Spedra

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Spedra 50 mg tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 50 mg of avanafil. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Tablet. 
Pale yellow oval tablets, debossed with “50” on one side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of erectile dysfunction in adult men. 
 
In order for Spedra to be effective, sexual stimulation is required. 
 
4.2 Posology and method of administration 
 
Posology 
 
Use in adult men 
The recommended dose is 100 mg taken as needed approximately 15 to 30 minutes before sexual 
activity (see section 5.1). Based on individual efficacy and tolerability, the dose may be increased to a 
maximum dose of 200 mg or decreased to 50 mg. The maximum recommended dosing frequency is 
once per day. Sexual stimulation is required for a response to treatment. 
 
Special populations 
 
Elderly(≥ 65 years old) 
Dose adjustments are not required in elder patients. Limited data are available in elder patients aged 
70 years or above. 
 
Renal impairment 
Dose adjustments are not required in patients with mild to moderate renal impairment (creatinine 
clearance ≥ 30 mL/min). Spedra is contraindicated in patients with severe renal impairment (creatinine 
clearance < 30 mL/min) (see sections 4.3 and 5.2). Patients with mild or moderate renal impairment 
(creatinine clearance ≥30 mL/min but <80 mL/min) who were enrolled in phase 3 studies showed 
decreased efficacy compared to those with normal renal function. 
 
Hepatic impairment 
Spedra is contraindicated in patients with severe hepatic impairment (Child Pugh class C) (see 
sections 4.3 and 5.2). Patients with mild to moderate hepatic impairment (Child-Pugh class A or B) 
should initiate treatment with the minimum efficacious dose and adjust posology based on tolerance. 
 
Use in men with diabetes 
Dose adjustments are not required in diabetic patients. 



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Paediatric population 
There is no relevant use of Spedra in the paediatric population in the indication of erectile dysfunction. 
 
Use in patients using other medicinal products 
 
Concomitant use of CYP3A4 inhibitors 
Co-administration of avanafil with potent CYP3A4 inhibitors (including ketoconazole, ritonavir, 
atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir and 
telithromycin) is contraindicated (see sections 4.3, 4.4 and 4.5). 
 
In patients receiving concomitant treatment with moderate CYP3A4 inhibitors (including 
erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the 
maximum recommended dose of avanafil should not exceed 100 mg, with an interval of at least 
48 hours between doses (see section 4.5). 
 
Method of administration 
For oral use. If Spedra is taken with food, the onset of activity may be delayed compared to the fasted 
state (see section 5.2). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Patients who are using any form of organic nitrate or nitric oxide donors (such as amyl nitrite) (see 
section 4.5). 
 
The co-administration of type 5 phosphodiesterase (PDE5) inhibitors, including avanafil, with 
guanylate cyclase stimulators, such as riociguat is contraindicated as it may potentially lead to 
symptomatic hypotension (see section 4.5). 
 
Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing 
cardiovascular disease before prescribing Spedra. 
 
The use of avanafil is contraindicated in: 
 
- Patients who have suffered from a myocardial infarction, stroke, or life-threatening arrhythmia 
 within the last 6 months; 
- Patients with resting hypotension (blood pressure < 90/50 mmHg) or hypertension (blood 
 pressure > 170/100 mmHg); 
- Patients with unstable angina, angina with sexual intercourse, or congestive heart failure 
 categorised as New York Heart Association  Class 2 or greater. 
 
Patients with severe hepatic impairment (Child-Pugh C). 
 
Patients with severe renal impairment (creatinine clearance < 30 mL/min). 
 
Patients who have loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy 
(NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor 
exposure (see section 4.4). 
 
Patients with known hereditary degenerative retinal disorders. 
 
Patients who are using potent CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, 
clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir and telithromycin) (see 
sections 4.2, 4.4 and 4.5). 
 



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4.4 Special warnings and precautions for use 
 
A medical history and physical examination should be undertaken to diagnose erectile dysfunction and 
determine potential underlying causes, before pharmacological treatment is considered. 
 
Cardiovascular status 
Prior 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. 
 
Priapism 
Patients 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 problems 
Visual 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 bleeding 
In 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 hearing 
Patients 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-blockers 
The 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. 



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• 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 inhibitors 
Co-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 dysfunction 
The 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 alcohol 
Consumption 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 studied 
Avanafil 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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Potential for pharmacodynamic interactions with avanafil 
Nitrates 
Avanafil was shown to augment the hypotensive effects of nitrates compared to placebo in healthy 
subjects. This is thought to result from the combined effects of nitrates and avanafil on the nitric 
oxide/cGMP pathway. Therefore, administration of avanafil to patients who are using any form of 
organic nitrate or nitric oxide donor (such as amyl nitrite) is contraindicated. In a patient who has 
taken avanafil within 12 hours, where nitrate administration is deemed medically necessary in a life-
threatening situation, the likelihood of a significant and potentially dangerous drop in blood pressure is 
increased. In such circumstances, nitrates should still only be administered under close medical 
supervision with appropriate haemodynamic monitoring (see section 4.3). 
 
Medicinal products reducing systemic blood pressure 
As a vasodilator, avanafil may reduce systemic blood pressure. If Spedra is used in combination with 
another medicinal product which reduces systemic blood pressure, the additive effects may result in 
symptomatic hypotension (e.g. dizziness, light-headedness, syncope or near-syncope). In phase III 
clinical trials no events of “hypotension” but occasional episodes of “dizziness” were observed (see 
section 4.8). One episode of “syncope” was observed in placebo and one episode on 100 mg of 
avanafil in phase III clinical trials. 
 
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 avanafil (see section 4.4). 
 
Alpha-blockers 
Haemodynamic interactions with doxazosin and tamsulosin were studied in healthy subjects in a two-
period crossover-design trial. In patients receiving stable doxazosin treatment, the placebo-subtracted 
mean maximum decreases in standing and supine systolic blood pressure following avanafil dosing 
were 2.5 mmHg and 6.0 mmHg, respectively. In total, 7/24 subjects experienced values or decreases 
from baseline that were of potential clinical significance following avanafil dosing (see section 4.4). 
 
In patients receiving stable tamsulosin treatment, the placebo-subtracted mean maximum decreases in 
standing and supine systolic blood pressure following avanafil dosing were 3.6 mmHg and 3.1 mmHg, 



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respectively and 5/24 subjects experienced blood pressure values or decreases from baseline that were 
of potential clinical significance following avanafil dosing (see section 4.4).  
 
Antihypertensives other than alpha-blockers 
A clinical study was conducted to assess the effect of avanafil on the potentiation of the blood 
pressure-lowering effects of selected antihypertensive medicinal products (amlodipine and enalapril). 
Results showed a mean maximum decrease in supine blood pressure of 2/3 mmHg compared to 
placebo with enalapril and 1/-1 mmHg with amlodipine when avanafil was co-administered. There 
was a statistically significant difference in maximum decrease from baseline in supine diastolic blood 
pressure with enalapril and avanafil only, which returned to baseline 4 hours after the dose of avanafil. 
In both cohorts, one subject experienced a decrease in blood pressure without symptoms of 
hypotension, which resolved within 1 hour of onset. Avanafil had no effect on the pharmacokinetics of 
amlodipine, but amlodipine increased the maximum and total exposure of avanafil by 28% and 60%, 
respectively (see section 4.4). 
 
Alcohol 
Consumption of alcohol in combination with avanafil can increase the potential for symptomatic 
hypotension. In a single-dose three-way crossover design study evaluating healthy subjects, the mean 
maximum reduction in diastolic blood pressure was significantly greater following avanafil 
administered in combination with alcohol than following avanafil alone (3.2 mmHg) or alcohol alone 
(5.0 mmHg) (see section 4.4). 
 
Other treatments for erectile dysfunction 
The safety and efficacy of combinations of avanafil and other PDE5 inhibitors or other treatments for 
erectile dysfunction have not been studied (see section 4.4). 
 
Effects of other substances on avanafil 
Avanafil is a substrate of and predominantly metabolised by CYP3A4. Studies have shown that 
medicinal products that inhibit CYP3A4 can increase avanafil exposure (see section 4.2). 
 
CYP3A4 Inhibitors 
Ketoconazole (400 mg daily), a selective and highly potent inhibitor of CYP3A4, increased avanafil 
50 mg single-dose Cmax and exposure (AUC) equal to 3-fold and 14-fold respectively and prolonged 
the half-life of avanafil to approximately 9 hours. Ritonavir (600 mg twice daily), a highly potent 
CYP3A4 inhibitor, which also inhibits CYP2C9, increased avanafil 50 mg single-dose Cmax and AUC 
equal to approximately 2-fold and 13-fold, and prolonged the half-life of avanafil to approximately 
9 hours. Other strong inhibitors of CYP3A4 (e.g. itraconazole, voriconazole, clarithromycin, 
nefazodone, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin) would be expected to have 
similar effects. Consequently, co-administration of avanafil with potent CYP3A4 inhibitors is 
contraindicated (see sections 4.2, 4.3 and 4.4). 
 
Erythromycin (500 mg twice daily), a moderate CYP3A4 inhibitor, increased avanafil 200 mg single-
dose Cmax and AUC equal to approximately 2-fold and 3-fold, respectively, and prolonged the half-life 
of avanafil to approximately 8 hours. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, 
diltiazem, fluconazole, fosamprenavir, and verapamil) would be expected to have similar effects. 
Consequently, the maximum recommended dose of avanafil is 100 mg, not to exceed once every 
48 hours for patients taking concomitant moderate CYP3A4 inhibitors (see section 4.2). 
 
Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit 
juice would likely increase avanafil exposure. Patients should be advised to avoid grapefruit juice 
within 24 hours prior to taking avanafil. 
 
CYP3A4 substrate 
Amlodipine (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. 
 



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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 Induction 
The 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. 
 
Transporters 
In 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). 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
Spedra is not indicated for use in women. 
 
There are no data from the use of avanafil in pregnant women. Animal studies do not indicate direct or 
indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition, or 
postnatal development (see section 5.3). 
 
Breast-feeding 
There are no data on the use of avanafil during breast-feeding. 
 
Fertility 



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There was no effect on sperm motility or morphology after single 200 mg oral doses of avanafil in 
healthy volunteers. 
 
In a clinical trial performed in healthy volunteers and adult males with mild erectile dysfunction, the 
daily administration of avanafil 100 mg oral doses over a period of 26 weeks was not associated with 
any untoward effects on sperm concentration, count, motility, or morphology. 
 
