SPEDRA - PACKAGE LEAFLET - LEAFLETS

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Spedra - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Avanafil

Spedra 50 mg tablets

Spedra package inserts are available for packs:

Spedra 50 mg tablets
SHIPPING 100 mg tablets
SPEDRA 200 mg tablets

Why is Spedra used? What is it for?

The active substance in Spedra is called avanafil and belongs to a group of medicines called phosphodiesterase type 5 (PDE5) inhibitors.

Spedra is used to treat adult men suffering from erectile dysfunction (also known as impotence), which is the inability to achieve or maintain an erection suitable for sexual activity.

Spedra works by helping the blood vessels in the penis to widen; the increased blood flow into the penis helps it remain rigid and erect during sexual arousal. Spedra does not cure your dysfunction.

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 prepare for intercourse, just as you would if she was not taking any medications. Spedra won't help you if you don't have erectile dysfunction.

Spedra is not a medicine for women.

Contraindications When Spedra should not be used

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 pains (angina), such as amyl nitrite or nitroglycerin. Spedra can enhance the effects of these medicines and seriously lower your blood pressure;
if you are taking medicines 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;
if you have severe heart problems;
if you have had a stroke or heart attack in the past 6 months;
if you have low blood pressure or high blood pressure which is not controlled with medicines;
if you have chest pain (angina) or chest pain comes during sexual intercourse
if you have a severe liver or kidney problem;
if you have lost your vision in one eye due to a disease (nonarteritic ischemic optic neuropathy [NAION]) which reduces the amount of blood in the eye;
if other people in your family have severe eye problems (such as retinitis pigmentosa);
if you are hiring riociguat. This medicine is used to treat pulmonary arterial hypertension (ie high blood pressure in the lungs) and chronic thromboembolic pulmonary hypertension (ie high blood pressure in the lungs due to blood clots). PDE5 inhibitors have been shown to increase the hypotensive effects of this medicine. If you are taking riociguat or are unsure, please consult your doctor.

Do not take Spedra if any of the above applies to you. If you are unsure, talk to your doctor or pharmacist before taking Spedra.

Precautions for use What you need to know before taking Spedra

Talk to your doctor or pharmacist before taking Spedra:

if you have heart problems. It may be risky for you to have sexual intercourse;
if you have "priapism", ie a "persistent erection lasting 4 hours or more (this can occur in men with diseases such as sickle cell anemia, multiple myeloma or leukemia);
if you have an abnormality in the shape of your penis (such as angulation, Peyronie's disease or cavernous fibrosis);
if you have a bleeding disorder or an active 'peptic ulcer.

If any of the above apply to you, talk to your doctor or pharmacist before taking Spedra. If in doubt, consult your doctor or pharmacist.

Problems with sight or hearing

Some men taking medicines such as Spedra have had problems with their sight or hearing (see "Serious side effects" in section 4 for more details). It is not known whether these problems are directly due to Spedra, to other concomitant diseases or to a set of factors.

Children and adolescents

Spedra should not be taken by children and adolescents under the age of 18.

Interactions Which drugs or foods can modify the effect of Spedra

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, as Spedra can affect the effect of some of them. Some other medicines can also affect the effect of Spedra.

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 nitroglycerin. Spedra enhances the effects of these medicines and seriously lowers 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 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 "Do not take Spedra").

Tell your doctor or pharmacist if you are taking any of the following medicines:

the so-called alpha-blockers, for prostate problems or for lowering 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 stabilize mood or for certain types of pain;
other medicines that may reduce the metabolism of Spedra in the body ("moderate CYP3A4 inhibitors"), including amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir and verapamil;
riociguat.

Do not use Spedra together with other erectile dysfunction treatments, such as sildenafil, tadalafil or vardenafil.

If any of the above apply to you, talk to your doctor or pharmacist before taking Spedra. If in doubt, consult your doctor or pharmacist.

Spedra with drinks and alcohol

Grapefruit juice may increase exposure to the medicine and should be avoided within 24 hours of taking Spedra. Drinking alcohol along with taking Spedra can increase your heart rate and lower your blood pressure.You may feel dizzy (especially when standing) and headache or feel your heart beating in your chest (palpitations). Drinking alcohol can also reduce your ability to have an "erection."

Warnings It is important to know that:

Fertility

Spedra did not affect sperm motility or shape after single 200 mg oral doses in healthy volunteers.

