Apicalis

Treatment of erectile dysfunction in adult males.

In order for tadalafil to be effective for the treatment of erectile dysfunction, sexual stimulation is required.

5 mg only: Treatment of the signs and symptoms of benign prostatic hyperplasia in adult males.

Apicalis is not indicated for use by women.

Treatment of erectile dysfunction in adult males.

In order for Apicalis to be effective for the treatment of erectile dysfunction, sexual stimulation is required.

Apicalis10 mg is not indicated for use by women.

Posology

Erectile dysfunction in adult Men

In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or without food.

In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried. It may be taken at least 30 minutes prior to sexual activity.

The maximum dose frequency is once per day.

Tadalafil 10 and 20 mg is intended for use prior to anticipated sexual activity and it is not recommended for continuous daily use.

In patients who anticipate a frequent use of Apicalis (i.e., at least twice weekly) a once daily regimen with the lowest doses of Apicalis might be considered suitable, based on patient choice and the physician's judgement.

In these patients, the recommended dose is 5mg taken once a day at approximately the same time of day. The dose may be decreased to 2.5mg once a day based on individual tolerability.

The appropriateness of continued use of the daily regimen should be reassessed periodically.

Benign prostatic hyperplasia in adult men (tadalafil 5 mg only)

The recommended dose is 5 mg, taken at approximately the same time every day with or without food. For adult men being treated for both benign prostatic hyperplasia and erectile dysfunction the recommended dose is also 5 mg taken at approximately the same time every day. Patients who are unable to tolerate tadalafil 5 mg for the treatment of benign prostatic hyperplasia should consider an alternative therapy as the efficacy of tadalafil 2.5 mg for the treatment of benign prostatic hyperplasia has not been demonstrated.

Special Populations

Elderly Men

Dose adjustments are not required in elderly patients.

Men with Renal Impairment

Dose adjustments are not required in patients with mild to moderate renal impairment. For patients with severe renal impairment, 10 mg is the maximum recommended dose.

Once-a-day dosing of 2.5 or 5 mg tadalafil both for the treatment of erectile dysfunction or benign prostatic hyperplasia is not recommended in patients with severe renal impairment.

Men with Hepatic Impairment

For the treatment of erectile dysfunction using on-demand Apicalis the recommended dose of Apicalis is 10 mg taken prior to anticipated sexual activity and with or without food. There is limited clinical data on the safety of Apicalis in patients with severe hepatic impairment (Child-Pugh class C); if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of doses higher than 10mg of tadalafil to patients with hepatic impairment.

Once-a-day dosing both for the treatment of erectile dysfunction and benign prostatic hyperplasia has not been evaluated in patients with hepatic impairment; therefore, if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.

Men with Diabetes

Dose adjustments are not required in diabetic patients.

Paediatric population

There is no relevant use of Apicalis in the paediatric population with regard to the treatment of erectile dysfunction.

Method of administration

Apicalis is available as 2.5, 5, 10, and 20 mg film-coated tablets for oral use.

Posology

Adult Men

In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or without food.

In those patients in whom Apicalis 10 mg does not produce an adequate effect, 20 mg might be tried. It may be taken at least 30 minutes prior to sexual activity.

The maximum dose frequency is once per day.

Apicalis 10 mg and 20 mg is intended for use prior to anticipated sexual activity and it is not recommended for continuous daily use.

Special Populations

Elderly Men

Dose adjustments are not required in elderly patients.

Men with Renal Impairment

Dose adjustments are not required in patients with mild to moderate renal impairment. For patients with severe renal impairment, 10 mg is the maximum recommended dose for on-demand treatment.

Once-a-day dosing of Apicalis is not recommended in patients with severe renal impairment.

Men with Hepatic Impairment

For the treatment of erectile dysfunction using on-demand Apicalis the recommended dose of Apicalis is 10 mg taken prior to anticipated sexual activity and with or without food. There is limited clinical data on the safety of Apicalis in patients with severe hepatic impairment (Child-Pugh class C); if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of doses higher than 10 mg of Apicalis to patients with hepatic impairment.

Once-a-day dosing of Apicalis for the treatment of erectile dysfunction has not been evaluated in patients with hepatic impairment; therefore if prescribed, a careful individual benefit/risk evaluation must be undertaken by the prescribing physician.