4.7 Effects on ability to drive and use machines 
 
Spedra has minor influence on the ability to drive and use machines. As dizziness and altered vision 
were reported in clinical trials with avanafil, patients should be aware of how they react to Spedra 
before driving or using machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The safety profile of Spedra is based on 2,566 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 reactions 
The 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 
Epistaxis 



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Adverse reaction (MedDRA Preferred Term) 
System Organ Class Common Uncommon Rare 

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 

 
Description of selected adverse reactions observed with other PDE5 inhibitors 
Non-arteritic anterior ischaemic optic neuropathy (NAION) and sudden loss of hearing have been 
reported in a small number of postmarketing and clinical trial cases with other PDE5 inhibitors. No 
cases were reported during clinical trials of avanafil (see section 4.4). 
 
Priapism has been reported in a small number of post-marketing and clinical trial cases with other 
PDE5 inhibitors. No cases were reported during clinical trials of avanafil. 
 
Haematuria, haematospermia and penile haemorrhage has been reported in a small number of post-
marketing and clinical trial cases with other PDE5 inhibitors. 
 
Hypotension has been reported post marketing with other PDE5 inhibitors, and dizziness, a symptom 
commonly caused by lowered blood pressure, has been reported in clinical trials with avanafil (see 
section 4.5). 
 
Reporting of suspected adverse reactions 
Reporting 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 national reporting system 
listed in Appendix V. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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4.9 Overdose 
 
Single dose of up to 800 mg of avanafil have been given to healthy subjects and multiple daily doses 
up to 300 mg have been given to patients. Adverse reactions were similar to those seen at lower doses 
but incidence rates and severities were increased. 
 
In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is 
not expected to accelerate clearance as avanafil is highly bound to plasma proteins and it is not 
eliminated in the urine. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Urologicals; Drugs used in erectile dysfunction.  
ATC code: G04BE10. 
 
Mechanism of action 
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. 
 
Pharmacodynamic effects 
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. 
 
Clinical efficacy and safety 
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. 



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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. 
 
Paediatric population 
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). 
 
5.2 Pharmacokinetic properties 
 
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. 
 
Absorption 
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. 
 
Distribution 
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. 
 
Biotransformation 



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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. 
 
Elimination 
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). 
 
Other special populations 
ElderlyOlder 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 impairment 
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. 
 
Hepatic impairment 
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. 
 
5.3 Preclinical safety data 
 
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. 
 



13 

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).  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol 
Fumaric acid 
Hydroxypropylcellulose 
Hydroxypropylcellulose, low substituted 
Calcium carbonate 
Magnesium stearate 
Yellow iron oxide (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
5 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
PVC/PCTFE/Aluminium perforated unit dose blisters in cartons of 4x1, 8x1 and 12x1 tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
MENARINI INTERNATIONAL OPERATIONS LUXEMBOURG S.A. 
1, Avenue de la Gare,  
L-1611 Luxembourg 
Luxembourg  
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/841/001-003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 21 June 2013 
Date of latest renewal: 



14 

 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu  
 

http://www.ema.europa.eu/


15 

 
1. NAME OF THE MEDICINAL PRODUCT 
 
Spedra 100 mg tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 100 mg of avanafil. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Tablet. 
Pale yellow oval tablets, debossed with “100” on one side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of erectile dysfunction in adult men. 
 
In order for Spedra to be effective, sexual stimulation is required. 
 
4.2 Posology and method of administration 
 
Posology 
 
Use in adult men 
The recommended dose is 100 mg taken as needed approximately 15 to 30minutes before sexual 
activity (see section 5.1). Based on individual efficacy and tolerability, the dose may be increased to a 
maximum dose of 200 mg or decreased to 50 mg. The maximum recommended dosing frequency is 
once per day. Sexual stimulation is required for a response to treatment. 
 
Special populations 
 
Elderly (≥ 65 years old) 
Dose adjustments are not required in elder patients. Limited data are available in elder patients aged 
70 years or above. 
 
Renal impairment 
Dose adjustments are not required in patients with mild to moderate renal impairment (creatinine 
clearance ≥ 30 mL/min). Spedra is contraindicated in patients with severe renal impairment (creatinine 
clearance < 30 mL/min) (see sections 4.3 and 5.2). Patients with mild or moderate renal impairment 
(creatinine clearance ≥30 mL/min but <80 mL/min) who were enrolled in phase 3 studies showed 
decreased efficacy compared to those with normal renal function. 
 
Hepatic impairment 
Spedra is contraindicated in patients with severe hepatic impairment (Child Pugh class C) (see 
sections 4.3 and 5.2). Patients with mild to moderate hepatic impairment (Child-Pugh class A or B) 
should initiate treatment with the minimum efficacious dose and adjust posology based on tolerance. 
 
Use in men with diabetes 
Dose adjustments are not required in diabetic patients. 



16 

 
Paediatric population 
There is no relevant use of Spedra in the paediatric population in the indication of erectile dysfunction. 
 
Use in patients using other medicinal products 
 
Concomitant use of CYP3A4 inhibitors 
Co-administration of avanafil with potent CYP3A4 inhibitors (including ketoconazole, ritonavir, 
atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir and 
telithromycin) is contraindicated (see sections 4.3, 4.4 and 4.5). 
 
In patients receiving concomitant treatment with moderate CYP3A4 inhibitors (including 
erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the 
maximum recommended dose of avanafil should not exceed 100 mg, with an interval of at least 
48 hours between doses (see section 4.5). 
 
Method of administration 
For oral use. If Spedra is taken with food, the onset of activity may be delayed compared to the fasted 
state (see section 5.2). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Patients who are using any form of organic nitrate or nitric oxide donors (such as amyl nitrite) (see 
section 4.5). 
 
The co-administration of type 5 phosphodiesterase (PDE5) inhibitors, including avanafil, with 
guanylate cyclase stimulators, such as riociguat is contraindicated as it may potentially lead to 
symptomatic hypotension (see section 4.5). 
 
Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing 
cardiovascular disease before prescribing Spedra. 
 
The use of avanafil is contraindicated in: 
 
- Patients who have suffered from a myocardial infarction, stroke, or life-threatening arrhythmia 
 within the last 6 months; 
- Patients with resting hypotension (blood pressure < 90/50 mmHg) or hypertension (blood 
 pressure > 170/100 mmHg); 
- Patients with unstable angina, angina with sexual intercourse, or congestive heart failure 
 categorised as New York Heart Association  Class 2 or greater. 
 
Patients with severe hepatic impairment (Child-Pugh C). 
 
Patients with severe renal impairment (creatinine clearance < 30 mL/min). 
 
Patients who have loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy 
(NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor 
exposure (see section 4.4). 
 
Patients with known hereditary degenerative retinal disorders. 
 
Patients who are using potent CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, 
clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir and telithromycin) (see 
sections 4.2, 4.4 and 4.5). 
 



17 

4.4 Special warnings and precautions for use 
 
A medical history and physical examination should be undertaken to diagnose erectile dysfunction and 
determine potential underlying causes, before pharmacological treatment is considered. 
 
Cardiovascular status 
Prior 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. 
 
Priapism 
Patients 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 problems 
Visual 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 bleeding 
In 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 hearing 
Patients 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-blockers 
The 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. 



18 

• 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 inhibitors 
Co-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 dysfunction 
The 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 alcohol 
Consumption 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 studied 
Avanafil 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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Potential for pharmacodynamic interactions with avanafil 
Nitrates 
Avanafil was shown to augment the hypotensive effects of nitrates compared to placebo in healthy 
subjects. This is thought to result from the combined effects of nitrates and avanafil on the nitric 
oxide/cGMP pathway. Therefore, administration of avanafil to patients who are using any form of 
organic nitrate or nitric oxide donor (such as amyl nitrite) is contraindicated. In a patient who has 
taken avanafil within 12 hours, where nitrate administration is deemed medically necessary in a life-
threatening situation, the likelihood of a significant and potentially dangerous drop in blood pressure is 
increased. In such circumstances, nitrates should still only be administered under close medical 
supervision with appropriate haemodynamic monitoring (see section 4.3). 
 
Medicinal products reducing systemic blood pressure 
As a vasodilator, avanafil may reduce systemic blood pressure. If Spedra is used in combination with 
another medicinal product which reduces systemic blood pressure, the additive effects may result in 
symptomatic hypotension (e.g. dizziness, light-headedness, syncope or near-syncope). In phase III 
clinical trials no events of “hypotension” but occasional episodes of “dizziness” were observed (see 
section 4.8). One episode of “syncope” was observed in placebo and one episode on 100 mg of 
avanafil in phase III clinical trials. 
 
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 avanafil (see section 4.4). 
 
Alpha-blockers 
Haemodynamic interactions with doxazosin and tamsulosin were studied in healthy subjects in a two-
period crossover-design trial. In patients receiving stable doxazosin treatment, the placebo-subtracted 
mean maximum decreases in standing and supine systolic blood pressure following avanafil dosing 
were 2.5 mmHg and 6.0 mmHg, respectively. In total, 7/24 subjects experienced values or decreases 
from baseline that were of potential clinical significance following avanafil dosing (see section 4.4). 
 
In patients receiving stable tamsulosin treatment, the placebo-subtracted mean maximum decreases in 
standing and supine systolic blood pressure following avanafil dosing were 3.6 mmHg and 3.1 mmHg, 



19 

respectively and 5/24 subjects experienced blood pressure values or decreases from baseline that were 
of potential clinical significance following avanafil dosing (see section 4.4).  
 
Antihypertensives other than alpha-blockers 
A clinical study was conducted to assess the effect of avanafil on the potentiation of the blood 
pressure-lowering effects of selected antihypertensive medicinal products (amlodipine and enalapril). 
Results showed a mean maximum decrease in supine blood pressure of 2/3 mmHg compared to 
placebo with enalapril and 1/-1 mmHg with amlodipine when avanafil was co-administered. There 
was a statistically significant difference in maximum decrease from baseline in supine diastolic blood 
pressure with enalapril and avanafil only, which returned to baseline 4 hours after the dose of avanafil. 
In both cohorts, one subject experienced a decrease in blood pressure without symptoms of 
hypotension, which resolved within 1 hour of onset. Avanafil had no effect on the pharmacokinetics of 
amlodipine, but amlodipine increased the maximum and total exposure of avanafil by 28% and 60%, 
respectively (see section 4.4). 
 
Alcohol 
Consumption of alcohol in combination with avanafil can increase the potential for symptomatic 
hypotension. In a single-dose three-way crossover design study evaluating healthy subjects, the mean 
maximum reduction in diastolic blood pressure was significantly greater following avanafil 
administered in combination with alcohol than following avanafil alone (3.2 mmHg) or alcohol alone 
(5.0 mmHg) (see section 4.4). 
 
Other treatments for erectile dysfunction 
The safety and efficacy of combinations of avanafil and other PDE5 inhibitors or other treatments for 
erectile dysfunction have not been studied (see section 4.4). 
 