There are currently no data on sperm development in healthy adults and adults suffering from mild erectile dysfunction.

Driving and using machines

Spedra can cause dizziness or impair vision. If this happens, do not drive, do not ride a bicycle and do not use any tools or machinery.

Dose, Method and Time of Administration How to use Spedra: Posology

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

The recommended dose is one 100 mg tablet, as needed. Do not take Spedra more than once a day. Tell your doctor if you think Spedra is too strong or too weak. He may suggest that you switch to a different dose of the medicine. Dose adjustments may also be needed when Spedra is used together with other medicines. If you are taking a medicine such as erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir and verapamil ("moderate CYP3A inhibitors"), the recommended dose of Spedra is one 100 mg tablet, with an interval of at least 2 days between doses.

Take Spedra approximately 30 minutes before sexual intercourse. Remember that Spedra will only help you achieve an erection if you are sexually stimulated.

Spedra can be taken with or without food; when taken with food, it may take longer to take effect.

Overdose What to do if you have taken an overdose of Spedra

If you take too much Spedra, you must tell your doctor immediately. It may have more side effects than usual and they may be more serious.

If you have any further questions on the use of Spedra, ask your doctor or pharmacist.

Side Effects What are the side effects of Spedra

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Serious side effects

Stop taking Spedra and see a doctor immediately if you notice any of the following serious side effects (you may need urgent medical treatment):

an "erection that does not go away (" priapism "). If you have an" erection that lasts more than 4 hours, you need to treat it as soon as possible or your penis may be damaged for a long period of time (including the inability to get erections);
blurred vision;
sudden decrease or loss of vision in one or both eyes;
sudden decrease or loss of hearing (you may also sometimes feel dizzy or ringing in your ears).

Stop taking Spedra and see a doctor immediately if you notice any of the serious side effects mentioned above.

Other side effects include:

Common (may affect up to 1 in 10 people)

headache;
hot flashes;
nasal congestion.

Uncommon (may affect up to 1 in 100 people)

dizziness
sleepiness or tiredness;
sinus congestion;
back pain;
hot flashes;
shortness of breath during exercise;
altered heartbeat on electrocardiogram (ECG);
increased heart rate;
rapid heartbeat (palpitations);
indigestion, feeling of pain in the stomach;
blurred vision;
increased liver enzymes.

Rare (may affect up to 1 in 1000 people)

influence;
flu-like illness;
stuffy or runny nose;
allergic rhinitis;
congestion of the nose, sinuses or upper respiratory tract that carries air to the lungs;
gout;
sleep disturbances (insomnia);
premature ejaculation;
feeling of discomfort;
inability to sit still;
chest pain;
severe chest pain;
rapid heartbeat;
high blood pressure;
dry mouth;
stomach pain or heartburn;
pain or discomfort in the lower abdomen;
diarrhea;
rash;
pain in the lower back or lower side of the chest;
muscle aches;
muscle twitching;
frequent need to urinate;
penis disorders;
spontaneous erection without sexual stimulation;
itching in the genital area;
persistent feeling of weakness and fatigue;
swelling of the feet or ankles;
increased blood pressure;
pink or red urine, blood in the urine;
abnormal additional noise of the heart;
abnormal results in a prostate test called "PSA";
abnormal test results for bilirubin, a chemical produced by the normal breakdown of red blood cells;
abnormal test results for creatinine, a chemical excreted in the urine, which is useful for assessing kidney function;
weight gain;
fever.

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.

Expiry and Retention

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 conditions.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Other information

What Spedra contains

The active ingredient is avanafil. Each tablet contains 50 mg of avanafil.
The other ingredients are mannitol, fumaric acid, hydroxypropylcellulose, poorly substituted hydroxypropylcellulose, calcium carbonate, magnesium stearate and yellow ferric oxide (E172).

Description of Spedra's appearance and contents of the package

Spedra is a pale yellow oval tablet, debossed with "50" on one side. The tablets are supplied in blisters containing 4, 8 or 12 tablets.

Not all pack sizes may be marketed in your country.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Spedra is available in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

SHIP 50 MG TABLETS

▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50 mg of avanafil.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Tablet.

Pale yellow oval tablets, debossed with "50" on one side.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Treatment of erectile dysfunction in adult men.

For Spedra to be effective, sexual stimulation is required.

04.2 Posology and method of administration

Dosage

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 of 200 mg or reduced to 50 mg. The maximum recommended dosing frequency is once daily. For a response to treatment to occur, it is sexual stimulation required.

