- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
Cardiovascular statusPrior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their patients since there is a degree of cardiac risk associated with sexual activity (see section 4.3). Avanafil has vasodilator properties, resulting in mild and transient decreases in blood pressure (see section 4.5), and as such potentiates the hypotensive effect of nitrates (see section 4.3). Patients with left ventricular outflow obstruction, e.g. aortic stenosis and idiopathic hypertrophic subaortic stenosis, can be sensitive to the action of vasodilators, including PDE5 inhibitors.
PriapismPatients who experience erections lasting 4 hours or more (priapism) should be instructed to seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result. Avanafil 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 anaemia, multiple myeloma or leukaemia).
Visual problemsVisual defects and cases of non-arteritic anterior ischaemic optic neuropathy (NAION) have been reported in connection with the intake of other PDE5 inhibitors. The patient should be advised that in case of sudden visual effects, he should stop taking Spedra and consult a physician immediately (see section 4.3).
Effect on bleedingIn vitro studies with human platelets indicate that PDE5 inhibitors do not have an effect on platelet aggregation on their own, but at supratherapeutic doses they potentiate the anti-aggregatory effect of the nitric oxide donor sodium nitroprusside. In humans, PDE5 inhibitors do not appear to affect bleeding time alone or in combination with acetylsalicylic acid.There is no safety information on the administration of avanafil to patients with bleeding disorders or active peptic ulceration. Therefore, avanafil should be administered to such patients only after careful benefit-risk assessment.
Decreased or sudden loss of hearingPatients should be advised to stop taking PDE5 inhibitors, including avanafil, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.
Concomitant use of alpha-blockersThe concomitant use of alpha-blockers and avanafil may lead to symptomatic hypotension in some patients due to additive vasodilatory effects (see section 4.5). Consideration should be given to the following: • Patients should be stable on alpha-blocker therapy prior to initiating Spedra. Patients who demonstrate haemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of avanafil. • In those patients who are stable on alpha-blocker therapy, avanafil should be initiated at the lowest dose of 50 mg. • In those patients already taking an optimised dose of Spedra, 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 avanafil. • The safety of combined use of avanafil and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive medicinal products.
Concomitant use of CYP3A4 inhibitorsCo-administration of avanafil with potent inhibitors of CYP3A4, such as ketoconazole or ritonavir is contraindicated (see sections 4.2, 4.3 and 4.5).
Concomitant use of other treatments for erectile dysfunctionThe safety and efficacy of combinations of Spedra and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. Patients should be informed not to take Spedra in such combinations.
Concomitant use of alcoholConsumption of alcohol in combination with avanafil can increase the potential for symptomatic hypotension (see section 4.5). Patients should be advised that concurrent use of avanafil and alcohol may increase the likelihood of hypotension, dizziness, or syncope. Physicians should also advise patients on what to do in the event of postural hypotensive symptoms.
Populations not studiedAvanafil has not been evaluated in patients with erectile dysfunction due to spinal cord injury or other neurological disorders and in subjects with severe renal or hepatic impairment.
CYP3A4 substrateAmlodipine (5 mg daily) increased avanafil 200 mg single-dose Cmax and AUC by approximately 28% and 60%, respectively. These exposure changes are not considered clinically significant. There was no effect of a single dose of avanafil on amlodipine plasma levels.Although specific interactions of avanafil with rivaroxaban and apixaban (both CYP3A4 substrates) have not been studied, an interaction is not expected. Cytochrome P450 Inducers The potential effect of CYP inducers, especially inducers of CYP3A4 (e.g. bosentan, carbamazepine, efavirenz, phenobarbital and rifampicin) on the pharmacokinetics and efficacy of avanafil has not been evaluated. The concomitant use of avanafil and a CYP inducer is not recommended as it may decrease the efficacy of avanafil. Effects of avanafil on other medicinal products Cytochrome P450 Inhibition In in vitro studies in human liver microsomes, avanafil showed a negligible potential for drug-drug interactions with CYP1A1/2, 2A6, 2B6 and 2E1. Further, the metabolites of avanafil (M4, M16 and M27), also demonstrated a minimal inhibition of CYPs 1A1/2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. Based on these data avanafil is not anticipated to have a significant effect on other medicinal products metabolised by these enzymes.Since the in vitro data identified potential avanafil interactions with CYPs 2C19, 2C8/9, 2D6 and 3A4, further clinical studies using omeprazole, rosiglitazone and desipramine did not reveal clinically relevant interactions with CYPs 2C19, 2C8/9 and 2D6.