Effects of other substances on avanafil 
Avanafil is a substrate of and predominantly metabolised by CYP3A4. Studies have shown that 
medicinal products that inhibit CYP3A4 can increase avanafil exposure (see section 4.2). 
 
CYP3A4 Inhibitors 
Ketoconazole (400 mg daily), a selective and highly potent inhibitor of CYP3A4, increased avanafil 
50 mg single-dose Cmax and exposure (AUC) equal to 3-fold and 14-fold respectively and prolonged 
the half-life of avanafil to approximately 9 hours. Ritonavir (600 mg twice daily), a highly potent 
CYP3A4 inhibitor, which also inhibits CYP2C9, increased avanafil 50 mg single-dose Cmax and AUC 
equal to approximately 2-fold and 13-fold, and prolonged the half-life of avanafil to approximately 
9 hours. Other strong inhibitors of CYP3A4 (e.g. itraconazole, voriconazole, clarithromycin, 
nefazodone, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin) would be expected to have 
similar effects. Consequently, co-administration of avanafil with potent CYP3A4 inhibitors is 
contraindicated (see sections 4.2, 4.3 and 4.4). 
 
Erythromycin (500 mg twice daily), a moderate CYP3A4 inhibitor, increased avanafil 200 mg single-
dose Cmax and AUC equal to approximately 2-fold and 3-fold, respectively, and prolonged the half-life 
of avanafil to approximately 8 hours. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, 
diltiazem, fluconazole, fosamprenavir, and verapamil) would be expected to have similar effects. 
Consequently, the maximum recommended dose of avanafil is 100 mg, not to exceed once every 
48 hours for patients taking concomitant moderate CYP3A4 inhibitors (see section 4.2). 
 
Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit 
juice would likely increase avanafil exposure. Patients should be advised to avoid grapefruit juice 
within 24 hours prior to taking avanafil. 
 
CYP3A4 substrate 
Amlodipine (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. 
 



20 

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 Induction 
The 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. 
 
Transporters 
In 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 PDE 5 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). 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
Spedra is not indicated for use in women. 
 
There are no data from the use of avanafil in pregnant women. Animal studies do not indicate direct or 
indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition, or 
postnatal development (see section 5.3). 
 
Breast-feeding 
There are no data on the use of avanafil during breast-feeding. 
 
Fertility 



21 

There was no effect on sperm motility or morphology after single 200 mg oral doses of avanafil in 
healthy volunteers. 
 
In a clinical trial performed in healthy volunteers and adult males with mild erectile dysfunction, the 
daily administration of avanafil 100 mg oral doses over a period of 26 weeks was not associated with 
any untoward effects on sperm concentration, count, motility, or morphology. 
 
4.7 Effects on ability to drive and use machines 
 
Spedra has minor influence on the ability to drive and use machines. As dizziness and altered vision 
were reported in clinical trials with avanafil, patients should be aware of how they react to Spedra 
before driving or using machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The safety profile of Spedra is based on 2,566 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 reactions 
The 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 
Epistaxis 



22 

Adverse reaction (MedDRA Preferred Term) 
System Organ Class Common Uncommon Rare 

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 

 
Description of selected adverse reactions observed with other PDE5 inhibitors 
Non-arteritic anterior ischaemic optic neuropathy (NAION) and sudden loss of hearing have been 
reported in a small number of postmarketing and clinical trial cases with other PDE5 inhibitors. No 
cases were reported during clinical trials of avanafil (see section 4.4). 
 
Priapism has been reported in a small number of post-marketing and clinical trial cases with other 
PDE5 inhibitors. No cases were reported during clinical trials of avanafil. 
 
Haematuria, haematospermia and penile haemorrhage has been reported in a small number of post-
marketing and clinical trial cases with other PDE5 inhibitors. 
 
Hypotension has been reported post marketing with other PDE5 inhibitors, and dizziness, a symptom 
commonly caused by lowered blood pressure, has been reported in clinical trials with avanafil (see 
section 4.5). 
 
Reporting of suspected adverse reactions 
Reporting 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 national reporting system 
listed in Appendix V. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


23 

4.9 Overdose 
 
Single dose of up to 800 mg of avanafil have been given to healthy subjects and multiple daily doses 
up to 300 mg have been given to patients. Adverse reactions were similar to those seen at lower doses 
but incidence rates and severities were increased. 
 
In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is 
not expected to accelerate clearance as avanafil is highly bound to plasma proteins and it is not 
eliminated in the urine. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Urologicals: Drugs used in erectile dysfunction.  
ATC code: G04BE10. 
 
Mechanism of action 
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. 
 
Pharmacodynamic effects 
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. 
 
Clinical efficacy and safety 
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 
1774patients 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. 



24 

 
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. 
 
Paediatric population 
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). 
 
5.2 Pharmacokinetic properties 
 
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. 
 
 
Absorption 
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. 
 
Distribution 
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. 
 



25 

Biotransformation 
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. 
 
Elimination 
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). 
 
Other special populations 
Elderly 
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. 
 
Renal impairment 
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. 
 
Hepatic impairment 
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. 
 
5.3 Preclinical safety data 
 
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. 
 



26 

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). 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol 
Fumaric acid 
Hydroxypropylcellulose 
Hydroxypropylcellulose, low substituded 
Calcium carbonate 
Magnesium stearate 
Yellow iron oxide (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
5 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
PVC/PCTFE/Aluminium perforated unit dose blisters in cartons of 2x1, 4x1, 8x1 and 12x1 tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
MENARINI INTERNATIONAL OPERATIONS LUXEMBOURG S.A. 
1, Avenue de la Gare, L-1611 Luxembourg 
Luxembourg  
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/841/004-007 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 21 June 2013 
Date of latest renewal:  
 



27 

 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu  
 
 

http://www.ema.europa.eu/


28 

 
1. NAME OF THE MEDICINAL PRODUCT 
 
Spedra 200 mg tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 200 mg of avanafil. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Tablet. 
Pale yellow oval tablets, debossed with “200” on one side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of erectile dysfunction in adult men. 
 
In order for Spedra to be effective, sexual stimulation is required. 
 
4.2 Posology and method of administration 
 
Posology 
 
Use in adult men 
The recommended dose is 100 mg taken as needed approximately 15 to 30 minutes before sexual 
activity (see section 5.1). Based on individual efficacy and tolerability, the dose may be increased to a 
maximum dose of 200 mg or decreased to 50 mg. The maximum recommended dosing frequency is 
once per day. Sexual stimulation is required for a response to treatment. 
 
Special populations 
 
 Elderly  (≥ 65 years old) 
Dose adjustments are not required in elder patients. Limited data are available in elder patients aged 
70 years or above. 
 
Renal impairment 
Dose adjustments are not required in patients with mild to moderate renal impairment (creatinine 
clearance ≥ 30 mL/min). Spedra is contraindicated in patients with severe renal impairment (creatinine 
clearance < 30 mL/min) (see sections 4.3 and 5.2). Patients with mild or moderate renal impairment 
(creatinine clearance ≥30 mL/min but <80 mL/min) who were enrolled in phase 3 studies showed 
decreased efficacy compared to those with normal renal function. 
 
Hepatic impairment 
Spedra is contraindicated in patients with severe hepatic impairment (Child Pugh class C) (see 
sections 4.3 and 5.2). Patients with mild to moderate hepatic impairment (Child-Pugh class A or B) 
should initiate treatment with the minimum efficacious dose and adjust posology based on tolerance. 
 
Use in men with diabetes 
Dose adjustments are not required in diabetic patients. 



29 

 
Paediatric population 
There is no relevant use of Spedra in the paediatric population in the indication of erectile dysfunction. 
 
Use in patients using other medicinal products 
 
Concomitant use of CYP3A4 inhibitors 
Co-administration of avanafil with potent CYP3A4 inhibitors (including ketoconazole, ritonavir, 
atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir and 
telithromycin) is contraindicated (see sections 4.3, 4.4 and 4.5). 
 
In patients receiving concomitant treatment with moderate CYP3A4 inhibitors (including 
erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the 
maximum recommended dose of avanafil should not exceed 100 mg, with an interval of at least 
48 hours between doses (see section 4.5). 
 
Method of administration 
For oral use. If Spedra is taken with food, the onset of activity may be delayed compared to the fasted 
state (see section 5.2). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Patients who are using any form of organic nitrate or nitric oxide donors (such as amyl nitrite) (see 
section 4.5). 
 
The co-administration of type 5 phosphodiesterase (PDE5) inhibitors, including avanafil, with 
guanylate cyclase stimulators, such as riociguat is contraindicated as it may potentially lead to 
symptomatic hypotension (see section 4.5). 
 
Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing 
cardiovascular disease before prescribing Spedra. 
 
The use of avanafil is contraindicated in: 
 
- Patients who have suffered from a myocardial infarction, stroke, or life-threatening arrhythmia 
 within the last 6 months; 
- Patients with resting hypotension (blood pressure < 90/50 mmHg) or hypertension (blood 
 pressure > 170/100 mmHg); 
- Patients with unstable angina, angina with sexual intercourse, or congestive heart failure 
 categorised as New York Heart Association  Class 2 or greater. 
 
Patients with severe hepatic impairment (Child-Pugh C). 
 
Patients with severe renal impairment (creatinine clearance < 30 mL/min). 
 
Patients who have loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy 
(NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor 
exposure (see section 4.4). 
 
Patients with known hereditary degenerative retinal disorders. 
 
Patients who are using potent CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, 
clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir and telithromycin) (see 
sections 4.2, 4.4 and 4.5). 
 



30 

4.4 Special warnings and precautions for use 
 
A medical history and physical examination should be undertaken to diagnose erectile dysfunction and 
determine potential underlying causes, before pharmacological treatment is considered. 
 
Cardiovascular status 
Prior 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. 
 
Priapism 
Patients 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 problems 
Visual 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 bleeding 
In 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 hearing 
Patients 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-blockers 
The 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. 



31 

• 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 inhibitors 
Co-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 dysfunction 
The 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 alcohol 
Consumption 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 studied 
Avanafil 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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Potential for pharmacodynamic interactions with avanafil 
Nitrates 
Avanafil was shown to augment the hypotensive effects of nitrates compared to placebo in healthy 
subjects. This is thought to result from the combined effects of nitrates and avanafil on the nitric 
oxide/cGMP pathway. Therefore, administration of avanafil to patients who are using any form of 
organic nitrate or nitric oxide donor (such as amyl nitrite) is contraindicated. In a patient who has 
taken avanafil within 12 hours, where nitrate administration is deemed medically necessary in a life-
threatening situation, the likelihood of a significant and potentially dangerous drop in blood pressure is 
increased. In such circumstances, nitrates should still only be administered under close medical 
supervision with appropriate haemodynamic monitoring (see section 4.3). 
 