Men with Diabetes

Dose adjustments are not required in diabetic patients.

Paediatric population

There is no relevant use of Apicalis in the paediatric population with regard to the treatment of erectile dysfunction.

Method of administration

Tablets for oral use.

In clinical studies, 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 Apicalis to patients who are using any form of organic nitrate is contraindicated.

Apicalis must not be used in men with cardiac disease for whom sexual activity is inadvisable. Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease.

The following groups of patients with cardiovascular disease were not included in clinical trials and the use of tadalafil is therefore contraindicated:

- patients with myocardial infarction within the last 90 days,

- patients with unstable angina or angina occurring during sexual intercourse,

- patients with New York Heart Association Class 2 or greater heart failure in the last 6 months,

- patients with uncontrolled arrhythmias, hypotension (<90/50 mm Hg), or uncontrolled hypertension,

- patients with a stroke within the last 6 months.

Apicalis is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure.

The co-administration of PDE5 inhibitors, including tadalafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension.

In clinical studies, Apicalis was shown to augment the hypotensive effects of nitrates. This is thought to result from the combined effects of nitrates and Apicalis on the nitric oxide/cGMP pathway. Therefore, administration of Apicalis to patients who are using any form of organic nitrate is contraindicated.

Apicalis must not be used in men with cardiac disease for whom sexual activity is inadvisable. Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease.

The following groups of patients with cardiovascular disease were not included in clinical trials and the use of Apicalis is therefore contraindicated:

- patients with myocardial infarction within the last 90 days,

- patients with unstable angina or angina occurring during sexual intercourse,

- patients with New York Heart Association Class 2 or greater heart failure in the last 6 months,

- patients with uncontrolled arrhythmias, hypotension (< 90/50mmHg), or uncontrolled hypertension,

- patients with a stroke within the last 6 months.

Apicalis is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure.

The co-administration of PDE5 inhibitors, including Apicalis, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension.

Before treatment with Apicalis

A medical history and physical examination should be undertaken to diagnose erectile dysfunction or benign prostatic hyperplasia and determine potential underlying causes, before pharmacological treatment is considered.

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. Tadalafil has vasodilator properties, resulting in mild and transient decreases in blood pressure and as such potentiates the hypotensive effect of nitrates.

The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following an appropriate medical assessment. It is not known if Apicalis is effective in patients who have undergone pelvic surgery or radical non-nerve-sparing prostatectomy.

Tadalafil 5 mg - Prior to initiating treatment with tadalafil for benign prostatic hyperplasia patients should be examined to rule out the presence of carcinoma of the prostate and carefully assessed for cardiovascular conditions.

Cardiovascular

Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular arrhythmia, stroke, transient ischaemic attacks, chest pain, palpitations and tachycardia, have been reported either post marketing and/or in clinical trials. Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors. However, it is not possible to definitively determine whether these events are related directly to these risk factors, to Apicalis, to sexual activity, or to a combination of these or other factors.

Tadalafil 2.5 mg and 5 mg - In patients receiving concomitant antihypertensive medicinal products, tadalafil may induce a blood pressure decrease. When initiating daily treatment with tadalafil, appropriate clinical considerations should be given to a possible dose adjustment of the antihypertensive therapy.

In patients who are taking alpha₁ blockers, concomitant administration of Apicalis may lead to symptomatic hypotension in some patients. The combination of tadalafil and doxazosin is not recommended.

Vision

Visual defects and cases of NAION have been reported in connection with the intake of Apicalis and other PDE5 inhibitors. 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, he should stop taking Apicalis and consult a physician immediately.

Decreased or sudden hearing loss

Cases of sudden hearing loss have been reported after the use of tadalafil. Although other risk factors were present in some cases (such as age, diabetes, hypertension and previous hearing loss history) patients should be advised to stop taking tadalafil and seek prompt medical attention in the event of sudden decrease or loss of hearing.

Renal and hepatic impairment (tadalafil 2.5 mg and 5 mg)

Due to increased tadalafil exposure (AUC), limited clinical experience and the lack of ability to influence clearance by dialysis, once-a-day dosing of Apicalis is not recommended in patients with severe renal impairment.