Special populations

Elderly men (age ≥ 65 years)

No dose adjustment is necessary in elderly patients. Limited data are available in elderly patients over 70 years of age.

Renal impairment

No dose adjustment is 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 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 lowest effective dose and adjust the dosage based on tolerability.

Use in diabetic men

No dose adjustment is necessary in diabetic patients.

Pediatric population

There is no indication for the use of Spedra in the treatment of erectile dysfunction in the pediatric population.

Use in patients using other medicines

Concomitant use of CYP3A4 inhibitors

Co-administration of avanafil with potent CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefadozone, nelfinavir, saquinavir and telithromycin) is contraindicated (see sections 4.3, 4.4 and 4.5).

In patients on 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

Oral use. If Spedra is taken with food, the onset of efficacy may be delayed compared to taking in the fasted state (see section 5.2).

04.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Patients who are using nitric oxide donors (such as amyl nitrite) or organic nitrates in any form (see section 4.5).

The concomitant use of phosphodiesterase type 5 (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).

Before prescribing Spedra, physicians should consider the potential cardiac risk related to sexual activity in patients with pre-existing cardiovascular disease.

The use of avanafil is contraindicated in:

- patients who have suffered from myocardial infarction, stroke or life-threatening arrhythmia in the 6 months prior to use;

- patients with hypotension (blood pressure hypertension (blood pressure> 170/100 mmHg) at rest;

- Patients with unstable angina, sexual intercourse angina or congestive heart failure class 2 or higher according to the New York Heart Association.

Patients with severe hepatic impairment (Child-Pugh C).

Patients with severe renal impairment (creatinine clearance

Patients who have lost sight in one eye due to non-arteritic anterior ischemic optic neuropathy (NAION) regardless of whether or not this episode was related to previous exposure to a PDE5 inhibitor (see section 4.4).

Patients with hereditary degenerative disorders of the retina.

Patients 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).

04.4 Special warnings and appropriate precautions for use

Before considering drug treatment, a history and clinical examination should be done to diagnose erectile dysfunction and determine possible underlying causes.

Cardiovascular condition

Before starting any treatment for erectile dysfunction, the physician should analyze the cardiovascular condition of patients, as some degree of cardiac risk is associated with sexual activity (see section 4.3). Avanafil has vasodilatory properties, resulting in minor reductions and transient blood pressure (see section 4.5) thereby potentiating the hypotensive effect of nitrates (see section 4.3). Patients with left ventricular outflow obstruction (eg aortic stenosis or idiopathic hypertrophic subaortic stenosis) may be sensitive to the action of vasodilators, including PDE5 inhibitors.

Priapism

Patients who experience erections lasting 4 hours or more (priapism) should seek immediate medical attention. If priapism is not treated immediately, damage to penile tissue and permanent loss of sexual potency can result. Avanafil should be used with caution in patients with anatomical deformations of the penis (such as angulation, cavernous fibrosis or Peyronie's disease) or in patients with conditions that could predispose to priapism (such as sickle cell anemia, multiple myeloma or leukemia).

Vision problems

Visual defects and cases of non-arteritic anterior ischemic optic neuropathy (NAION) have been reported in connection with the intake of other PDE5 inhibitors. Spedra and seek medical attention immediately (see section 4.3).

Effects on bleeding

Human platelet studies in vitro indicate that PDE5 inhibitors do not in themselves have any effect on platelet aggregation but, at supratherapeutic doses, potentiate the antiplatelet effect of the nitric oxide sodium nitroprusside donor. In humans, PDE5 inhibitors do not appear to affect bleeding time alone or in combination with acetylsalicylic acid.

There is no information on the safety of administering avanafil to patients with bleeding disorders or an active peptic ulcer. Avanafil should therefore only be administered to such patients after a "careful benefit-risk assessment."

Sudden decrease or loss of hearing

Patients should be advised to stop taking PDE5 inhibitors, including avanafil, and seek immediate medical attention in case of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the intake of PDE5 inhibitors. It is not possible to determine whether these events are directly related to the use of PDE5 inhibitors or to other factors.