Medicinal products reducing systemic blood pressure 
As a vasodilator, avanafil may reduce systemic blood pressure. If Spedra is used in combination with 
another medicinal product which reduces systemic blood pressure, the additive effects may result in 
symptomatic hypotension (e.g. dizziness, light-headedness, syncope or near-syncope). In phase III 
clinical trials no events of “hypotension” but occasional episodes of “dizziness” were observed (see 
section 4.8). One episode of “syncope” was observed in placebo and one episode on 100 mg of 
avanafil in phase III clinical trials. 
 
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 avanafil (see section 4.4). 
 
Alpha-blockers 
Haemodynamic interactions with doxazosin and tamsulosin were studied in healthy subjects in a two-
period crossover-design trial. In patients receiving stable doxazosin treatment, the placebo-subtracted 
mean maximum decreases in standing and supine systolic blood pressure following avanafil dosing 
were 2.5 mmHg and 6.0 mmHg, respectively. In total, 7/24 subjects experienced values or decreases 
from baseline that were of potential clinical significance following avanafil dosing (see section 4.4). 
 
In patients receiving stable tamsulosin treatment, the placebo-subtracted mean maximum decreases in 
standing and supine systolic blood pressure following avanafil dosing were 3.6 mmHg and 3.1 mmHg, 



32 

respectively and 5/24 subjects experienced blood pressure values or decreases from baseline that were 
of potential clinical significance following avanafil dosing (see section 4.4).  
 
Antihypertensives other than alpha-blockers 
A clinical study was conducted to assess the effect of avanafil on the potentiation of the blood 
pressure-lowering effects of selected antihypertensive medicinal products (amlodipine and enalapril). 
Results showed a mean maximum decrease in supine blood pressure of 2/3 mmHg compared to 
placebo with enalapril and 1/-1 mmHg with amlodipine when avanafil was co-administered. There 
was a statistically significant difference in maximum decrease from baseline in supine diastolic blood 
pressure with enalapril and avanafil only, which returned to baseline 4 hours after the dose of avanafil. 
In both cohorts, one subject experienced a decrease in blood pressure without symptoms of 
hypotension, which resolved within 1 hour of onset. Avanafil had no effect on the pharmacokinetics of 
amlodipine, but amlodipine increased the maximum and total exposure of avanafil by 28% and 60%, 
respectively (see section 4.4). 
 
Alcohol 
Consumption of alcohol in combination with avanafil can increase the potential for symptomatic 
hypotension. In a single-dose three-way crossover design study evaluating healthy subjects, the mean 
maximum reduction in diastolic blood pressure was significantly greater following avanafil 
administered in combination with alcohol than following avanafil alone (3.2 mmHg) or alcohol alone 
(5.0 mmHg) (see section 4.4). 
 
Other treatments for erectile dysfunction 
The safety and efficacy of combinations of avanafil and other PDE5 inhibitors or other treatments for 
erectile dysfunction have not been studied (see section 4.4). 
 
Effects of other substances on avanafil 
Avanafil is a substrate of and predominantly metabolised by CYP3A4. Studies have shown that 
medicinal products that inhibit CYP3A4 can increase avanafil exposure (see section 4.2). 
 
CYP3A4 Inhibitors 
Ketoconazole (400 mg daily), a selective and highly potent inhibitor of CYP3A4, increased avanafil 
50 mg single-dose Cmax and exposure (AUC) equal to 3-fold and 14-fold respectively and prolonged 
the half-life of avanafil to approximately 9 hours. Ritonavir (600 mg twice daily), a highly potent 
CYP3A4 inhibitor, which also inhibits CYP2C9, increased avanafil 50 mg single-dose Cmax and AUC 
equal to approximately 2-fold and 13-fold, and prolonged the half-life of avanafil to approximately 
9 hours. Other strong inhibitors of CYP3A4 (e.g. itraconazole, voriconazole, clarithromycin, 
nefazodone, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin) would be expected to have 
similar effects. Consequently, co-administration of avanafil with potent CYP3A4 inhibitors is 
contraindicated (see sections 4.2, 4.3 and 4.4). 
 
Erythromycin (500 mg twice daily), a moderate CYP3A4 inhibitor, increased avanafil 200 mg single-
dose Cmax and AUC equal to approximately 2-fold and 3-fold, respectively, and prolonged the half-life 
of avanafil to approximately 8 hours. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, 
diltiazem, fluconazole, fosamprenavir, and verapamil) would be expected to have similar effects. 
Consequently, the maximum recommended dose of avanafil is 100 mg, not to exceed once every 
48 hours for patients taking concomitant moderate CYP3A4 inhibitors (see section 4.2). 
 
Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit 
juice would likely increase avanafil exposure. Patients should be advised to avoid grapefruit juice 
within 24 hours prior to taking avanafil. 
 
CYP3A4 substrate 
Amlodipine (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. 
 



33 

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 Induction 
The 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. 
 
Transporters 
In 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 PDE 5 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). 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
Spedra is not indicated for use in women. 
 
There are no data from the use of avanafil in pregnant women. Animal studies do not indicate direct or 
indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition, or 
postnatal development (see section 5.3). 
 
Breast-feeding 
There are no data on the use of avanafil during breast-feeding. 
 
Fertility 



34 

There was no effect on sperm motility or morphology after single 200 mg oral doses of avanafil in 
healthy volunteers. 
 
In a clinical trial performed in healthy volunteers and adult males with mild erectile dysfunction, the 
daily administration of avanafil 100 mg oral doses over a period of 26 weeks was not associated with 
any untoward effects on sperm concentration, count, motility, or morphology . 
 
4.7 Effects on ability to drive and use machines 
 
Spedra has minor influence on the ability to drive and use machines. As dizziness and altered vision 
were reported in clinical trials with avanafil, patients should be aware of how they react to Spedra 
before driving or using machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The safety profile of Spedra is based on 2,566 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 reactions 
The 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 
Epistaxis 



35 

Adverse reaction (MedDRA Preferred Term) 
System Organ Class Common Uncommon Rare 

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 

 
Description of selected adverse reactions observed with other PDE5 inhibitors 
Non-arteritic anterior ischaemic optic neuropathy (NAION) and sudden loss of hearing have been 
reported in a small number of postmarketing and clinical trial cases with other PDE5 inhibitors. No 
cases were reported during clinical trials of avanafil (see section 4.4). 
 
Priapism has been reported in a small number of post-marketing and clinical trial cases with other 
PDE5 inhibitors. No cases were reported during clinical trials of avanafil. 
 
Haematuria, haematospermia and penile haemorrhage has been reported in a small number of post-
marketing and clinical trial cases with other PDE5 inhibitors. 
 
Hypotension has been reported post marketing with other PDE5 inhibitors, and dizziness, a symptom 
commonly caused by lowered blood pressure, has been reported in clinical trials with avanafil (see 
section 4.5). 
 
Reporting of suspected adverse reactions 
Reporting 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 national reporting system 
listed in Appendix V. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


36 

 
4.9 Overdose 
 
Single dose of up to 800 mg of avanafil have been given to healthy subjects and multiple daily doses 
up to 300 mg have been given to patients. Adverse reactions were similar to those seen at lower doses 
but incidence rates and severities were increased. 
 
In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is 
not expected to accelerate clearance as avanafil is highly bound to plasma proteins and it is not 
eliminated in the urine. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Urologicals: Drugs used in erectile dysfunction.  
ATC code: G04BE10. 
 
Mechanism of action 
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. 
 
Pharmacodynamic effects 
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. 
 
Clinical efficacy and safety 
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 



37 

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. 
 
Paediatric population 
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). 
 
5.2 Pharmacokinetic properties 
 
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. 
 
Absorption 
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. 
 
Distribution 
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. 
 



38 

Biotransformation 
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. 
 
Elimination 
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). 
 
Other special populations 
Elderly  
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. 
 
Renal impairment 
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. 
 
Hepatic impairment 
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. 
 
5.3 Preclinical safety data 
 
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. 
 



39 

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). 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol 
Fumaric acid 
Hydroxypropylcellulose 
Hydroxypropylcellulose, low substituted 
Calcium carbonate 
Magnesium stearate 
Yellow iron oxide (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
5 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
PVC/PCTFE/Aluminium perforated unit dose blisters in cartons of 2x1, 4x1, 8x1 and 12x1 tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
MENARINI INTERNATIONAL OPERATIONS LUXEMBOURG S.A. 
1, Avenue de la Gare, L-1611 Luxembourg 
Luxembourg  
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/841/008-011 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 21 June 2013 
Date of the latest renewal:  
 



40 

 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu  
 
 

http://www.ema.europa.eu/


41 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND 
USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 
SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 



42 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Menarini - Von Heyden GmbH 
Leipziger Straβe 7-13 
01097 Dresden  
Germany 
 
or 
 
Sanofi Winthrop Industrie 
1, rue de la Vierge 
Ambares et Lagrave 
33565 Carbon-Blanc-Cedex 
France 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to medical prescription. 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 



43 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



44 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 



45 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Spedra 50 mg tablets 
avanafil 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 50 mg avanafil. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
4x1 tablets 
8x1 tablets 
12x1 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
 



46 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
MENARINI INTERNATIONAL OPERATIONS LUXEMBOURG S.A. 
1, Avenue de la Gare, L-1611 Luxembourg 
Luxembourg  
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/841/001 4 tablets 
EU/1/13/841/002 8 tablets 
EU/1/13/841/003 12 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Spedra 50 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
PC: {number} 
SN: {number}  
NN: {number}  
 
 
 
 
 
 
 
 



47 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Spedra 50 mg tablets 
avanafil 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Menarini Luxembourg 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



48 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Spedra 100 mg tablets 
avanafil 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 100 mg avanafil. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
2x1 tablets 
4x1 tablets 
8x1 tablets 
12x1 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
 



49 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
MENARINI INTERNATIONAL OPERATIONS LUXEMBOURG S.A. 
1, Avenue de la Gare, L-1611 Luxembourg 
Luxembourg  
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/841/004 2 tablets 
EU/1/13/841/005 4 tablets 
EU/1/13/841/006 8 tablets 
EU/1/13/841/007 12 tablets 
 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Spedra 100 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
PC: {number} 
SN: {number}  
NN: {number}  
 
 
 
 
 
 



50 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Spedra 100 mg tablets 
avanafil 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Menarini Luxembourg 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



51 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Spedra 200 mg tablets 
avanafil 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 200 mg avanafil. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
4x1 tablets 
8x1 tablets 
12x1 tablets 
2x1 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
 
 



52 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
MENARINI INTERNATIONAL OPERATIONS LUXEMBOURG S.A. 
1, Avenue de la Gare, L-1611 Luxembourg 
Luxembourg 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/841/008 4 tablets 
EU/1/13/841/009 8 tablets 
EU/1/13/841/010 12 tablets 
EU/1/13/841/011 2 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Spedra 200 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
PC: {number} 
SN: {number}  
NN: {number}  
 
 
 



53 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Spedra 200 mg tablets 
avanafil 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Menarini Luxembourg 
 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



54 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



55 

Package leaflet: Information for the patient 
 

Spedra 50 mg tablets 
avanafil 

 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 
 even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Spedra is and what it is used for 
2. What you need to know before you take Spedra 
3. How to take Spedra 
4. Possible side effects 
5. How to store Spedra 
6. Contents of the pack and other information 
 
 
1. What Spedra is and what it is used for 
 
Spedra contains the active substance avanafil. It belongs to a group of medicines called 
phosphodiesterase type 5 (PDE5) inhibitors. Spedra is a treatment for adult men suffering from 
erectile dysfunction (also known as impotence). This is when you cannot get, or keep a hard, erect 
penis suitable for sexual activity. 
 