There is limited clinical data on the safety of single-dose administration of Apicalis in patients with severe hepatic insufficiency (Child-Pugh Class C). Once-a-day administration has not been evaluated in patients with hepatic insufficiency. If Apicalis is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.

Hepatic impairment (tadalafil 10 mg and 20 mg)

There is limited clinical data on the safety of single-dose administration of Apicalis in patients with severe hepatic insufficiency (Child-Pugh Class C). If Apicalis is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.

Priapism and anatomical deformation of the penis

Patients who experience erections lasting 4 hours or more should be instructed to seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

Apicalis, 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).

Use with CYP3A4 inhibitors

Caution should be exercised when prescribing Apicalis to patients using potent CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, and erythromycin), as increased tadalafil exposure (AUC) has been observed if the medicinal products are combined.

Apicalis and other treatments for erectile dysfunction

The safety and efficacy of combinations of Apicalis and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. The patients should be informed not to take Apicalis in such combinations.

Lactose

Apicalis contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Before treatment with Apicalis

A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potential underlying causes, before pharmacological treatment is considered.

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. Apicalis has vasodilator properties, resulting in mild and transient decreases in blood pressure , and as such potentiates the hypotensive effect of nitrates.

The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following an appropriate medical assessment. It is not known if Apicalis is effective in patients who have undergone pelvic surgery or radical non-nerve-sparing prostatectomy.

Cardiovascular

Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular arrhythmia, stroke, transient ischaemic attacks, chest pain, palpitations and tachycardia, have been reported either post marketing and/or in clinical trials. Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors. However, it is not possible to definitively determine whether these events are related directly to these risk factors, to Apicalis, to sexual activity, or to a combination of these or other factors.

In patients who are taking alpha₁ blockers, concomitant administration of Apicalis may lead to symptomatic hypotension in some patients. The combination of Apicalis and doxazosin is not recommended.

Vision

Visual defects and cases of NAION have been reported in connection with the intake of Apicalis and other PDE5 inhibitors. Analyses of observational data suggest an increased risk of acute NAION in men with erectile dysfunction following exposure to Apicalis or other PDE5 inhibitors. As this may be relevant for all patients exposed to Apicalis, the patient should be advised that in case of sudden visual defect, he should stop taking Apicalis and consult a physician immediately.

Decreased or sudden hearing loss

Cases of sudden hearing loss have been reported after the use of Apicalis. Although other risk factors were present in some cases (such as age, diabetes, hypertension and previous hearing loss history) patients should be advised to stop taking Apicalis and seek prompt medical attention in the event of sudden decrease or loss of hearing.

Renal and hepatic impairment

Due to increased Apicalis exposure (AUC), limited clinical experience and the lack of ability to influence clearance by dialysis, once-a-day dosing of Apicalis is not recommended in patients with severe renal impairment.

There is limited clinical data on the safety of single-dose administration of Apicalis in patients with severe hepatic insufficiency (Child-Pugh class C). If Apicalis is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.

Priapism and anatomical deformation of the penis

Patients who experience erections lasting 4 hours or more should be instructed to seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

Apicalis 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).

Use with CYP3A4 inducers or inhibitors

Caution should be exercised when prescribing Apicalis to patients using potent CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, and erythromycin), as increased Apicalis exposure (AUC) has been observed if the medicinal products are combined.

Apicalis and other treatments for erectile dysfunction

The safety and efficacy of combinations of Apicalis and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. The patients should be informed not to take Apicalis in such combinations.

Lactose

Apicalis contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Apicalis has negligible influence on the ability to drive or use machines. Although the frequency of reports of dizziness in placebo and tadalafil arms in clinical trials was similar, patients should be aware of how they react to Apicalis before driving or using machines.

Apicalis has negligible influence on the ability to drive or use machines. Although the frequency of reports of dizziness in placebo and Apicalis arms in clinical trials was similar, patients should be aware of how they react to Apicalis, before driving or using machines.

Summary of the safety profile

The most commonly reported adverse reactions in patients taking Apicalis for the treatment of erectile dysfunction or benign prostatic hyperplasia were headache, dyspepsia, back pain and myalgia, in which the incidences increase with increasing dose of Apicalis. The adverse reactions reported were transient, and generally mild or moderate. The majority of headaches reported with Apicalis once-a-day dosing are experienced within the first 10 to 30 days of starting treatment.