Concomitant use of alpha-blockers

Concomitant use of alpha-blockers and avanafil may cause symptomatic hypotension in some patients due to additive vasodilatory effects (see section 4.5). Attention should be paid to the following:

• Patients taking alpha-blockers should be stabilized before starting Spedra. Patients who exhibit haemodynamic instability while on alpha-blocker alone therapy have an increased risk of symptomatic hypotension with concomitant use of avanafil;

• in those patients who are taking alpha-blockers and are stabilized, avanafil should be started at the lowest dose (50 mg);

• in those patients already taking an optimized dose of Spedra, alpha blocker therapy should be started at the lowest dose. A gradual increase in the dose of the alpha-blocker may be associated with a further lowering of blood pressure while taking avanafil;

• the safety of the combined use of avanafil and alpha-blockers may be compromised by other variables including intravascular volume depletion and the use of other antihypertensive medicinal products.

Concomitant use of CYP3A4 inhibitors

Concomitant administration of avanafil and potent CYP3A4 inhibitors, 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 concomitant treatment of Spedra with other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. Patients should be advised that they should not take Spedra in such combinations.

Concomitant use of alcohol

Alcohol consumption in combination with avanafil may increase the risk of symptomatic hypotension (see section 4.5). Patients should be advised that concomitant use of avanafil and alcohol may increase the chances of experiencing hypotension, dizziness or syncope. Physicians should also advise patients on what to do in the event of symptoms of postural hypotension.

Populations not studied

Avanafil has not been studied in patients with erectile dysfunction due to spinal cord injury or other neurological disorders and in individuals with severe renal or hepatic impairment.

04.5 Interactions with other medicinal products and other forms of interaction

Possible pharmacodynamic interactions with avanafil

Nitrates

Avanafil has been shown to potentiate the hypotensive effects of nitrates compared to placebo in healthy subjects. This is believed to result from the combined effects of nitrates and avanafil in the nitric oxide / cGMP pathway. Administration of avanafil to patients who are using organic nitrates in any form or nitric oxide donors (such as amyl nitrite) is contraindicated. In a patient who has been taking avanafil for less than 12 hours and who is deemed medically necessary in a life-threatening situation, the likelihood of a significant and potentially life-threatening reduction in blood pressure increases. , nitrates should only be administered under close medical supervision, with appropriate haemodynamic monitoring (see section 4.3).

Medicines that lower systemic blood pressure

Being a vasodilator, avanafil can reduce systemic blood pressure. If Spedra is used in combination with another medicine that reduces systemic blood pressure, the additive effects may cause symptomatic hypotension (e.g. dizziness, lightheadedness, syncope or near-syncope). In Phase 3 clinical studies, no "hypotension" events were observed, but occasional episodes of "dizziness" were observed (see section 4.8). In Phase 3 clinical trials, one episode of 'syncope' was observed during treatment with placebo and one episode during treatment with avanafil 100 mg.

Patients with left ventricular outflow obstruction (eg, aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic nervous system control of blood pressure may be particularly sensitive to the action of vasodilators, including avanafil.

Alpha blockers

Hemodynamic interactions with doxazosin and tamsulosin were studied in healthy subjects in a two-way crossover study. In patients receiving stable treatment with doxazosin, the mean of maximum reductions, subtracted from the placebo effect, in standing and supine systolic blood pressure following administration of avanafil were 2.5 mmHg and 6.0, respectively. mmHg A total of 7 of 24 patients had blood pressure values or decreases from baseline of potential clinical significance following administration of avanafil (see section 4.4).

In patients receiving stable treatment with tamsulosin, the mean of maximum reductions, subtracted from placebo, in standing and supine systolic blood pressure following administration of avanafil were 3.6 mmHg and 3.1 mmHg, respectively. mmHg and 5 of 24 patients experienced blood pressure or reductions from baseline of potential clinical significance following administration of avanafil (see section 4.4). No cases of syncope or other serious adverse events associated with decreased blood pressure in any cohort of subjects.

Antihypertensives other than alpha blockers

A clinical study was conducted to evaluate the effect of avanafil on the potentiation of the blood pressure lowering effects of some antihypertensive medicinal products (amlodipine and enalapril). Results showed a mean maximum reduction in supine blood pressure of 2 / 3 mmHg versus placebo with enalapril and 1 / -1 mmHg with amlodipine when avanafil was administered concomitantly. There was a statistically significant difference in maximum reduction from baseline in supine diastolic blood pressure with enalapril and avanafil alone, value that returned to baseline 4 hours after the avanafil dose. In both cohorts, one subject experienced a reduction in blood pressure without symptoms of hypotension, which resolved within 1 hour of onset. Avanafil has no effect on the pharmacokinetics of amlodipine, but amlodipine increased the maximum and total exposure to avanafil by 28% and 60%, respectively.