Spedra works by helping the blood vessels in your penis to relax. This increases the blood flow into 
your penis, helping it stay hard and erect when you get sexually excited. Spedra does not cure your 
condition. 
 
It is important to note that Spedra only works if you are sexually stimulated. You and your partner will 
still need to use foreplay to get ready for sex – just as you would if you were not taking a medicine to 
help you. 
 
Spedra will not help you if you do not have erectile dysfunction. Spedra is not for women. 
 
 
2. What you need to know before you take Spedra 
 
Do not take Spedra: 
 
• If you are allergic to avanafil or any of the other ingredients of this medicine (listed in section 6) 
• If you are taking “nitrate” medicines for chest pain (angina), such as amyl nitrite or glyceryl 

trinitrate. Spedra can increase the effects of these medicines and severely lower your blood 
pressure 

• If you are taking   s for HIV or AIDS such as ritonavir, indinavir, saquinavir, nelfinavir or 
atazanavir 

• If you are taking medicines for fungal infections such as ketoconazole, itraconazole or 
voriconazole or certain antibiotics for bacterial infections, such as clarithromycin or 
telithromycin 



56 

• If you have a serious cardiac problem 
• If you have had a stroke or heart attack in the last 6 months 
• If you have low blood pressure or high blood pressure not controlled by medicines 
• If you have chest pain (angina) or you get chest pain during sexual intercourse 
• If you have a serious liver or kidney problem 
• If you have loss of vision in one eye due to not enough blood getting to your eye (non-arteritic 

ischemic optic neuropathy [NAION]) 
• If certain serious eye problems run in your family (such as retinitis pigmentosa). 
• If you are taking riociguat. This medicine is used to treat pulmonary arterial hypertension (i.e., 

high blood pressure in the lungs) and chronic thromboembolic pulmonary hypertension (i.e., 
high blood pressure in the lungs secondary to blood clots). PDE5 inhibitors have been shown to 
increase the hypotensive effects of this medicine. If you are taking riociguat or are unsure tell 
your doctor. 
 

Do not take Spedra if any of the above apply to you. If you are not sure, talk to your doctor or 
pharmacist before taking Spedra. 
 
Warnings and precautions 
 
Talk to your doctor or pharmacist before taking Spedra: 
• If you have heart trouble. It may be risky for you to have sexual intercourse 
• If you suffer from priapism, that is a persistent erection lasting 4 hours or more. This can 

happen in men with conditions like sickle cell disease, multiple myeloma or leukaemia. 
• If you have a physical condition that affects the shape of your penis (such as angulation, 

Peyronie’s disease or cavernosal fibrosis) 
• If you have any bleeding disorder or active peptic ulceration. 
 
If any of the above apply to you talk to your doctor or pharmacist before taking Spedra. Check with 
your doctor or pharmacist if you are not sure. 
 
Problems with your sight or hearing 
Some men taking medicines like Spedra have had problems with their sight and hearing – see “Serious 
side effects” in section 4 for more details. It is not known if these problems are related directly to 
Spedra, other diseases that you may have or a combination of factors. 
 
Children and adolescents 
 
Spedra should not be taken by children and adolescents under 18 years of age. 
 
Other medicines and Spedra 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This is because Spedra can affect the way some other medicines work. Also some other 
medicines can affect the way Spedra works. 
 
In particular, tell your doctor and do not take Spedra if you are taking “nitrate” medicines for chest 
pain (angina) such as amyl nitrite or glyceryl trinitrate. Spedra has been shown to increase the effects 
of these medicines and severely lower your blood pressure. Also do not take Spedra if you are taking 
medicines for HIV or AIDS such as ritonavir, indinavir, saquinavir, nelfinavir or atazanavir or if you 
are taking medicines for fungal infections such as ketoconazole, itraconazole or voriconazole or 
certain antibiotics for bacterial infections, such as clarithromycin or telithromycin (see beginning of 
section 2 under ‘Do not take Spedra’). 
 
Tell your doctor or pharmacist if you are taking any of the following medicines: 
• so called “alpha-blockers” – for prostate problems or for lowering your high blood pressure 



57 

• medicines for an irregular heartbeat (“arrhythmia”) such as quinidine, procainamide, 
amiodarone or sotalol 

• antibiotics for infections such as erythromycin 
• phenobarbital or primidone – for epilepsy 
• carbamazepine – for epilepsy, to stabilise your mood or for certain types of pain 
• other medicines that may reduce the breakdown of Spedra in the body (‘moderate CYP3A4 

inhibitors’) including amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and 
verapamil. 

• riociguat 
 
Do not use Spedra together with other treatments for erectile dysfunction such as sildenafil, tadalafil or 
vardenafil. 
 
If any of the above apply to you talk to your doctor or pharmacist before taking Spedra. Check with 
your doctor or pharmacist if you are not sure. 
 
Spedra with drink and alcohol 
 
Grapefruit juice can increase exposure to the medicine and should be avoided within 24 hours prior to 
taking Spedra. 
Drinking alcohol at the same time as taking Spedra may increase your heart rate and lower your blood 
pressure. You may feel dizzy (especially when standing), have a headache or feel your heart beating in 
your chest (palpitations). Drinking alcohol may also decrease your ability to get an erection. 
 
Fertility 
 
There was no effect on sperm movement or structure after single 200 mg oral doses of avanafil in 
healthy volunteers. 
 
The repeated oral administration of avanafil 100 mg over a period of 26 weeks to healthy volunteers 
and adult males with mild erectile dysfunction was not associated with any untoward effects on sperm 
concentration, count, motility, or morphology. 
 
 
Driving and using machines 
 
Spedra can make you feel dizzy or affect your vision. If this happens, do not drive, cycle, use tools or 
machines. 
 
 
3. How to take Spedra 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
The recommended dose is a 100 mg tablet, as needed. You should not take Spedra more than once a 
day. You could have been given the dose of one 200 mg tablet if your doctor has decided that the  100 
mg dose was too weak for you, or the dose of one 50 mg tablet if your doctor has decided  that the 100 
mg tablet was too strong for you. Dose adjustments can also be required if Spedra is used together 
with certain other medicines. If you are taking a medicine such as erythromycin, amprenavir, 
aprepitant, diltiazem, fluconazole, fosamprenavir or verapamil (‘moderate CYP3A4 inhibitors’) the 
recommended dose of Spedra is a 100 mg tablet, with an interval of at least 2 days between doses. 
You should take Spedra about 30 minutes before you have sexual intercourse. Remember that Spedra 
will only help you to get an erection if you are sexually stimulated. 
Spedra can be taken with or without food; if taken with food, it may take longer to work. 
 



58 

If you take more Spedra than you should 
 
If you take too much Spedra, you should tell your doctor straight away. You may get more side effects 
than usual and they may be worse. 
 
If you have any further questions on the use of Spedra, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects 
 
Stop taking Spedra and see a doctor straight away if you notice any of the following serious side 
effects – you may need urgent medical treatment: 
• an erection that will not go away (“priapism”). If you get an erection that lasts more than 

4 hours, this must be treated as soon as possible or lasting damage can happen to your penis 
(including not being able to get erections). 

• blurred vision. 
• sudden decrease or loss of vision in one or both eyes. 
• sudden decrease or loss of hearing (sometimes you may also feel dizzy or have ringing in your 

ears). 
 
Stop taking Spedra and see a doctor straight away, if you notice any of the serious side effects above. 
 
Other side effects include: 
 
Common (may affect up to 1 in 10 people) 
• headache 
• flushing 
• nasal congestion 
 
Uncommon (may affect up to 1 in 100 people) 
• feeling dizzy 
• feeling sleepy or very tired 
• sinus congestion 
• back pain 
• hot flush 
• feeling out of breath when you exert yourself 
• heartbeat changes seen on a heart tracing (ECG) 
• increased heart beat 
• feeling your heartbeat in your chest (palpitations) 
• indigestion, feeling or being sick to your stomach 
• blurry vision 
• raised liver enzymes 
 
Rare (may affect up to 1 in 1,000 people) 
• influenza 
• influenza-like illness 
• stuffy or runny nose 
• hayfever 
• congestion in the nose, sinuses or upper part of the airway bringing air into the lungs 
• gout 
• trouble sleeping (insomnia) 



59 

• premature ejaculation 
• feeling strange 
• feeling unable to keep still 
• chest pain 
• serious chest pain 
• fast heart beat 
• high blood pressure 
• dry mouth 
• stomach ache or heartburn 
• pain or discomfort in the lower abdomen 
• diarrhoea 
• rash 
• pain in the lower back or side of lower chest 
• muscle aches or pains 
• muscle spasms 
• frequent urination 
• penile disorder 
• spontaneous erection without sexual stimulation 
• itching in the genital area 
• feeling weak or tired all the time 
• swelling in the feet or ankles 
• increased blood pressure 
• pink or red urine, blood in the urine 
• abnormal extra sound from the heart 
• an abnormal blood test result for a prostate test called ‘PSA’ 
• an abnormal blood test result for bilirubin, a chemical produced from the normal breakdown of 

red blood cells 
• an abnormal blood test result for creatinine, a chemical excreted in the urine, and a measure of 

kidney function 
• weight gain 
• fever 
• nosebleed 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Spedra 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the blister and carton after “EXP”. 
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage condition. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


60 

 
What Spedra contains 
 
• The active substance is avanafil. Each tablet contains 50 mg of avanafil. 
• The other ingredients are mannitol, fumaric acid, hydroxypropylcellulose, 

hydroxypropylcellulose low substituted, calcium carbonate, magnesium stearate and ferric oxide 
yellow (E172). 
 

What Spedra looks like and contents of the pack 
 
Spedra is a pale yellow oval tablet, marked “50”on one side. The tablets are provided in perforated 
unit dose blister packs containing 4x1, 8x1, or 12x1 tablets. 
 
Not all pack sizes may be marketed in your country. 
 