Tabulated summary of adverse reactions

The table below lists the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 8022 patients on Apicalis and 4422 patients on placebo) for on-demand and once-a-day treatment of erectile dysfunction and the once-a-day treatment of benign prostatic hyperplasia.

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 the available data).

(1) Most of the patients had pre-existing cardiovascular risk factors.

(2) Postmarketing surveillance reported adverse reactions not observed in placebo-controlled clinical trials.

(3) More commonly reported when tadalafil is given to patients who are already taking antihypertensive medicinal products.

Description of selected adverse reactions

A slightly higher incidence of ECG abnormalities, primarily sinus bradycardia, has been reported in patients treated with tadalafil once a day as compared with placebo. Most of these ECG abnormalities were not associated with adverse reactions.

Other special populations

Data in patients over 65 years of age receiving tadalafil in clinical trials, either for the treatment of erectile dysfunction or the treatment of benign prostatic hyperplasia, are limited. In clinical trials with tadalafil taken on demand for the treatment of erectile dysfunction, diarrhoea was reported more frequently in patients over 65 years of age. In clinical trials with tadalafil 5 mg taken once a day for the treatment of benign prostatic hyperplasia, dizziness and diarrhoea were reported more frequently in patients over 75 years of age.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, e-mail: [email protected], or United Kingdom: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

Summary of the safety profile

The most commonly reported adverse reactions in patients taking Apicalis for the treatment of erectile dysfunction or benign prostatic hyperplasia were headache, dyspepsia, back pain and myalgia, in which the incidences increase with increasing dose of Apicalis. The adverse reactions reported were transient, and generally mild or moderate. The majority of headaches reported with Apicalis once-a-day dosing are experienced within the first 10 to 30 days of starting treatment.

Tabulated summary of adverse reactions

The table below lists the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 8022 patients on Apicalis and 4422 patients on placebo) for on-demand and once-a-day treatment of erectile dysfunction and the once-a-day treatment of benign prostatic hyperplasia.

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) and very rare (<1/10,000) and not known (cannot be estimated from the available data).

¹ Most of the patients had pre-existing cardiovascular risk factors.

² Postmarketing surveillance reported adverse reactions not observed in placebo-controlled clinical trials.

³ More commonly reported when Apicalis is given to patients who are already taking antihypertensive medicinal products.

Description of selected adverse reactions

A slightly higher incidence of ECG abnormalities, primarily sinus bradycardia, has been reported in patients treated with Apicalis once a day as compared with placebo. Most of these ECG abnormalities were not associated with adverse reactions.

Other special populations

Data in patients over 65 years of age receiving Apicalis in clinical trials, either for the treatment of erectile dysfunction or the treatment of benign prostatic hyperplasia, are limited. In clinical trials with Apicalis taken on demand for the treatment of erectile dysfunction, diarrhoea was reported more frequently in patients over 65 years of age. In clinical trials with Apicalis 5 mg taken once a day for the treatment of benign prostatic hyperplasia, dizziness and diarrhoea were reported more frequently in patients over 75 years of age.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

Single doses of up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients. Adverse events were similar to those seen at lower doses.

In cases of overdose, standard supportive measures should be adopted, as required. Haemodialysis contributes negligibly to tadalafil elimination.

Single doses of up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients. Adverse events were similar to those seen at lower doses.

In cases of overdose, standard supportive measures should be adopted, as required. Haemodialysis contributes negligibly to Apicalis elimination.

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction. ATC code: G04BE08.

Mechanism of action

Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Tadalafil has no effect in the treatment of erectile dysfunction in the absence of sexual stimulation.

Tadalafil 5 mg - The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum is also observed in the smooth muscle of the prostate, the bladder and their vascular supply. The resulting vascular relaxation increases blood perfusion which may be the mechanism by which symptoms of benign prostatic hyperplasia are reduced. These vascular effects may be complemented by inhibition of bladder afferent nerve activity and smooth muscle relaxation of the prostate and bladder.