Cytochrome P450 InductionThe potential induction of CYP1A2, CYP2B6 and CYP3A4 by avanafil evaluated in primary human hepatocytes in vitro did not reveal any potential interaction at clinically relevant concentrations.
TransportersIn vitro results showed for avanafil a modest potential for acting as P-gp substrate and P-gp inhibitor with digoxin as a substrate at concentrations lower than the calculated intestinal concentration. The potential of avanafil to interfere with the transport of other medicinal products mediated by P-gp is not known. Based on in vitro data, at clinically relevant concentrations avanafil could be an inhibitor of BCRP. At clinically relevant concentrations avanafil is not an inhibitor of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3 and BSEP. The impact of avanafil on other transporters is unknown. Riociguat Preclinical studies showed additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. In clinical studies, riociguat has shown to augment the hypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including avanafil, is contraindicated (see section 4.3).
Summary of the safety profileThe safety profile of Spedra is based on 2436 subjects exposed to avanafil during the clinical development program. The most common adverse reactions reported in clinical studies were headache, flushing, nasal and sinus congestion and back pain. Overall adverse events and adverse reactions for avanafil-treated subjects were more frequent in subjects with a Body Mass Index (BMI) <25 (normal BMI subjects).In the long term clinical study, the percentage of patients who experienced adverse reactions decreased with increasing length of exposure.
Tabulated list of adverse reactionsThe table below lists the adverse reactions observed in placebo-controlled clinical trials according to the MedDRA frequency convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
|Adverse reaction (MedDRA Preferred Term)|
|System Organ Class||Common||Uncommon||Rare|
|Infections and infestations||Influenza Nasopharyngitis|
|Immune system disorders||Seasonal allergy|
|Metabolism and nutrition disorders||Gout|
|Psychiatric disorders||Insomnia Premature ejaculation Inappropriate affect|
|Nervous system disorders||Headache||Dizziness Somnolence Sinus headache||Psychomotor hyperactivity|
|Eye disorders||Vision blurred|
|Cardiac disorders||Palpitations||Angina pectoris Tachycardia|
|Vascular disorders||Flushing||Hot flush||Hypertension|
|Respiratory, thoracic and mediastinal disorders||Nasal congestion||Sinus congestion Dyspnoea exertional||Rhinorrhoea Upper respiratory tract congestion|
|Gastrointestinal disorders||Dyspepsia Nausea Vomiting Stomach discomfort||Dry mouth Gastritis Abdominal pain lower Diarrhoea|
|Skin and subcutaneous tissue disorders||Rash|
|Musculoskeletal and connective tissue disorders||Back pain Muscle tightness||Flank pain Myalgia Muscle spasms|
|Renal and urinary disorders||Pollakiuria|
|Reproductive system and breast disorders||Penis disorder Spontaneous penile erection Pruritus genital|
|General disorders and administration site conditions||Fatigue||Asthenia Chest pain Influenza like illness Oedema peripheral|
|Investigations||Hepatic enzyme increased Electrocardiogram abnormal Heart rate increased||Blood pressure increased Blood urine present Cardiac murmur Prostate specific antigen increased Weight increased Blood bilirubin increased Blood creatinine increased Body temperature increased|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme.Website: www.mhra.gov.uk/yellowcard.
Mechanism of actionAvanafil 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.
Pharmacodynamic effectsStudies 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.
Clinical efficacy and safetyIn 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 medication 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 ED and 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.
Paediatric populationThe 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).
AbsorptionAvanafil 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.
DistributionAvanafil 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.
BiotransformationAvanafil 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.
EliminationAvanafil 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).
Other special populations
Older menOlder 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.
Renal impairmentIn 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.
Hepatic impairmentSubjects 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.
A. Menarini Farmaceutica Internazionale SRL
Menarini House, Mercury Park, Wycombe Lane, Wooburn Green, Buckinghamshire, HP10 0HH
+44 (0) 1628 856402
0800 085 8678
0800 085 8678
0800 085 8678