 
Marketing Authorisation Holder:  
MENARINI INTERNATIONAL OPERATIONS LUXEMBOURG S.A.,  
1, Avenue de la Gare,  
L-1611 Luxembourg,  
Luxembourg. 
 
Manufacturer:  
Menarini - Von Heyden GmbH 
Leipziger Straβe 7-13 
01097 Dresden  
Germany 
 
or 
 
Sanofi Winthrop Industrie 
1, rue de la Vierge 
Ambares et Lagrave 
33565 Carbon-Blanc-Cedex 
France 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
Menarini Benelux NV/SA 
Tél/Tel: + 32 (0)2 721 4545 

Lietuva 
UAB “BERLIN-CHEMIE MENARINI 
BALTIC” 
Tel: +370 52 691 947 
 

България 
“Берлин-Хеми/А. Менарини България” 
ЕООД 
тел.: +359 2 96 55 365 
 

Luxembourg/Luxemburg 
Menarini Benelux NV/SA 
Tél/Tel: + 32 (0)2 721 4545 

Česká republika 
Berlin-Chemie/A.Menarini Ceska republika 
s.r.o. 
Tel: +420 267 199 333 
 

Magyarország 
Berlin-Chemie/A. Menarini Kft. 
Tel.: +36 23501301 



61 

Danmark 
Pharmaprim AB 
Tlf: +46 8355933 
 

Malta 
Menarini International Operations Luxembourg 
S.A. 
Tel: +352 264976 
 

Deutschland 
Berlin-Chemie AG 
Tel: +49 (0) 30 67070 
 

Nederland 
Menarini Benelux NV/SA 
Tel: +32 (0)2 721 4545 
 

 
Eesti 
OÜ Berlin-Chemie Menarini Eesti 
Tel: +372 667 5001 
 

 
Norge 
Pharmaprim AB 
Tlf: +46 8355933 

Ελλάδα 
MENARINI HELLAS AE 
Τηλ: +30 210 8316111-13 

Österreich 
A. Menarini Pharma GmbH. 
Tel: +43 1 879 95 85-0 
 

España 
Laboratorios Menarini S.A. 
Tel: +34-93 462 88 00 

Polska 
Berlin-Chemie/Menarini Polska Sp. z o.o. 
Tel.: +48 22 566 21 00 

France 
MENARINI France 
Tél: +33 (0)1 45 60 77 20 

Portugal 
A. Menarini Portugal – Farmacêutica, S.A. 
Tel: +351 210 935 500 

Hrvatska 
Berlin-Chemie Menarini Hrvatska d.o.o. 
Tel: + 385 1 4821 361 

România 
Berlin-Chemie A. Menarini S.R.L. 
Tel: +40 21 232 34 32 

Ireland 
A. Menarini Pharmaceuticals Ireland Ltd 
Tel: +353 1 284 6744 

Slovenija 
Berlin-Chemie AG, Podružnica Ljubljana 
Tel: +386 01 300 2160 

Ísland 
Pharmaprim AB 
Sími: +46 8355933 
 

Slovenská republika 
Berlin-Chemie AG - obchodné zastúpenie v SR 
Tel: +421 2 544 30 730 

Italia 
A. Menarini Industrie Farmaceutiche Riunite 
s.r.l. 
Tel: +39-055 56801 
 

Suomi/Finland 
Berlin-Chemie/A.Menarini Suomi OY 
Puh/Tel: +358 403 000 760 

Κύπρος 
MENARINI HELLAS AE 
Τηλ: +30 210 8316111-13 

Sverige 
Pharmaprim AB 
Tel: +46 8355933 

Latvija 
SIA Berlin-Chemie/Menarini Baltic 
Tel: +371 67103210 

United Kingdom 
A. Menarini Farmaceutica Internazionale S.R.L. 
Tel: +44 (0)1628 856400 

This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/


62 

Package leaflet: Information for the patient 
 

Spedra 100 mg tablets 
 

avanafil 
 
 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 
 even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Spedra is and what it is used for 
2. What you need to know before you take Spedra 
3. How to take Spedra 
4. Possible side effects 
5. How to store Spedra 
6. Contents of the pack and other information 
 
 
1. What Spedra is and what it is used for 
 
Spedra contains the active substance avanafil. It belongs to a group of medicines called 
phosphodiesterase type 5 (PDE5) inhibitors. Spedra is a treatment for adult men suffering from 
erectile dysfunction (also known as impotence). This is when you cannot get, or keep a hard, erect 
penis suitable for sexual activity. 
 
Spedra works by helping the blood vessels in your penis to relax. This increases the blood flow into 
your penis, helping it stay hard and erect when you get sexually excited. Spedra does not cure your 
condition. 
 
It is important to note that Spedra only works if you are sexually stimulated. You and your partner will 
still need to use foreplay to get ready for sex – just as you would if you were not taking a medicine to 
help you. 
 
Spedra will not help you if you do not have erectile dysfunction. Spedra is not for women. 
 
 
2. What you need to know before you take Spedra 
 
Do not take Spedra: 
 
• If you are allergic to avanafil or any of the other ingredients of this medicine (listed in section 6) 
• If you are taking “nitrate” medicines for chest pain (angina), such as amyl nitrite or glyceryl 

trinitrate. Spedra can increase the effects of these medicines and severely lower your blood 
pressure 

• If you are taking medicines for HIV or AIDS such as ritonavir, indinavir, saquinavir, nelfinavir 
or atazanavir 



63 

• If you are taking medicines for fungal infections such as ketoconazole, itraconazole or 
voriconazole or certain antibiotics for bacterial infections, such as clarithromycin or 
telithromycin 

• If you have a serious cardiac problem 
• If you have had a stroke or heart attack in the last 6 months 
• If you have low blood pressure or high blood pressure not controlled by medicines 
• If you have chest pain (angina) or you get chest pain during sexual intercourse 
• If you have a serious liver or kidney problem 
• If you have loss of vision in one eye due to not enough blood getting to your eye (non-arteritic 

ischemic optic neuropathy [NAION]) 
• If certain serious eye problems run in your family (such as retinitis pigmentosa). 
• If you are taking riociguat. This medicine is used to treat pulmonary arterial hypertension (i.e., 

high blood pressure in the lungs) and chronic thromboembolic pulmonary hypertension (i.e., 
high blood pressure in the lungs secondary to blood clots). PDE5 inhibitors have been shown to 
increase the hypotensive effects of this medicine. If you are taking riociguat or are unsure tell 
your doctor. 
 

Do not take Spedra if any of the above apply to you. If you are not sure, talk to your doctor or 
pharmacist before taking Spedra. 
 
Warnings and precautions 
 
Talk to your doctor or pharmacist before taking Spedra: 
• If you have heart trouble. It may be risky for you to have sexual intercourse 
• If you suffer from priapism, that is a persistent erection lasting 4 hours or more. This can 

happen in men with conditions like sickle cell disease, multiple myeloma or leukaemia. 
• If you have a physical condition that affects the shape of your penis (such as angulation, 

Peyronie’s disease or cavernosal fibrosis) 
• If you have any bleeding disorder or active peptic ulceration. 
 
If any of the above apply to you talk to your doctor or pharmacist before taking Spedra. Check with 
your doctor or pharmacist if you are not sure. 
 
Problems with your sight or hearing 
Some men taking medicines like Spedra have had problems with their sight and hearing – see “Serious 
side effects” in section 4 for more details. It is not known if these problems are related directly to 
Spedra, other diseases that you may have or a combination of factors. 
 
Children and adolescents 
 
Spedra should not be taken by children and adolescents under 18 years of age. 
 
Other medicines and Spedra 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This is because Spedra can affect the way some other medicines work. Also some other 
medicines can affect the way Spedra works. 
 
In particular, tell your doctor and do not take Spedra if you are taking “nitrate” medicines for chest 
pain (angina) such as amyl nitrite or glyceryl trinitrate. Spedra has been shown to increase the effects 
of these medicines and severely lower your blood pressure. Also do not take Spedra if you are taking 
medicines for HIV or AIDS such as ritonavir, indinavir, saquinavir, nelfinavir or atazanavir or if you 
are taking medicines for fungal infections such as ketoconazole, itraconazole or voriconazole or 
certain antibiotics for bacterial infections, such as clarithromycin or telithromycin (see beginning of 
section 2 under ‘Do not take Spedra’). 
 



64 

Tell your doctor or pharmacist if you are taking any of the following medicines: 
• so called “alpha-blockers” – for prostate problems or for lowering your high blood pressure 
• medicines for an irregular heartbeat (“arrhythmia”) such as quinidine, procainamide, 

amiodarone or sotalol 
• antibiotics for infections such as erythromycin 
• phenobarbital or primidone – for epilepsy 
• carbamazepine – for epilepsy, to stabilise your mood or for certain types of pain 
• other medicines that may reduce the breakdown of Spedra in the body (‘moderate CYP3A4 

inhibitors’) including amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and 
verapamil. 

• riociguat 
 
Do not use Spedra together with other treatments for erectile dysfunction such as sildenafil, tadalafil or 
vardenafil. 
 
If any of the above apply to you talk to your doctor or pharmacist before taking Spedra. Check with 
your doctor or pharmacist if you are not sure. 
 
Spedra with drink and alcohol 
 
Grapefruit juice can increase exposure to the medicine and should be avoided within 24 hours prior to 
taking Spedra. 
Drinking alcohol at the same time as taking Spedra may increase your heart rate and lower your blood 
pressure. You may feel dizzy (especially when standing), have a headache or feel your heart beating in 
your chest (palpitations). Drinking alcohol may also decrease your ability to get an erection. 
 
Fertility 
 
There was no effect on sperm movement or structure after single 200 mg oral doses of avanafil in 
healthy volunteers. 
 
The repeated oral administration of avanafil 100 mg over a period of 26 weeks to healthy volunteers 
and adult males with mild erectile dysfunction was not associated with any untoward effects on sperm 
concentration, count, motility, or morphology. 
 
 
Driving and using machines 
 
Spedra can make you feel dizzy or affect your vision. If this happens, do not drive, cycle, use tools or 
machines. 
 
 
3. How to take Spedra 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
The recommended dose is a 100 mg tablet, as needed. You should not take Spedra more than once a 
day. You could have been given the dose of one 200 mg tablet if your doctor has decided that the  100 
mg dose was too weak for you, or the dose of one 50 mg tablet if your doctor has decided  that the 100 
mg tablet was too strong for you. Dose adjustments can also be required if Spedra is used together 
with certain other medicines. If you are taking a medicine such as erythromycin, amprenavir, 
aprepitant, diltiazem, fluconazole, fosamprenavir or verapamil (‘moderate CYP3A4 inhibitors’) the 
recommended dose of Spedra is a 100 mg tablet, with an interval of at least 2 days between doses. 
You should take Spedra approximately 15 to 30 minutes before you have sexual intercourse. 
Remember that Spedra will only help you to get an erection if you are sexually stimulated. 
Spedra can be taken with or without food; if taken with food, it may take longer to work. 
 