Pharmacodynamic effects

Studies in vitro have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, and cerebellum. The effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. Tadalafil is >10,000-fold more potent for PDE5 than for PDE1, PDE2, and PDE4 enzymes which are found in the heart, brain, blood vessels, liver, and other organs. Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility. Additionally, tadalafil is approximately 700-fold more potent for PDE5 than for PDE6, an enzyme which is found in the retina and is responsible for phototransduction. Tadalafil is also >10,000-fold more potent for PDE5 than for PDE7 through PDE10.

Clinical efficacy and safety

Tadalafil administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8mmHg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6mmHg, respectively), and no significant change in heart rate.

In a study to assess the effects of tadalafil on vision, no impairment of colour discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test. This finding is consistent with the low affinity of tadalafil for PDE6 compared to PDE5. Across all clinical studies, reports of changes in colour vision were rare (<0.1%).

Three studies were conducted in men to assess the potential effect on spermatogenesis of Apicalis 10mg (one 6-month study) and 20mg (one 6-month and one 9-month study) administered daily. In two of these studies decreases were observed in sperm count and concentration related to tadalafil treatment of unlikely clinical relevance. These effects were not associated with changes in other parameters, such as motility, morphology, and FSH.

Erectile dysfunction

Three clinical studies were conducted in 1054 patients in an at-home setting to define the period of responsiveness to Apicalis on demand. Tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well as patients' ability to attain and maintain erections for successful intercourse compared to placebo as early as 16 minutes following dosing.

In a 12-week study performed in 186 patients (142 tadalafil, 44 placebo) with erectile dysfunction secondary to spinal cord injury, tadalafil significantly improved the erectile function leading to a mean per-subject proportion of successful attempts in patients treated with tadalafil 10 or 20 mg (flexible-dose, on demand) of 48% as compared to 17% with placebo.

Tadalafil at doses of 2 to 100mg has been evaluated in 16 clinical studies involving 3250 patients, including patients with erectile dysfunction of various severities (mild, moderate, severe), etiologies, ages (range 21-86 years), and ethnicities. Most patients reported erectile dysfunction of at least 1 year in duration. In the primary efficacy studies of general populations, 81% of patients reported that Apicalis improved their erections as compared to 35% with placebo. Also, patients with erectile dysfunction in all severity categories reported improved erections whilst taking Apicalis (86%, 83%, and 72% for mild, moderate, and severe, respectively, as compared to 45%, 42%, and 19% with placebo). In the primary efficacy studies, 75% of intercourse attempts were successful in Apicalis-treated patients as compared to 32% with placebo.

For once-a-day evaluation of tadalafil at doses of 2.5, 5, and 10 mg 3 clinical studies were initially conducted involving 853 patients of various ages (range 21-82 years) and ethnicities, with erectile dysfunction of various severities (mild, moderate, severe) and etiologies. In the two primary efficacy studies of general populations, the mean per-subject proportion of successful intercourse attempts were 57 and 67% on Apicalis 5mg, 50% on Apicalis 2.5mg as compared to 31 and 37% with placebo. In the study in patients with erectile dysfunction secondary to diabetes, the mean per-subject proportion of successful attempts were 41 and 46% on Apicalis 5mg and 2.5mg, respectively, as compared to 28% with placebo. Most patients in these three studies were responders to previous on-demand treatment with PDE5 inhibitors. In a subsequent study, 217 patients who were treatment-naive to PDE5 inhibitors were randomised to Apicalis 5mg once a day vs. placebo. The mean per-subject proportion of successful sexual intercourse attempts was 68% for Apicalis patients compared to 52% for patients on placebo.

Benign prostatic hyperplasia

Apicalis was studied in 4 clinical studies of 12 weeks duration enrolling over 1500 patients with signs and symptoms of benign prostatic hyperplasia. The improvement in the total international prostate symptom score with Apicalis 5mg in the four studies were -4.8, -5.6, -6.1 and -6.3 compared to -2.2, -3.6, -3.8 and -4.2 with placebo. The improvements in total international prostate symptom score occurred as early as 1 week. In one of the studies, which also included tamsulosin 0.4 mg as an active comparator, the improvement in total international prostate symptom score with Apicalis 5mg, tamsulosin and placebo were -6.3, -5.7 and -4.2 respectively.