Alcohol

Consumption of alcohol in combination with avanafil may increase the possibility of symptomatic hypotension. In a three-way, single-dose crossover study in healthy subjects, the mean maximum reduction in diastolic blood pressure was significantly higher following administration of avanafil with alcohol, compared to avanafil alone (3.2 mmHg) or alcohol from alone (5.0 mmHg) (see section 4.4).

Other treatments for erectile dysfunction

The safety and efficacy of the combination 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 CYP3A4 and is mainly metabolised by this cytochrome. Studies have shown that medicinal products that inhibit CYP3A4 may increase avanafil exposure (see section 4.2).

CYP3A4 inhibitors

Ketoconazole (400 mg daily), a selective and very potent inhibitor of CYP3A4, increased the Cmax and exposure (AUC) of a single 50 mg dose of avanafil by 3-fold and 14-fold, respectively, and lengthened the half-life. of avanafil about 9 hours. Ritonavir (600 mg daily), a very potent CYP3A4 inhibitor, which also inhibits CYP2C9, increased Cmax and AUC of a single 50 mg dose of avanafil by 2-fold and 13-fold, respectively, and lengthened l " half-life of avanafil about 9 hours. Other potent CYP3A4 inhibitors (e.g. itraconazole, voriconazole, clarithromycin, nefazodone, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin) are expected to have similar effects. Consequently, concomitant administration of avanafil and potent CYP3A4 inhibitors is contraindicated (see sections 4.2, 4.3 and 4.4).

Erythromycin (500 mg daily), a moderate inhibitor of CYP3A4, increased the Cmax and AUC of a single 200 mg dose of avanafil by approximately 2-fold and 3-fold, respectively, and lengthened the half-life of avanafil to approximately 8 hours. . Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir and verapamil) are expected to have similar effects. Consequently, the maximum recommended dose of avanafil is 100 mg, not to be exceeded 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, are likely to increase avanafil exposure. Patients should be advised to avoid drinking grapefruit juice within 24 hours prior to taking avanafil.

CYP3A4 substrates

Amlodipine (5 mg daily) increased the Cmax and AUC of a single 200 mg dose of avanafil by approximately 28% and 60%, respectively. These changes in exposure are not considered to be clinically significant. A single dose of avanafil had no effect on plasma levels of amlodipine.

Although specific interactions of avanafil with rivaroxaban and apixaban (both CYP3A4 substrates) have not been studied, such interactions are not expected.

Inducers of cytochrome P450

The potential effect of CYP inducers, especially CYP3A4 inducers (eg bosentan, carbamazepine, efavirenz, phenobarbital and rifampicin) on the pharmacokinetics and efficacy of avanafil has not been evaluated. Concomitant use of avanafil and a CYP inducer is not recommended as it may reduce the efficacy of avanafil.

Effects of avanafil on other medicinal products

Inhibition of cytochrome P450

In the studies in vitro in human liver microsomes, avanafil showed negligible potential for drug-drug interactions with CYP1A1 / 2, 2A6, 2B6 and 2E1. In addition, the metabolites of avanafil (M4, M16 and M & SUP2; 7) also demonstrated minimal inhibition of CYPs 1A1 / 2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. Based on these data, avanafil is not expected to have a significant effect on other medicinal products metabolised by these enzymes.

The data in vitro identified potential interactions of avanafil with CYPs 2C19, 2C8 / 9, 2D6 and 3A4, while further clinical studies using omeprazole, rosiglitazone and desipramine did not reveal clinically relevant interactions with CYPs 2C19, 2C8 / 9 and 2D6.

Induction of cytochrome P450

The potential induction of CYP1A2, CYP2B6 and CYP3A4 by avanafil evaluated in primary human hepatocytes in vitro did not reveal potential interactions at clinically relevant concentrations.

Conveyors

The results in vitro showed modest ability for avanafil to act as a substrate for P-gp and as a P-gp inhibitor with digoxin as substrate, at avanafil concentrations below the calculated intestinal concentration. The potential for avanafil to interfere with the transport of other P-gp mediated drugs is unknown.

Based on data from in vitro studies, avanafil may act as a BCRP inhibitor at clinically relevant concentrations.

At clinically relevant concentrations avanafil does not act as an inhibitor of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3 and BSEP.

The effect of avanafil on other transporters is unknown.