65 

If you take more Spedra than you should 
 
If you take too much Spedra, you should tell your doctor straight away. You may get more side effects 
than usual and they may be worse. 
 
If you have any further questions on the use of Spedra, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects 
 
Stop taking Spedra and see a doctor straight away if you notice any of the following serious side 
effects – you may need urgent medical treatment: 
• an erection that will not go away (“priapism”). If you get an erection that lasts more than 

4 hours, this must be treated as soon as possible or lasting damage can happen to your penis 
(including not being able to get erections). 

• blurred vision. 
• sudden decrease or loss of vision in one or both eyes. 
• sudden decrease or loss of hearing (sometimes you may also feel dizzy or have ringing in your 

ears). 
 
Stop taking Spedra and see a doctor straight away, if you notice any of the serious side effects above. 
 
Other side effects include: 
 
Common (may affect up to 1 in 10 people) 
• headache 
• flushing 
• nasal congestion 
 
Uncommon (may affect up to 1 in 100 people) 
• feeling dizzy 
• feeling sleepy or very tired 
• sinus congestion 
• back pain 
• hot flush 
• feeling out of breath when you exert yourself 
• heartbeat changes seen on a heart tracing (ECG) 
• increased heart beat 
• feeling your heartbeat in your chest (palpitations) 
• indigestion, feeling or being sick to your stomach 
• blurry vision 
• raised liver enzymes 
 
Rare (may affect up to 1 in 1,000 people) 
• influenza 
• influenza-like illness 
• stuffy or runny nose 
• hayfever 
• congestion in the nose, sinuses or upper part of the airway bringing air into the lungs 
• gout 
• trouble sleeping (insomnia) 



66 

• premature ejaculation 
• feeling strange 
• feeling unable to keep still 
• chest pain 
• serious chest pain 
• fast heart beat 
• high blood pressure 
• dry mouth 
• stomach ache or heartburn 
• pain or discomfort in the lower abdomen 
• diarrhoea 
• rash 
• pain in the lower back or side of lower chest 
• muscle aches or pains 
• muscle spasms 
• frequent urination 
• penile disorder 
• spontaneous erection without sexual stimulation 
• itching in the genital area 
• feeling weak or tired all the time 
• swelling in the feet or ankles 
• increased blood pressure 
• pink or red urine, blood in the urine 
• abnormal extra sound from the heart 
• an abnormal blood test result for a prostate test called ‘PSA’ 
• an abnormal blood test result for bilirubin, a chemical produced from the normal breakdown of 

red blood cells 
• an abnormal blood test result for creatinine, a chemical excreted in the urine, and a measure of 

kidney function 
• weight gain 
• fever 
• nosebleed 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Spedra 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the blister and carton after “EXP”. 
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage condition. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


67 

 
What Spedra contains 
 
• The active substance is avanafil. Each tablet contains 100 mg of avanafil. 
• The other ingredients are mannitol, fumaric acid, hydroxypropylcellulose, 

hydroxypropylcellulose low substituted, calcium carbonate, magnesium stearate and ferric oxide 
yellow (E172). 
 

What Spedra looks like and contents of the pack 
 
Spedra is a pale yellow oval tablet, marked “100” on one side. The tablets are provided in perforated 
unit dose blister packs containing 2x1, 4x1, 8x1, or 12x1 tablets. 
 
Not all pack sizes may be marketed in your country. 
 
 
Marketing Authorisation Holder:  
MENARINI INTERNATIONAL OPERATIONS LUXEMBOURG S.A.,  
1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg 
 
Manufacturer:  
Menarini - Von Heyden GmbH 
Leipziger Straβe 7-13 
01097 Dresden  
Germany 
 
or 
 
Sanofi Winthrop Industrie 
1, rue de la Vierge 
Ambares et Lagrave 
33565 Carbon-Blanc-Cedex 
France 
 
For any information about this medicine l product, please contact the local representative of the 
Marketing Authorisation Holder. 
 
België/Belgique/Belgien 
Menarini Benelux NV/SA 
Tél/Tel: + 32 (0)2 721 4545 

Lietuva 
UAB “BERLIN-CHEMIE MENARINI 
BALTIC” 
Tel: +370 52 691 947 
 

България 
“Берлин-Хеми/А. Менарини България” 
ЕООД 
тел.: +359 2 96 55 365 

Luxembourg/Luxemburg 
Menarini Benelux NV/SA 
Tél/Tel: + 32 (0)2 721 4545 

Česká republika 
Berlin-Chemie/A.Menarini Ceska republika 
s.r.o. 
Tel: +420 267 199 333 
 

Magyarország 
Berlin-Chemie/A. Menarini Kft. 
Tel.: +36 23501301 

Danmark 
Pharmaprim AB 
Tlf: +46 8355933 
 

Malta 
Menarini International Operations Luxembourg 
S.A. 
Tel: +352 264976 
 



68 

Deutschland 
Berlin-Chemie AG 
Tel: +49 (0) 30 67070 
 

Nederland 
Menarini Benelux NV/SA 
Tel: +32 (0)2 721 4545 
 

 
Eesti 
OÜ Berlin-Chemie Menarini Eesti 
Tel: +372 667 5001 
 

 
Norge 
Pharmaprim AB 
Tlf: +46 8355933 
 

Ελλάδα 
MENARINI HELLAS AE 
Τηλ: +30 210 8316111-13 

Österreich 
A. Menarini Pharma GmbH. 
Tel: +43 1 879 95 85-0 
 

España 
Laboratorios Menarini S.A. 
Tel: +34-93 462 88 00 

Polska 
Berlin-Chemie/Menarini Polska Sp. z o.o. 
Tel.: +48 22 566 21 00 

France 
MENARINI France 
Tél: +33 (0)1 45 60 77 20 

Portugal 
A. Menarini Portugal – Farmacêutica, S.A. 
Tel: +351 210 935 500 

Hrvatska 
Berlin-Chemie Menarini Hrvatska d.o.o. 
Tel: + 385 1 4821 361 

România 
Berlin-Chemie A. Menarini S.R.L. 
Tel: +40 21 232 34 32 

Ireland 
A. Menarini Pharmaceuticals Ireland Ltd 
Tel: +353 1 284 6744 

Slovenija 
Berlin-Chemie AG, Podružnica Ljubljana 
Tel: +386 01 300 2160 

Ísland 
Pharmaprim AB 
Sími: +46 8355933 
 

Slovenská republika 
Berlin-Chemie AG - obchodné zastúpenie v SR 
Tel: +421 2 544 30 730 

Italia 
A. Menarini Industrie Farmaceutiche Riunite 
s.r.l. 
Tel: +39-055 56801 
 

Suomi/Finland 
Berlin-Chemie/A.Menarini Suomi OY 
Puh/Tel: +358 403 000 760 

Κύπρος 
MENARINI HELLAS AE 
Τηλ: +30 210 8316111-13 

Sverige 
Pharmaprim AB 
Tel: +46 8355933 

Latvija 
SIA Berlin-Chemie/Menarini Baltic 
Tel: +371 67103210 

United Kingdom 
A. Menarini Farmaceutica Internazionale S.R.L. 
Tel: +44 (0)1628 856400 

 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/


69 

Package leaflet: Information for the patient 
 

Spedra 200 mg tablets 
 

avanafil 
 
 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 
 even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Spedra is and what it is used for 
2. What you need to know before you take Spedra 
3. How to take Spedra 
4. Possible side effects 
5. How to store Spedra 
6. Contents of the pack and other information 
 
 
1. What Spedra is and what it is used for 
 
Spedra contains the active substance avanafil. It belongs to a group of medicines called 
phosphodiesterase type 5 (PDE5) inhibitors. Spedra is a treatment for adult men suffering from 
erectile dysfunction (also known as impotence). This is when you cannot get, or keep a hard, erect 
penis suitable for sexual activity. 
 
Spedra works by helping the blood vessels in your penis to relax. This increases the blood flow into 
your penis, helping it stay hard and erect when you get sexually excited. Spedra does not cure your 
condition. 
 
It is important to note that Spedra only works if you are sexually stimulated. You and your partner will 
still need to use foreplay to get ready for sex – just as you would if you were not taking a medicine to 
help you. 
 
Spedra will not help you if you do not have erectile dysfunction. Spedra is not for women. 
 
 
2. What you need to know before you take Spedra 
 
Do not take Spedra: 
 
• If you are allergic to avanafil or any of the other ingredients of this medicine (listed in section 6) 
• If you are taking “nitrate” medicines for chest pain (angina), such as amyl nitrite or glyceryl 

trinitrate. Spedra can increase the effects of these medicines and severely lower your blood 
pressure 

• If you are taking medicines for HIV or AIDS such as ritonavir, indinavir, saquinavir, nelfinavir 
or atazanavir 



70 

• If you are taking medicines for fungal infections such as ketoconazole, itraconazole or 
voriconazole or certain antibiotics for bacterial infections, such as clarithromycin or 
telithromycin 

• If you have a serious cardiac problem 
• If you have had a stroke or heart attack in the last 6 months 
• If you have low blood pressure or high blood pressure not controlled by medicines 
• If you have chest pain (angina) or you get chest pain during sexual intercourse 
• If you have a serious liver or kidney problem 
• If you have loss of vision in one eye due to not enough blood getting to your eye (non-arteritic 

ischemic optic neuropathy [NAION]) 
• If certain serious eye problems run in your family (such as retinitis pigmentosa). 
• If you are taking riociguat. This medicine is used to treat pulmonary arterial hypertension (i.e., 

high blood pressure in the lungs) and chronic thromboembolic pulmonary hypertension (i.e., 
high blood pressure in the lungs secondary to blood clots). PDE5 inhibitors have been shown to 
increase the hypotensive effects of this medicine. If you are taking riociguat or are unsure tell 
your doctor. 

 
Do not take Spedra if any of the above apply to you. If you are not sure, talk to your doctor or 
pharmacist before taking Spedra. 
 
Warnings and precautions 
 
Talk to your doctor or pharmacist before taking Spedra: 
• If you have heart trouble. It may be risky for you to have sexual intercourse 
• If you suffer from priapism, that is a persistent erection lasting 4 hours or more. This can 

happen in men with conditions like sickle cell disease, multiple myeloma or leukaemia. 
• If you have a physical condition that affects the shape of your penis (such as angulation, 

Peyronie’s disease or cavernosal fibrosis) 
• If you have any bleeding disorder or active peptic ulceration. 
 
If any of the above apply to you talk to your doctor or pharmacist before taking Spedra. Check with 
your doctor or pharmacist if you are not sure. 
 