One of these studies assessed improvements in erectile dysfunction and signs and symptoms of benign prostatic hyperplasia in patients with both conditions. The improvements in the erectile function domain of the international index of erectile function and the total international prostate symptom score in this study were 6.5 and -6.1 with Apicalis 5 mg compared to 1.8 and -3.8 with placebo, respectively. The mean per-subject proportion of successful sexual intercourse attempts was 71.9% with Apicalis 5 mg compared to 48.3% with placebo.

The maintenance of the effect was evaluated in an open-label extension to one of the studies, which showed that the improvement in total international prostate symptom score seen at 12 weeks was maintained for up to 1 additional year of treatment with Apicalis 5mg.

Paediatric population

A single study has been performed in paediatric patients with Duchenne Muscular Dystrophy (DMD) in which no evidence of efficacy was seen. The randomised, double-blind, placebo-controlled, parallel, 3-arm study of tadalafil was conducted in 331 boys aged 7-14 years with DMD receiving concurrent corticosteroid therapy. The study included a 48-week double-blind period where patients were randomised to tadalafil 0.3 mg/kg, tadalafil 0.6 mg/kg, or placebo daily. Tadalafil did not show efficacy in slowing the decline in ambulation as measured by the primary 6 minute walk distance (6MWD) endpoint: least squares (LS) mean change in 6MWD at 48 weeks was -51.0 meters (m) in the placebo group, compared with -64.7 m in the tadalafil 0.3 mg/kg group (p = 0.307) and -59.1 m in the tadalafil 0.6 mg/kg group (p = 0.538). In addition, there was no evidence of efficacy from any of the secondary analyses performed in this study. The overall safety results from this study were generally consistent with the known safety profile of tadalafil and with adverse events (AEs) expected in a paediatric DMD population receiving corticosteroids.

The European Medicines Agency has waived the obligation to submit the results of studies in all subsets of the paediatric population in the treatment of the erectile dysfunction.

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction, ATC Code: G04BE08.

Mechanism of action

Apicalis is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by Apicalis produces increased levels of cGMP in the corpus cavernosum. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Apicalis has no effect in the treatment of erectile dysfunction in the absence of sexual stimulation.

Pharmacodynamic effects

Studies in vitro have shown that Apicalis is a selective inhibitor of PDE5. PDE5 is an enzyme found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, and cerebellum. The effect of Apicalis is more potent on PDE5 than on other phosphodiesterases. Apicalis is > 10,000-fold more potent for PDE5 than for PDE1, PDE2, and PDE4 enzymes which are found in the heart, brain, blood vessels, liver, and other organs. Apicalis is > 10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels.

This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility. Additionally, Apicalis is approximately 700-fold more potent for PDE5 than for PDE6, an enzyme which is found in the retina and is responsible for phototransduction. Apicalis is also > 10,000-fold more potent for PDE5 than for PDE7 through PDE10.

Clinical efficacy and safety

Apicalis administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8 mm Hg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6 mm Hg, respectively), and no significant change in heart rate.

In a study to assess the effects of Apicalis on vision, no impairment of colour discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test. This finding is consistent with the low affinity of Apicalis for PDE6 compared to PDE5. Across all clinical studies, reports of changes in colour vision were rare (< 0.1 %).

Three studies were conducted in men to assess the potential effect on spermatogenesis of Apicalis 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily. In two of these studies decreases were observed in sperm count and concentration related to Apicalis treatment of unlikely clinical relevance. These effects were not associated with changes in other parameters such as motility, morphology and FSH.

For Apicalis on demand, three clinical studies were conducted in 1,054 patients in an at-home setting to define the period of responsiveness. Apicalis demonstrated statistically significant improvement in erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well as patients' ability to attain and maintain erections for successful intercourse compared to placebo as early as 16 minutes following dosing.