Riociguat

Preclinical studies have shown an additional systemic blood pressure lowering effect when PDE5 inhibitors are taken in combination with riociguat. In clinical studies, riociguat was shown to increase the hypotensive effects of PDE5 inhibitors. In the population studied there was no evidence of a favorable clinical effect following the use of the combination. The concomitant use of riociguat with PDE5 inhibitors, including avanafil, is contraindicated (see section 4.3).

04.6 Pregnancy and breastfeeding

Pregnancy

Spedra is not indicated for use in women.

There are no data on the use of avanafil in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal / fetal development, parturition or postnatal development (see section 5.3).

Feeding time

There are no data on the use of avanafil during lactation.

Fertility

There was no effect on sperm motility or morphology after single oral administrations of 200 mg avanafil in healthy volunteers.

There are currently no data on spermatogenesis in healthy adult men and adult men with mild erectile dysfunction.

04.7 Effects on ability to drive and use machines

Spedra has minor effects on the ability to drive or use machines. As dizziness and visual disturbances were reported in clinical trials of avanafil, patients should be aware of their reaction to Spedra before driving or operating machinery.

04.8 Undesirable effects

Summary of the safety profile

The safety profile of Spedra is based on 2436 subjects exposed to avanafil during the clinical development program. The most common adverse reactions reported in clinical trials were headache, flushing, nasal and sinus congestion and back pain. General adverse events and adverse reactions for avanafil treated subjects were more frequent in subjects with normal body mass index (BMI)

In the long-term clinical study, the proportion of patients experiencing adverse reactions decreased with increasing duration of treatment.

Summary table of adverse reactions

The table below lists adverse reactions observed in placebo-controlled clinical trials according to the MedDRA frequency convention: very common (≥ 1/10), common (≥ 1/100,

Adverse reaction (MedDRA preferred term) System and organ classification common Uncommon Rare Infections and infestations Flu, Nasopharyngitis Disorders of the immune system Seasonal allergy Metabolism and nutrition disorders Gout Psychiatric disorders Insomnia, Premature Ejaculation, Inadequate Perceptions Nervous system disorders Headache Dizziness, Somnolence, Sinus headache Psychomotor hyperactivity Eye disorders Blurred vision Cardiac pathologies Palpitations Angina pectoris, Tachycardia Vascular pathologies Flushes Hot flashes Hypertension Respiratory, thoracic and mediastinal disorders Nasal congestion Sinus congestion, Dyspnea on exertion Rhinorrhea, Congestion of the upper respiratory system Gastrointestinal disorders Dyspepsia, Nausea, Vomiting, Upset stomach Dry mouth, Gastritis, Pain in the lower abdomen, Diarrhea Skin and subcutaneous tissue disorders Rash Musculoskeletal and connective tissue disorders Back pain, Muscle stiffness Pain in the hips, Myalgia, Muscle spasms Renal and urinary disorders Pollakiuria Diseases of the reproductive system and breast Penis Disorders, Spontaneous Penile Erection, Genital Itching General disorders and administration site conditions Fatigue Asthenia, Chest pain, Influenza-like illness, Peripheral edema Diagnostic tests Increased liver enzymes, abnormal electrocardiogram, increased heart rate Blood pressure increased, Blood in urine, Heart murmur, Increased prostate specific antigens, Weight increased, Blood bilirubin increased, Blood creatinine increased, Body temperature increased

Description of selected adverse reactions observed with other PDE5 inhibitors

Non-arteritic anterior ischemic optic neuropathy (NAION) and sudden hearing loss have been reported with other PDE5 inhibitors in a small number of cases in clinical trials and post-marketing experience. No cases were reported during clinical trials of avanafil (see section 4.4).

A small number of cases of priapism have been reported with other PDE5 inhibitors in post-marketing experience and clinical trials. No cases have been reported during clinical trials of avanafil.

A small number of cases of haematuria, haematospermia and penile haemorrhage have been reported with other PDE5 inhibitors in post-marketing experience and clinical trials.

Hypotension has been reported with other PDE5 inhibitors in post-marketing experience and dizziness, a symptom commonly caused by low blood pressure, has been reported in clinical trials with avanafil (see section 4.5).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous 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. in Annex V.

04.9 Overdose

Single doses of up to 800 mg of avanafil have been administered to healthy subjects and multiple daily doses of up to 300 mg have been administered to patients. Adverse reactions were similar to those seen at lower doses, but the incidence rates and severity were higher.

