Adcirca (previously Tadalafil Lilly) · 4.8 Undesirable effects · 2

HOS-154456 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The most commonly reported adverse reactions, occurring in ≥ 10 % of patients in the tadalafil 40 mg treatment arm, were headache, nausea, back pain, dyspepsia, flushing, myalgia, nasopharingitis and pain in extremity. The adverse reactions reported were transient, and generally mild or moderate. Adverse reaction data are limited in patients over 75 years of age. 8 In the pivotal placebo-controlled study of ADCIRCA for the treatment of PAH, a total of 323 patients were treated with ADCIRCA at doses ranging from 2.5 mg to 40 mg once daily and 82 patients were treated with placebo. The duration of treatment was 16 weeks. The overall frequency of discontinuation due to adverse events was low (ADCIRCA 11 %, placebo 16 %). Three hundred and fifty-seven (357) patients who completed the pivotal study entered a long-term extension study. Doses studied were 20 mg and 40 mg once daily. Tabulated list of adverse reactions The table below lists the adverse reactions reported during the placebo-controlled clinical trial in patients with PAH treated with ADCIRCA. Also included in the table are some adverse reactions which have been reported in clinical trials and/or post-marketing with tadalafil in the treatment of male erectile dysfunction. These events have either been assigned a frequency of “Not known,” as the frequency in PAH patients cannot be estimated from the available data or assigned a frequency based on the clinical trial data from the pivotal placebo-controlled study of ADCIRCA. Frequency estimate: 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 the available data). System Organ Very common Common Uncommon Rare Not known1 Class Immune system Hypersensitivity Angioedema disorders reactions5 Nervous system Headache6 Syncope, Seizures5, Stroke2 (including disorders Migraine5 Transient haemorrhagic amnesia5 events) Eye disorders Blurred vision Non-arteritic

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HOS-154462 · has-adverse-reaction-information · PDF-Seite 26

Summary of the safety profile The most commonly reported adverse reactions, occurring in ≥ 10 % of patients in the tadalafil 40 mg treatment arm, were headache, nausea, back pain, dyspepsia, flushing, myalgia, nasopharingitis and pain in extremity. The adverse reactions reported were transient, and generally mild or moderate. Adverse reaction data are limited in patients over 75 years of age. In the pivotal placebo-controlled study of ADCIRCA for the treatment of PAH, a total of 323 patients were treated with ADCIRCA at doses ranging from 2.5 mg to 40 mg once daily and 82 patients were treated with placebo. The duration of treatment was 16 weeks. The overall frequency of discontinuation due to adverse events was low (ADCIRCA 11 %, placebo 16 %). Three hundred and fifty-seven (357) patients who completed the pivotal study entered a long-term extension study. Doses studied were 20 mg and 40 mg once daily. Tabulated list of adverse reactions The table below lists the adverse reactions reported during the placebo-controlled clinical trial in patients with PAH treated with ADCIRCA. Also included in the table are some adverse reactions which have been reported in clinical trials and/or post-marketing with tadalafil in the treatment of male erectile dysfunction. These events have either been assigned a frequency of “Not known,” as the frequency in PAH patients cannot be estimated from the available data or assigned a frequency based on the clinical trial data from the pivotal placebo-controlled study of ADCIRCA. Frequency estimate: 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 the available data). System Organ Very common Common Uncommon Rare Not known1 Class Immune system Hypersensitivity Angioedema disorders reactions5 Nervous system Headache6 Syncope, Seizures5, Stroke2 (including disorders Migraine5 Transient haemorrhagic amnesia5 events) Eye disorders Blurred vision Non-arteritic

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HOS-154458 · has-contraindication-information · PDF-Seite 21

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Acute myocardial infarction within the last 90 days. Severe hypotension (< 90/50 mm Hg). In clinical trials, tadalafil was shown to augment the hypotensive effects of nitrates. This is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated (see section 4.5). The co-administration of phosphodiesterase type 5 (PDE5) inhibitors, including tadalafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension (see section 4.5). 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).

HOS-154452 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Acute myocardial infarction within the last 90 days. Severe hypotension (< 90/50 mm Hg). In clinical trials, tadalafil was shown to augment the hypotensive effects of nitrates. This is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated (see section 4.5). The co-administration of phosphodiesterase type 5 (PDE5) inhibitors, including tadalafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension (see section 4.5). 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).

HOS-154457 · has-indication-information · PDF-Seite 19

Adults Treatment of pulmonary arterial hypertension (PAH) classified as WHO functional class II and III, to improve exercise capacity (see section 5.1). Efficacy has been shown in idiopathic PAH (IPAH) and in PAH related to collagen vascular disease. Paediatric population Treatment of paediatric patients aged 2 years and above with pulmonary arterial hypertension (PAH) classified as WHO functional class II and III.