Apicalis at doses of 2 to 100 mg has been evaluated in 16 clinical studies involving 3250 patients, including patients with erectile dysfunction of various severities (mild, moderate, severe), etiologies, ages (range 21-86 years), and ethnicities. Most patients reported erectile dysfunction of at least 1 year in duration. In the primary efficacy studies of general populations, 81 % of patients reported that Apicalis improved their erections as compared to 35 % with placebo. Also, patients with erectile dysfunction in all severity categories reported improved erections whilst taking Apicalis (86 %, 83 %, and 72 % for mild, moderate, and severe, respectively, as compared to 45 %, 42 %, and 19 % with placebo). In the primary efficacy studies, 75 % of intercourse attempts were successful in Apicalis treated patients as compared to 32 % with placebo.

In a 12-week study performed in 186 patients (142 Apicalis, 44 placebo) with erectile dysfunction secondary to spinal cord injury, Apicalis significantly improved the erectile function leading to a mean per-subject proportion of successful attempts in patients treated with Apicalis 10 mg or 20 mg (flexible-dose, on demand) of 48 % as compared to 17 % with placebo.

Paediatric population

A single study has been performed in paediatric patients with Duchenne Muscular Dystrophy (DMD) in which no evidence of efficacy was seen. The randomised, double-blind, placebo-controlled, parallel, 3-arm study of Apicalis was conducted in 331 boys aged 7-14 years with DMD receiving concurrent corticosteroid therapy. The study included a 48-week double-blind period where patients were randomised to Apicalis 0.3 mg/kg, Apicalis 0.6 mg/kg, or placebo daily. Apicalis did not show efficacy in slowing the decline in ambulation as measured by the primary 6 minute walk distance (6MWD) endpoint: least squares (LS) mean change in 6MWD at 48 weeks was -51.0 meters (m) in the placebo group, compared with -64.7 m in the Apicalis 0.3 mg/kg group (p = 0.307) and -59.1 m in the Apicalis 0.6 mg/kg group (p = 0.538). In addition, there was no evidence of efficacy from any of the secondary analyses performed in this study. The overall safety results from this study were generally consistent with the known safety profile of Apicalis and with adverse events (AEs) expected in a paediatric DMD population receiving corticosteroids.

The European Medicines Agency has waived the obligation to submit the results of studies in all subsets of the paediatric population in the treatment of the erectile dysfunction.

Absorption

Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration (C_max) is achieved at a median time of 2 hours after dosing. Absolute bioavailability of tadalafil following oral dosing has not been determined.

The rate and extent of absorption of tadalafil are not influenced by food, thus Apicalis may be taken with or without food. The time of dosing (morning versus evening) had no clinically relevant effects on the rate and extent of absorption.

Distribution

The mean volume of distribution is approximately 63 l, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Protein binding is not affected by impaired renal function.

Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.

Biotransformation

Tadalafil is predominantly metabolised by the cytochrome P450 (CYP) 3A4 isoform. The major circulating metabolite is the methylcatechol glucuronide. This metabolite is at least 13,000-fold less potent than tadalafil for PDE5. Consequently, it is not expected to be clinically active at observed metabolite concentrations.

Elimination

The mean oral clearance for tadalafil is 2.5 l/h and the mean half-life is 17.5 hours in healthy subjects.

Tadalafil is excreted predominantly as inactive metabolites, mainly in the faeces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).

Linearity/Non-Linearity

Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range of 2.5 to 20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasma concentrations are attained within 5 days of once daily dosing.

Pharmacokinetics determined with a population approach in patients with erectile dysfunction are similar to pharmacokinetics in subjects without erectile dysfunction.

Special Populations

Elderly

Healthy elderly subjects (65 years or over) had a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) relative to healthy subjects aged 19 to 45 years. This effect of age is not clinically significant and does not warrant a dose adjustment.

Renal Insufficiency

In clinical pharmacology studies using single dose tadalafil (5 to 20mg), tadalafil exposure (AUC) approximately doubled in subjects with mild (creatinine clearance 51 to 80 ml/min) or moderate (creatinine clearance 31 to 50 ml/min) renal impairment and in subjects with end-stage renal disease on dialysis. In haemodialysis patients, C_max was 41% higher than that observed in healthy subjects. Haemodialysis contributes negligibly to tadalafil elimination.