Problems with your sight or hearing 
Some men taking medicines like Spedra have had problems with their sight and hearing – see “Serious 
side effects” in section 4 for more details. It is not known if these problems are related directly to 
Spedra, other diseases that you may have or a combination of factors. 
 
Children and adolescents 
 
Spedra should not be taken by children and adolescents under 18 years of age. 
 
Other medicines and Spedra 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This is because Spedra can affect the way some other medicines work. Also some other 
medicines can affect the way Spedra works. 
 
In particular, tell your doctor and do not take Spedra if you are taking “nitrate” medicines for chest 
pain (angina) such as amyl nitrite or glyceryl trinitrate. Spedra has been shown to increase the effects 
of these medicines and severely lower your blood pressure. Also do not take Spedra if you are taking 
medicines for HIV or AIDS such as ritonavir, indinavir, saquinavir, nelfinavir or atazanavir or if you 
are taking medicines for fungal infections such as ketoconazole, itraconazole or voriconazole or 
certain antibiotics for bacterial infections, such as clarithromycin or telithromycin (see beginning of 
section 2 under ‘Do not take Spedra’). 
 



71 

Tell your doctor or pharmacist if you are taking any of the following medicines: 
• so called “alpha-blockers” – for prostate problems or for lowering your high blood pressure 
• medicines for an irregular heartbeat (“arrhythmia”) such as quinidine, procainamide, 

amiodarone or sotalol 
• antibiotics for infections such as erythromycin 
• phenobarbital or primidone – for epilepsy 
• carbamazepine – for epilepsy, to stabilise your mood or for certain types of pain 
• other medicines that may reduce the breakdown of Spedra in the body (‘moderate CYP3A4 

inhibitors’) including amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and 
verapamil.  

• riociguat 
 
Do not use Spedra together with other treatments for erectile dysfunction such as sildenafil, tadalafil or 
vardenafil. 
 
If any of the above apply to you talk to your doctor or pharmacist before taking Spedra. Check with 
your doctor or pharmacist if you are not sure. 
 
Spedra with drink and alcohol 
 
Grapefruit juice can increase exposure to the medicine and should be avoided within 24 hours prior to 
taking Spedra. 
Drinking alcohol at the same time as taking Spedra may increase your heart rate and lower your blood 
pressure. You may feel dizzy (especially when standing), have a headache or feel your heart beating in 
your chest (palpitations). Drinking alcohol may also decrease your ability to get an erection. 
 
Fertility 
 
There was no effect on sperm movement or structure after single 200 mg oral doses of avanafil in 
healthy volunteers. 
 
The repeated oral administration of avanafil 100 mg over a period of 26 weeks to healthy volunteers 
and adult males with mild erectile dysfunction was not associated with any untoward effects on sperm 
concentration, count, motility, or morphology. 
 
 
Driving and using machines 
 
Spedra can make you feel dizzy or affect your vision. If this happens, do not drive, cycle, use tools or 
machines. 
 
 
3. How to take Spedra 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. The recommended dose is a 100 mg tablet, as needed. You should not take Spedra 
more than once a day. You could have been given the dose of one 200 mg tablet if your doctor has 
decided that the  100 mg dose was too weak for you, or the dose of one 50 mg tablet if your doctor has 
decided that the 100 mg tablet was too strong for you. 
Dose adjustments can also be required if Spedra is used together with certain other medicines. If you 
are taking a medicine such as erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, 
fosamprenavir or verapamil (‘moderate CYP3A4 inhibitors’) the recommended dose of Spedra is a 
100 mg tablet, with an interval of at least 2 days between doses. 
You should take Spedra approximately 15 to 30 minutes before you have sexual intercourse. 
Remember that Spedra will only help you to get an erection if you are sexually stimulated. 
Spedra can be taken with or without food; if taken with food, it may take longer to work. 
 



72 

If you take more Spedra than you should 
 
If you take too much Spedra, you should tell your doctor straight away. You may get more side effects 
than usual and they may be worse. 
If you have any further questions on the use of Spedra, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects 
 
Stop taking Spedra and see a doctor straight away if you notice any of the following serious side 
effects – you may need urgent medical treatment: 
• an erection that will not go away (“priapism”). If you get an erection that lasts more than 

4 hours, this must be treated as soon as possible or lasting damage can happen to your penis 
(including not being able to get erections). 

• blurred vision. 
• sudden decrease or loss of vision in one or both eyes. 
• sudden decrease or loss of hearing (sometimes you may also feel dizzy or have ringing in your 

ears). 
 
Stop taking Spedra and see a doctor straight away, if you notice any of the serious side effects above. 
 
Other side effects include: 
 
Common (may affect up to 1 in 10 people) 
• headache 
• flushing 
• nasal congestion 
 
Uncommon (may affect up to 1 in 100 people) 
• feeling dizzy 
• feeling sleepy or very tired 
• sinus congestion 
• back pain 
• hot flush 
• feeling out of breath when you exert yourself 
• heartbeat changes seen on a heart tracing (ECG) 
• increased heart beat 
• feeling your heartbeat in your chest (palpitations) 
• indigestion, feeling or being sick to your stomach 
• blurry vision 
• raised liver enzymes 
 
Rare (may affect up to 1 in 1,000 people) 
• influenza 
• influenza-like illness 
• stuffy or runny nose 
• hayfever 
• congestion in the nose, sinuses or upper part of the airway bringing air into the lungs 
• gout 
• trouble sleeping (insomnia) 
• premature ejaculation 



73 

• feeling strange 
• feeling unable to keep still 
• chest pain 
• serious chest pain 
• fast heart beat 
• high blood pressure 
• dry mouth 
• stomach ache or heartburn 
• pain or discomfort in the lower abdomen 
• diarrhoea 
• rash 
• pain in the lower back or side of lower chest 
• muscle aches or pains 
• muscle spasms 
• frequent urination 
• penile disorder 
• spontaneous erection without sexual stimulation 
• itching in the genital area 
• feeling weak or tired all the time 
• swelling in the feet or ankles 
• increased blood pressure 
• pink or red urine, blood in the urine 
• abnormal extra sound from the heart 
• an abnormal blood test result for a prostate test called ‘PSA’ 
• an abnormal blood test result for bilirubin, a chemical produced from the normal breakdown of 

red blood cells 
• an abnormal blood test result for creatinine, a chemical excreted in the urine, and a measure of 

kidney function 
• weight gain 
• fever 
• nosebleed 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Spedra 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the blister and carton after “EXP”. 
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage condition. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


74 

What Spedra contains 
 
• The active substance is avanafil. Each tablet contains 200 mg of avanafil. 
• The other ingredients are mannitol, fumaric acid, hydroxypropylcellulose, 

hydroxypropylcellulose low substituted, calcium carbonate, magnesium stearate and ferric oxide 
yellow (E172). 
 

What Spedra looks like and contents of the pack 
 
Spedra is a pale yellow oval tablet, marked “200” on one side. The tablets are provided in perforated 
unit dose blister packs containing 2x1, 4x1, 8, or 12x1 tablets. 
 
Not all pack sizes may be marketed in your country. 
 
 
Marketing Authorisation Holder:  
MENARINI INTERNATIONAL OPERATIONS LUXEMBOURG S.A.,  
1, Avenue de la Gare,  
L-1611 Luxembourg,  
Luxembourg 
 
Manufacturer:  
Menarini - Von Heyden GmbH 
Leipziger Straβe 7-13 
01097 Dresden  
Germany 
 
or 
 
Sanofi Winthrop Industrie 
1, rue de la Vierge 
Ambares et Lagrave 
33565 Carbon-Blanc-Cedex 
France 
 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
Menarini Benelux NV/SA 
Tél/Tel: + 32 (0)2 721 4545 

Lietuva 
UAB “BERLIN-CHEMIE MENARINI 
BALTIC” 
Tel: +370 52 691 947 
 

България 
“Берлин-Хеми/А. Менарини България” 
EООД 
тел.: +359 2 96 55 365 
 

Luxembourg/Luxemburg 
Menarini Benelux NV/SA 
Tél/Tel: + 32 (0)2 721 4545 

Česká republika 
Berlin-Chemie/A.Menarini Ceska republika 
s.r.o. 
Tel: +420 267 199 333 
 

Magyarország 
Berlin-Chemie/A. Menarini Kft. 
Tel.: +36 23501301 



75 

Danmark 
Pharmaprim AB 
Tlf: +46 8355933 
 

Malta 
Menarini International Operations Luxembourg 
S.A. 
Tel: +352 264976 
 

Deutschland 
Berlin-Chemie AG 
Tel: +49 (0) 30 67070 
 

Nederland 
Menarini Benelux NV/SA 
Tel: +32 (0)2 721 4545 
 

 
Eesti 
OÜ Berlin-Chemie Menarini Eesti 
Tel: +372 667 5001 
 

 
Norge 
Pharmaprim AB 
Tlf: +46 8355933 
 

Ελλάδα 
MENARINI HELLAS AE 
Τηλ: +30 210 8316111-13 

Österreich 
A. Menarini Pharma GmbH. 
Tel: +43 1 879 95 85-0 
 

España 
Laboratorios Menarini S.A. 
Tel: +34-93 462 88 00 

Polska 
Berlin-Chemie/Menarini Polska Sp. z o.o. 
Tel.: +48 22 566 21 00 

France 
MENARINI France 
Tél: +33 (0)1 45 60 77 20 

Portugal 
A. Menarini Portugal – Farmacêutica, S.A. 
Tel: +351 210 935 500 

Hrvatska 
Berlin-Chemie Menarini Hrvatska d.o.o. 
Tel: + 385 1 4821 361 

România 
Berlin-Chemie A. Menarini S.R.L. 
Tel: +40 21 232 34 32 

Ireland 
A. Menarini Pharmaceuticals Ireland Ltd 
Tel: +353 1 284 6744 

Slovenija 
Berlin-Chemie AG, Podružnica Ljubljana 
Tel: +386 01 300 2160 

Ísland 
Pharmaprim AB 
Sími: +46 8355933 
 

Slovenská republika 
Berlin-Chemie AG - obchodné zastúpenie v SR 
Tel: +421 2 544 30 730 

Italia 
A. Menarini Industrie Farmaceutiche Riunite 
s.r.l. 
Tel: +39-055 56801 
 

Suomi/Finland 
Berlin-Chemie/A.Menarini Suomi OY 
Puh/Tel: +358 403 000 760 

Κύπρος 
MENARINI HELLAS AE 
Τηλ: +30 210 8316111-13 

Sverige 
Pharmaprim AB 
Tel: +46 8355933 

Latvija 
SIA Berlin-Chemie/Menarini Baltic 
Tel: +371 67103210 

United Kingdom 
A. Menarini Farmaceutica Internazionale S.R.L. 
Tel: +44 (0)1628 856400 

This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING
AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET