2.5 Mg Cialis Effectiveness


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Efficacy and safety of once-daily tadalafil in men with erectile dysfunction who reported no successful intercourse attempts at baseline

Three studies were conducted in men to assess the potential effect on spermatogenesis of CIALIS 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.

Evaluation of the long-term safety and effectiveness of tadalafil once daily in Chinese men with erectile dysfunction: interim results of a multicenter, randomized, open-label trial

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Abstract

Once-daily tadalafil administration has been well established; however, studies about tadalafil once-daily treatment in the Chinese population are lacking. In this phase 4, postmarketing study, we ascertained the long-term safety and effectiveness of tadalafil 2.5 mg and 5.0 mg once daily in Chinese men with erectile dysfunction (n = 635). The primary endpoint of the study was safety at 12 months as assessed by the proportion of patients experiencing at least one treatment-emergent adverse event (serious or nonserious). The secondary endpoints included safety and effectiveness, measured by the International Index of Erectile Function-Erectile Function (IIEF-EF) domain scores. Similar adverse events to the known safety profile of tadalafil, such as nasopharyngitis, upper respiratory tract infection, headache, and dizziness, were detected. No new cardiovascular safety concerns were observed. After 3 months of treatment, significant increases in IIEF-EF domain scores were detected for both 2.5-mg (least squares [LS] mean change: 6.3; 95% confidence interval [CI]: 5.4–7.1; P < 0.001) and 5.0-mg (LS mean change: 7.4; 95% CI: 6.8–7.9; P < 0.001) tadalafil doses, and significance was maintained up to 12 months. In addition, approximately 40% of patients regained normal erectile function (IIEF-EF ≥26) following 1 year of tadalafil once-daily treatment. The findings in this study provide evidence for the extended effectiveness and tolerability of tadalafil, demonstrating no new safety concerns, in a Chinese population and make once-daily tadalafil administration a viable option for improving sexual performance and satisfaction in Chinese men with erectile dysfunction.

INTRODUCTION

Tadalafil is approved for erectile dysfunction (ED) in more than 90 countries, including the United States, European Union, Australia, and China.1,2,3,4 Previously, clinical development of tadalafil focused on on-demand oral administration at 10-mg or 20-mg doses.5,6,7,8 While phosphodiesterase type-5 (PDE5) inhibitors are effective on-demand, they require time after administration to achieve full efficacy, which may reduce spontaneity in sexual activity.9,10 Pharmacokinetic analyses demonstrate that the 17.5-h half-life of tadalafil allows for once-daily dosing, with stable serum concentrations attained within 5 days.11 Under steady-state conditions, tadalafil exposure is 1.6-fold more than that after a single dose, which may increase the rate of obtaining an erection upon sexual stimulation.11,12 Tadalafil once-daily dosing has been extensively tested in multiple clinical trials, with results suggesting that once-daily administration boosts the patient’s ability for spontaneity while still maintaining confidence in and effectiveness of treatment.12,13,14,15,16 Extended safety and tolerability of tadalafil after long-term use has also been reported in an open-label study with 5.0-mg once-daily dosing.17 The most frequent treatment-emergent adverse events (TEAEs) were back pain, influenza, headache, and dyspepsia, while clinical laboratory measures as well as electrocardiograms did not indicate any meaningful abnormalities after 1- and 2-year tadalafil once-daily dosing.17 However, the long-term safety and effectiveness of tadalafil once-daily administration in Chinese men with ED has not been studied. In this study, we report the effectiveness and safety results of 2.5-mg and 5.0-mg once-daily dosing after 1–3 months (period 1) and 5.0-mg once-daily dosing after 12 months (period 2) of tadalafil treatment in Chinese men.

PATIENTS AND METHODS

Study design

This study was a phase 4, prospective, multicenter, randomized, open-label study to determine the effectiveness and long-term safety of tadalafil given once daily to Chinese men with ED ( > NCT02224846). Patients were enrolled in the study between October 2014 and May 2015, provided that they met the following inclusion criteria. Briefly, the population included Chinese men ≥22 years old and e.g., hypothyroidism, hypopituitarism, or hypogonadism); clinically meaningful hepatobiliary disease or renal insufficiency; history of cardiac conditions; recent central nervous system injury; uncontrolled diabetes; or current use of nitrates, chemotherapy, androgens, antiandrogens, estrogens, anabolic steroids, or other approved or traditional Chinese medicine as ED treatment. All patients provided written informed consent, and the study was conducted in accordance with the Declaration of Helsinki. An ethical review board at each site approved the study protocol. The study was conducted at 24 centers in China. The last patient visit was in July 2017.