Hepatic Insufficiency

Tadalafil exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh class A and B) is comparable to exposure in healthy subjects when a dose of 10 mg is administered. There is limited clinical data on the safety of Apicalis in patients with severe hepatic insufficiency (Child-Pugh class C). If Apicalis is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of once-a-day dosing of tadalafil to patients with hepatic impairment. If Apicalis is prescribed once-a-day, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of doses higher than 10 mg of tadalafil to patients with hepatic impairment.

Patients with Diabetes

Tadalafil exposure (AUC) in patients with diabetes was approximately 19% lower than the AUC value for healthy subjects. This difference in exposure does not warrant a dose adjustment.

Absorption

Apicalis is readily absorbed after oral administration and the mean maximum observed plasma concentration (C_max) is achieved at a median time of 2 hours after dosing. Absolute bioavailability of Apicalis following oral dosing has not been determined.

The rate and extent of absorption of Apicalis are not influenced by food, thus Apicalis may be taken with or without food. The time of dosing (morning versus evening after a single 10 mg administration) had no clinically relevant effects on the rate and extent of absorption.

Distribution

The mean volume of distribution is approximately 63 liters, indicating that Apicalis is distributed into tissues. At therapeutic concentrations, 94 % of Apicalis in plasma is bound to proteins. Protein binding is not affected by impaired renal function.

Less than 0.0005 % of the administered dose appeared in the semen of healthy subjects.

Biotransformation

Apicalis is predominantly metabolised by the cytochrome P450 (CYP) 3A4 isoform. The major circulating metabolite is the methylcatechol glucuronide. This metabolite is at least 13,000-fold less potent than Apicalis for PDE5. Consequently, it is not expected to be clinically active at observed metabolite concentrations.

Elimination

The mean oral clearance for Apicalis is 2.5 L/h and the mean half-life is 17.5 hours in healthy subjects. Apicalis is excreted predominantly as inactive metabolites, mainly in the faeces (approximately 61 % of the dose) and to a lesser extent in the urine (approximately 36 % of the dose).

Linearity/Non-Linearity

Apicalis pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range of 2.5 mg to 20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasma concentrations are attained within 5 days of once daily dosing.

Pharmacokinetics determined with a population approach in patients with erectile dysfunction are similar to pharmacokinetics in subjects without erectile dysfunction.

Special Populations

Elderly

Healthy elderly subjects (65 years or over) had a lower oral clearance of Apicalis, resulting in 25 % higher exposure (AUC) relative to healthy subjects aged 19 to 45 years. This effect of age is not clinically significant and does not warrant a dose adjustment.

Renal Insufficiency

In clinical pharmacology studies using single dose Apicalis (5 mg to 20 mg), Apicalis exposure (AUC) approximately doubled in subjects with mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min) renal impairment and in subjects with end-stage renal disease on dialysis. In haemodialysis patients, C_max was 41 % higher than that observed in healthy subjects. Haemodialysis contributes negligibly to Apicalis elimination.

Hepatic Insufficiency

Apicalis exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh class A and B) is comparable to exposure in healthy subjects when a dose of 10 mg is administered. There is limited clinical data on the safety of Apicalis in patients with severe hepatic insufficiency (Child-Pugh class C). There are no available data about the administration of once-a-day dosing of Apicalis to patients with hepatic impairment. If Apicalis is prescribed once-a-day, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.

Patients with diabetes

Apicalis exposure (AUC) in patients with diabetes was approximately 19 % lower than the AUC value for healthy subjects. This difference in exposure does not warrant a dose adjustment.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.

There was no evidence of teratogenicity, embryotoxicity, or foetotoxicity in rats or mice that received up to 1000 mg/kg/day tadalafil. In a rat prenatal and postnatal development study, the no observed effect dose was 30 mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was approximately 18-times the human AUC at a 20 mg dose.

There was no impairment of fertility in male and female rats. In dogs given tadalafil daily for 6 to 12 months at doses of 25 mg/kg/day (resulting in at least a 3-fold greater exposure [range 3.7-18.6] than seen in humans given a single 20 mg dose) and above, there was regression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.

There was no evidence of teratogenicity, embryotoxicity, or foetotoxicity in rats or mice that received up to 1000 mg/kg/day Apicalis. In a rat prenatal and postnatal development study, the no observed effect dose was 30 mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was approximately 18-times the human AUC at a 20 mg dose.

There was no impairment of fertility in male and female rats.