HOS-154451 · has-indication-information · PDF-Seite 2

Adults Treatment of pulmonary arterial hypertension (PAH) classified as WHO functional class II and III, to improve exercise capacity (see section 5.1). Efficacy has been shown in idiopathic PAH (IPAH) and in PAH related to collagen vascular disease. Paediatric population Treatment of paediatric patients aged 2 years and above with pulmonary arterial hypertension (PAH) classified as WHO functional class II and III.

HOS-154460 · has-interaction-information · PDF-Seite 23

Effects of other medicinal products on tadalafil Cytochrome P450 inhibitors Azole antifungals (e.g. ketoconazole) Ketoconazole (200 mg daily), increased tadalafil (10 mg) single dose exposure (AUC) 2-fold and Cmax by 15 %, relative to the AUC and Cmax values for tadalafil alone. Ketoconazole (400 mg daily) increased tadalafil (20 mg) single dose exposure (AUC) 4-fold and Cmax by 22 %. Protease inhibitors (e.g. ritonavir) Ritonavir (200 mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg) single dose exposure (AUC) 2-fold with no change in Cmax. Ritonavir (500 mg or 600 mg twice daily) increased tadalafil (20 mg) single-dose exposure (AUC) by 32 % and decreased Cmax by 30 %. Cytochrome P450 inducers Endothelin-1 receptor antagonists (e.g. bosentan) Bosentan (125 mg twice daily), a substrate of CYP2C9 and CYP3A4 and a moderate inducer of CYP3A4, CYP2C9 and possibly CYP2C19, reduced tadalafil (40 mg once per day) systemic exposure by 42 % and Cmax by 27 % following multiple dose co-administration. The efficacy of tadalafil in 23 patients already on bosentan therapy has not been conclusively demonstrated (see sections 4.4 and 5.1). Tadalafil did not affect the exposure (AUC and Cmax) of bosentan or its metabolites. The safety and efficacy of combinations of tadalafil and other endothelin-1 receptor antagonists have not been studied. Antimycobacterials (e.g. rifampicin) A CYP3A4 inducer, rifampicin (600 mg daily), reduced tadalafil AUC by 88 % and Cmax by 46 %, relative to the AUC and Cmax values for tadalafil alone (10 mg). Effects of tadalafil on other medicinal products Nitrates In clinical trials, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of nitrates. This interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed after the last tadalafil dose. Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated (see section 4.3). Anti-hypertensives (including Calcium channel blockers) The co-administration of doxazosin (4 and 8 mg daily) and tadalafil (5 mg daily dose and 20 mg as a single dose) increases the blood pressure-lowering effect of this alpha-blocker in a significant manner. This effect lasts at least twelve hours and may be symptomatic, including syncope. Therefore, this combination is not recommended (see section 4.4).

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HOS-154454 · has-interaction-information · PDF-Seite 6

Effects of other medicinal products on tadalafil Cytochrome P450 inhibitors Azole antifungals (e.g. ketoconazole) Ketoconazole (200 mg daily), increased tadalafil (10 mg) single dose exposure (AUC) 2-fold and Cmax by 15 %, relative to the AUC and Cmax values for tadalafil alone. Ketoconazole (400 mg daily) increased tadalafil (20 mg) single dose exposure (AUC) 4-fold and Cmax by 22 %. Protease inhibitors (e.g. ritonavir) Ritonavir (200 mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg) single dose exposure (AUC) 2-fold with no change in Cmax. Ritonavir (500 mg or 600 mg twice daily) increased tadalafil (20 mg) single-dose exposure (AUC) by 32 % and decreased Cmax by 30 %. Cytochrome P450 inducers Endothelin-1 receptor antagonists (e.g. bosentan) Bosentan (125 mg twice daily), a substrate of CYP2C9 and CYP3A4 and a moderate inducer of CYP3A4, CYP2C9 and possibly CYP2C19, reduced tadalafil (40 mg once per day) systemic exposure by 42 % and Cmax by 27 % following multiple dose co-administration. The efficacy of tadalafil in patients already on bosentan therapy has not been conclusively demonstrated (see sections 4.4 and 5.1). Tadalafil did not affect the exposure (AUC and Cmax) of bosentan or its metabolites. The safety and efficacy of combinations of tadalafil and other endothelin-1 receptor antagonists have not been studied. Antimycobacterials (e.g. rifampicin) A CYP3A4 inducer, rifampicin (600 mg daily), reduced tadalafil AUC by 88 % and Cmax by 46 %, relative to the AUC and Cmax values for tadalafil alone (10 mg). 6 Effects of tadalafil on other medicinal products Nitrates In clinical trials, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of nitrates. This interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed after the last tadalafil dose. Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated (see section 4.3). Anti-hypertensives (including Calcium channel blockers) The co-administration of doxazosin (4 and 8 mg daily) and tadalafil (5 mg daily dose and 20 mg as a single dose) increases the blood pressure-lowering effect of this alpha-blocker in a significant manner. This effect lasts at least twelve hours and may be symptomatic, including syncope. Therefore, this combination is not recommended (see section 4.4).

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HOS-154461 · has-pregnancy-information · PDF-Seite 25

Pregnancy There are limited data from the use of tadalafil in pregnant women. Animal trials do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid the use of tadalafil during pregnancy. Breast-feeding Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk. A risk to the breastfed child cannot be excluded. ADCIRCA should not be used during breast feeding. Fertility Effects were seen in dogs that might indicate impairment of fertility. Two subsequent clinical trials suggest that this effect is unlikely in humans, although a decrease in sperm concentration was seen in some men (see sections 5.1 and 5.3).

HOS-154455 · has-pregnancy-information · PDF-Seite 8

Pregnancy There are limited data from the use of tadalafil 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). As a precautionary measure, it is preferable to avoid the use of tadalafil during pregnancy. Breast-feeding Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk. A risk to the breastfed child cannot be excluded. ADCIRCA should not be used during breast feeding. Fertility Effects were seen in dogs that might indicate impairment of fertility. Two subsequent clinical trials suggest that this effect is unlikely in humans, although a decrease in sperm concentration was seen in some men (see sections 5.1 and 5.3).

HOS-154453 · has-warning-information · PDF-Seite 4

Cardiovascular diseases The following groups of patients with cardiovascular disease were not included in PAH clinical trials: - Patients with clinically significant aortic and mitral valve disease - Patients with pericardial constriction - Patients with restrictive or congestive cardiomyopathy - Patients with significant left ventricular dysfunction - Patients with life-threatening arrhythmias - Patients with symptomatic coronary artery disease - Patients with uncontrolled hypertension. Since there are no clinical data on the safety of tadalafil in these patients, the use of tadalafil is not recommended. Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of tadalafil to patients with veno-occlusive disease, administration of tadalafil to such patients is not recommended. Should signs of pulmonary oedema occur when tadalafil is administered, the possibility of associated PVOD should be considered. Tadalafil has systemic vasodilatory properties that may result in transient decreases in blood pressure. Physicians should carefully consider whether their patients with certain underlying conditions, such as severe left ventricular outflow obstruction, fluid depletion, autonomic hypotension or patients with resting hypotension, could be adversely affected by such vasodilatory effects. 4 In patients who are taking alpha1 blockers concomitant administration of tadalafil may lead to symptomatic hypotension in some patients (see section 4.5). Therefore, the combination of tadalafil and doxazosin is not recommended. Vision Visual defects, including Central Serous Chorioretinopathy (CSCR), and cases of NAION have been reported in connection with the intake of tadalafil and other PDE5 inhibitors. Most cases of CSCR resolved spontaneously after stopping tadalafil. Regarding NAION, analyses of observational data suggest an increased risk of acute NAION in men with erectile dysfunction following exposure to tadalafil or other PDE5 inhibitors. As this may be relevant for all patients exposed to tadalafil, the patient should be advised that in case of sudden visual defect, visual acuity impairment and/or visual distortion, he should stop taking ADCIRCA and consult a physician immediately (see section 4.3). Patients with known hereditary degenerative ret

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HOS-154459 · has-warning-information · PDF-Seite 21

Cardiovascular diseases The following groups of patients with cardiovascular disease were not included in PAH clinical trials: - Patients with clinically significant aortic and mitral valve disease - Patients with pericardial constriction - Patients with restrictive or congestive cardiomyopathy - Patients with significant left ventricular dysfunction - Patients with life-threatening arrhythmias - Patients with symptomatic coronary artery disease - Patients with uncontrolled hypertension. Since there are no clinical data on the safety of tadalafil in these patients, the use of tadalafil is not recommended. Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of tadalafil to patients with veno-occlusive disease, administration of tadalafil to such patients is not recommended. Should signs of pulmonary oedema occur when tadalafil is administered, the possibility of associated PVOD should be considered. 21 Tadalafil has systemic vasodilatory properties that may result in transient decreases in blood pressure. Physicians should carefully consider whether their patients with certain underlying conditions, such as severe left ventricular outflow obstruction, fluid depletion, autonomic hypotension or patients with resting hypotension, could be adversely affected by such vasodilatory effects. In patients who are taking alpha1 blockers concomitant administration of tadalafil may lead to symptomatic hypotension in some patients (see section 4.5). Therefore, the combination of tadalafil and doxazosin is not recommended. Vision Visual defects, including Central Serous Chorioretinopathy (CSCR), and cases of NAION have been reported in connection with the intake of tadalafil and other PDE5 inhibitors. Most cases of CSCR resolved spontaneously after stopping tadalafil. Regarding NAION, analyses of observational data suggest an increased risk of acute NAION in men with erectile dysfunction following exposure to tadalafil or other PDE5 inhibitors. As this may be relevant for all patients exposed to tadalafil, the patient should be advised that in case of sudden visual defect, visual acuity impairment and/or visual distortion, he should stop taking ADCIRCA and consult a physician immediately (see section 4.3). Patients with known hereditary degenerative reti

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