MRHD on a mg/m² basis) and delayed sexual development at 600 mg/kg/day (approximately 29 times the MRHD on a mg/m² basis).
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