Spedra · 4.6 Fertility, pregnancy and lactation · 3

HOS-096412 · has-adverse-reaction-information · PDF-Seite 8

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 Influenza infestations Nasopharyngitis Immune system Seasonal allergy disorders Metabolism and Gout nutrition disorders Insomnia Psychiatric disorders Premature ejaculation Inappropriate affect Dizziness Nervous system Psychomotor Headache Somnolence disorders hyperactivity Sinus headache Eye disorders Vision blurred Angina pectoris Cardiac disorders

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HOS-096418 · has-adverse-reaction-information · PDF-Seite 21

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 Influenza infestations Nasopharyngitis Immune system Seasonal allergy disorders Metabolism and Gout nutrition disorders Insomnia Psychiatric disorders Premature ejaculation Inappropriate affect Dizziness Nervous system Psychomotor Headache Somnolence disorders hyperactivity Sinus headache Eye disorders Vision blurred Angina pectoris Cardiac disorders

Auszug; vollständigen Abschnitt im Original lesen.

HOS-096424 · has-adverse-reaction-information · PDF-Seite 34

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 Influenza infestations Nasopharyngitis Immune system Seasonal allergy disorders Metabolism and Gout nutrition disorders Insomnia Psychiatric disorders Premature ejaculation Inappropriate affect Dizziness Nervous system Psychomotor Headache Somnolence disorders hyperactivity Sinus headache Eye disorders Vision blurred Angina pectoris Cardiac disorders

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HOS-096408 · has-contraindication-information · PDF-Seite 3

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).

HOS-096414 · has-contraindication-information · PDF-Seite 16

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).

HOS-096420 · has-contraindication-information · PDF-Seite 29

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).

HOS-096419 · has-indication-information · PDF-Seite 28

Treatment of erectile dysfunction in adult men. In order for Spedra to be effective, sexual stimulation is required.

HOS-096407 · has-indication-information · PDF-Seite 2

Treatment of erectile dysfunction in adult men. In order for Spedra to be effective, sexual stimulation is required.

HOS-096413 · has-indication-information · PDF-Seite 15

Treatment of erectile dysfunction in adult men. In order for Spedra to be effective, sexual stimulation is required.

HOS-096416 · has-interaction-information · PDF-Seite 18

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, 18 respectively an

Auszug; vollständigen Abschnitt im Original lesen.

HOS-096422 · has-interaction-information · PDF-Seite 31

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, 31 respectively an

Auszug; vollständigen Abschnitt im Original lesen.

HOS-096410 · has-interaction-information · PDF-Seite 5

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, 5 respectively and

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HOS-096423 · has-pregnancy-information · PDF-Seite 33

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 33 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 .

HOS-096411 · has-pregnancy-information · PDF-Seite 7

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. 7 Fertility 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.

HOS-096417 · has-pregnancy-information · PDF-Seite 20

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 20 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.

HOS-096409 · has-warning-information · PDF-Seite 3

3 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, including Central Serous Chorioretinopathy (CSCR), and cases of non-arteritic anterior ischaemic optic neuropathy (NAION) have been reported in connection with the intake of 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 atten

Auszug; vollständigen Abschnitt im Original lesen.

HOS-096421 · has-warning-information · PDF-Seite 29

29 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, including Central Serous Chorioretinopathy (CSCR), and cases of non-arteritic anterior ischaemic optic neuropathy (NAION) have been reported in connection with the intake of 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 atte

Auszug; vollständigen Abschnitt im Original lesen.

HOS-096415 · has-warning-information · PDF-Seite 16

16 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, including Central Serous Chorioretinopathy (CSCR), and cases of non-arteritic anterior ischaemic optic neuropathy (NAION) have been reported in connection with the intake of 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 atte

Auszug; vollständigen Abschnitt im Original lesen.