In the event of an overdose, standard supportive measures should be employed when necessary. Renal dialysis is not expected to accelerate clearance as avanafil is highly bound to plasma proteins and is not eliminated in the urine.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: drugs used in erectile dysfunction.

ATC code: G04BE10.

Mechanism of action

Avanafil is a reversible, potent and highly selective inhibitor of phosphodiesterase type 5 (PDE5) specific for cyclic guanosine monophosphate (cGMP). When sexual stimulation causes local release of nitric oxide, inhibition of PDE5 by avanafil results in increased cGMP levels in the corpora cavernosa of the penis. This causes smooth muscle relaxation and blood flow to the penile tissues. , resulting in an erection. Avanafil has no effect in the absence of sexual stimulation.

Pharmacodynamic effects

Education in vitro demonstrated that avanafil is highly selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (> 100 times compared to PDE6;> 1 000 times compared to PDE4, PDE8 and PDE10;> 5 000 times compared to PDE2 and PDE7;> 10,000 times compared to PDE1, PDE3, PDE9 and PDE11). Avanafil is> 100 times more potent on PDE5 than on PDE6, which is found in the retina and is responsible for phototransduction.The approximately 20,000-fold selectivity for PDE5 over PDE3, an enzyme found in the heart and blood vessels, is important as PDE3 is involved in controlling cardiac contraction.

In a penile plethysmography study (RigiScan), avanafil 200 mg produced erections considered sufficient for penetration (60% rigidity according to RigiScan) in some men as early as 20 minutes after administration and the overall response of these subjects to avanafil was was statistically significant, compared to placebo, over the time interval of 20-40 minutes.

Clinical efficacy and safety

In clinical trials, the effect of avanafil on the ability of men with erectile dysfunction (ED) to achieve and maintain an "erection sufficient for satisfactory sexual activity" was evaluated. Avanafil was evaluated in 4 randomized, double-blind studies. , placebo-controlled, parallel group, lasting up to 3 months in the general ED population, in patients with type 1 or type 2 diabetes and ED, and in patients with ED following radical nerve prostatectomy - bilateral sparing. The fourth study examined the onset of action of avanafil in the two strengths of 100 and 200 mg, in terms of the percentage of sexual attempts resulting in successful completion of intercourse per subject. A total of 1774 patients received avanafil , as needed and at doses of 50 mg (in one study), 100 mg and 200 mg (in four studies), respectively. Patients were required to take 1 dose of study drug approximately 30 minutes i before the start of sexual activity. In the fourth study, patients were encouraged to attempt sexual intercourse approximately 15 minutes after administration to assess the onset of the erectogenic effect of avanafil, taken as needed, at a dose of 100 or 200 mg.

In addition, a subset of patients was enrolled in an open-label extension study in which 493 patients received 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 time during the study, could be required to increase the avanafil dose to 200 mg or to reduce it to 50 mg based on their individual response to treatment.

In all studies, statistically significant improvements in all primary efficacy measures were observed for all three doses of avanafil compared to placebo. These differences persisted in long-term treatment (as found in studies in the general ED population, in diabetics with ED, in men with ED following bilateral nerve-sparing radical prostatectomy, and in the open-label extension study).

In the general ED population, the mean percentage of attempts resulting in successful sexual intercourse was approximately 47%, 58%, and 59% in the avanafil 50 mg, 100 mg, and 200 mg groups, respectively, compared with about 28% with placebo.

In men with both type 1 and type 2 diabetes mellitus, the average percentage of attempts resulting in successful sexual intercourse was approximately 34% and 40%, for the groups treated with 100 mg and 200 mg, respectively. avanafil, compared with approximately 21% in the placebo group.

In men with ED following nerve-sparing bilateral radical prostatectomy, the mean rate of attempts resulting in successful intercourse was approximately 23% and 26% for the 100 mg and 200 mg treatment groups, respectively. avanafil, compared with approximately 9% in the placebo group.

In the "onset of action" study, avanafil demonstrated a statistically significant improvement in the primary efficacy variable (mean percentage of positive responses per subject, starting at the time of dosing, to Sexual Encounter Profile 3 - SEP3) compared to placebo, with a rate of successful intercourse approximately 15 minutes after dosing of 24.71% for the 100 mg dose and 28.18% for the 200 mg dose, compared with 13.78% for the placebo.

In all pivotal studies of avanafil, the rate of successful intercourse attempts was significantly higher for all doses of avanafil compared to placebo for all post-dose intervals examined.

Pediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Spedra in all subsets of the pediatric population in erectile dysfunction (see section 4.2 for information on pediatric use).

05.2 Pharmacokinetic properties

Avanafil is rapidly absorbed following oral administration, with a median Tmax ranging from 30 to 45 minutes. Its pharmacokinetics are dose proportional over the recommended dose range. It is eliminated primarily by hepatic metabolism (mainly CYP3A4). Concomitant use of potent CYP3A4 inhibitors (eg 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. The maximum observed plasma concentrations are reached within 0.5-0.75 hours after oral administration in the fasted state. When avanafil is taken with a high-fat meal, the absorption rate is reduced, with a mean delay in T of 1.25 hours and a mean reduction in C of 39% (200 mg). There is no effect on the magnitude of exposure (AUC). 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 concentrations of the active substance, age and renal or hepatic function.

Avanafil does not accumulate in plasma when administered twice daily for 7 days at a dose of 200 mg. Based on measurements of avanafil in the semen of healthy volunteers 45-90 minutes after administration, less than 0.0002% of the administered dose is present in the semen of patients.

Biotransformation

Avanafil is eliminated primarily by hepatic microsomal isoenzymes CYP3A4 (major route) and CYP2C9 (secondary route). The plasma concentrations of the main circulating metabolites, M4 and M16, are respectively 23% and 29% of the parent compound. Metabolite M4 exhibits a selectivity profile for phosphodiesterase similar to that of avanafil and inhibitory potency in vitro for PDE5 equal to 18% of that of avanafil. M4 is therefore responsible for approximately 4% of the total pharmacological activity. The metabolite M16 is inactive against PDE5.

Elimination

Avanafil is extensively metabolised in humans. After oral administration, avanafil is excreted as metabolites mainly in the faeces (approximately 63% of the administered oral dose) and to a lesser extent in the urine (approximately 21% of the administered oral dose).

Other particular populations

Elderly patients

Elderly patients (65 years or older) have comparable exposure to that seen in younger patients (18-45 years). However, data on people over 70 years of age are limited.

Renal impairment

In patients with mild renal impairment (creatinine clearance ≥ 50, severe renal insufficiency or end stage renal disease undergoing hemodialysis.

Hepatic impairment

Subjects with mild hepatic impairment (Child-Pugh A) have comparable exposure to subjects with normal hepatic function when given a single 200 mg dose of avanafil.

The exposure 4 hours after administration of avanafil 200 mg is lower in subjects with moderate hepatic impairment (Child-Pugh B) than in subjects with normal hepatic function. The maximum concentration and exposure are similar to those observed after subjects with normal liver function received an effective 100 mg dose of avanafil.

05.3 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 reproductive toxicity.

In a study on rat fertility and early embryonic development, reduced fertility and sperm motility, altered oestrus cycles and increased percentage of abnormal sperm occurred with the intake of 1 000 mg / kg / day, dose which also caused parental toxicity in treated males and females. No effect on fertility and sperm parameters was observed in male rats at doses up to 300 mg / kg / day (9 times the human exposure based on AUC unbound drug at the 200 mg dose) No treatment-related effects on the testes were detected in rats or mice treated with doses up to 600 or 1 000 mg / kg / day for 2 years, nor in dogs treated with avanafil for 9 months at exposures 110 times the maximum recommended human dose (MRHD - Maximum Recommended Human Dose).

In pregnant rats, no evidence of teratogenicity, embryotoxicity or foetotoxicity was observed at doses up to 300 mg / kg / day (approximately 15 times the MHRD on a mg / m2 basis in a 60 kg subject). At the maternally toxic dose of 1 000 mg / kg / day (approximately 49 times the MRHD based on mg / m2), there was a decrease in fetal body weight with no signs of teratogenicity. In pregnant rabbits, no evidence of teratogenicity, embryotoxicity or foetotoxicity was observed at doses up to 240 mg / kg / day (approximately 23 times the MHRD on a mg / m2 basis). In the rabbit study, maternal toxicity was observed at 240 mg / kg / day.

In a prenatal and postnatal development study in rats, pups experienced persistent reductions in body weight at doses of 300 mg / kg / day or greater (approximately 15 times the MRHD based on mg / m2) and delayed sexual development. at 600 mg / kg / day (approximately 29 times the MRHD based on mg / m2).