The study was conducted in three phases: the first phase was a 0.5- to 1-month run-in period for baseline sexual function assessment; the second phase (period 1) was a 3-month treatment period with 2.5 mg or 5.0 mg of oral tadalafil once daily to determine effectiveness and safety; and the third phase (period 2) was a 21-month extension period of the 5.0-mg oral tadalafil once-daily treatment to assess long-term safety. Upon completion of the run-in phase, patients were randomized (1:2) to the tadalafil 2.5-mg treatment group (n = 211) or 5.0-mg treatment group (n = 424) at the baseline visit. Study treatments were not blinded since no comparisons between the two doses were conducted. At the end of period 1, patients initially in the 2.5-mg treatment group were switched to the 5.0-mg tadalafil once-daily dose and those initially in the 5.0-mg treatment group remained on the same dose for the 21-month extension period (period 2). Figure 1 displays the study design.

A preplanned interim analysis was conducted after all patients completed 1 year of tadalafil treatment, and those results are presented here. A final analysis will be conducted after all patients complete the 2-year treatment.

The primary objective of the trial was safety of tadalafil once-daily treatment at 12 months. The secondary objectives included 1-month and 3-month effectiveness of 2.5-mg and 5.0-mg tadalafil once-daily dosing, 12-month effectiveness of 5.0-mg tadalafil once-daily dosing, and 3-month safety of 2.5-mg and 5.0-mg tadalafil once-daily dosing.

Safety analyses

The safety population included all enrolled patients who received at least one dose of tadalafil, and patients without follow-up data were excluded. Safety was analyzed via the proportion of patients at 3 and 12 months who experienced at least one TEAE (serious or nonserious). A TEAE was defined as an event that first occurred or worsened after baseline. Treatment-related adverse events were defined as events the investigator indicated to be related to treatment. Patient vital signs (blood pressure and heart rate) and laboratory assessments (hematology and clinical chemistry) were also reported.

Effectiveness outcome measures

The effectiveness population included all enrolled patients who received at least one dose of tadalafil and had both baseline and postbaseline data. The effectiveness of tadalafil once daily was measured by a change from baseline in the International Index of Erectile Function-Erectile Function (IIEF-EF) domain questionnaire18 (sum of questions Q1–5 and Q15) at months 1, 3, and 12; the proportion of patients who achieved normal erectile function (IIEF-EF ≥26) at months 1, 3, and 12; and the proportion of patients who responded “yes” to the Sexual Encounter Profile (SEP) diary Q2 (SEP2) and Q3 (SEP3)14 at months 1 and 3 upon a minimum of four sexual intercourse attempts.

Statistical analyses

Tadalafil exposure (in days) was calculated as the difference between the first day and the last day of treatment in each period. Treatment was self-administered. To establish treatment compliance, the number of tablets dispensed, the date of tadalafil dispensed, and the number of tablets returned were recorded at each patient visit.

The overall incidence and proportion of patients experiencing a TEAE (95% confidence interval [CI]) or discontinuation due to adverse events during the 1 st year of tadalafil once-daily treatment were calculated for all patients combined and for each treatment group.

A mixed-model with repeated measures (MMRM) was used for calculation of the adjusted mean changes in IIEF-EF domain scores from baseline to each follow-up visit, and the least squares (LS) mean changes and 95% CI are presented. For MMRM, the fixed effects of visit, pooled investigator, baseline score, and the interaction of visit and baseline score were fitted. The percentage of patients with IIEF-EF domain scores P values for significance of change from baseline to the follow-up visit were determined for each treatment group.

RESULTS

Patient disposition

A total of 689 patients entered into the study, and the study had 54 (7.8%) screen failures: 21 (38.9%) due to not meeting entry criteria, 29 (53.7%) due to withdrawal by patients, and 4 (7.4%) due to loss to follow-up ( Figure 2 ). The remaining 635 patients were randomized (1:2) to the 2.5-mg treatment group (n = 211) or the 5.0-mg treatment group (n = 424). By month 3, 9.0% of patients in the 2.5-mg treatment group and 8.5% of patients in the 5.0-mg treatment group had discontinued. The most common reason for discontinuation within period 1 was patient withdrawal (n = 26). Other reasons included protocol violation (n = 12), loss to follow-up (n = 11), adverse event (n = 3), and sponsor decision (n = 3). A total of 530 (83.5%) patients completed period 2, with 116 (18.3%) patients discontinuing up to the interim analysis. The most common reason for discontinuation within period 2 was patient withdrawal (n = 68). Other reasons included loss to follow-up (n = 20), protocol violation (n = 15), adverse event (n = 7), sponsor decision (n = 3), physician decision (n = 2), and death (n = 1).

Flow diagram of patient disposition. AE: adverse event.

Patient demographics

Baseline characteristics of patients, with preexisting conditions that occurred in at least 1% of the patients in any treatment group, are displayed in Table 1 . Patients had the mean age of 43.6 (range: 22.6–69.7) years, and 23.6% of the patients had previously been treated with an ED therapy, including tadalafil, sildenafil, and vardenafil. The severity of ED was mostly mild to moderate, with a median IIEF-EF domain score of 15.0 (range: 5.0–30.0). Overall, clinical characteristics and domain scores were well balanced between the two treatment groups.

Table 1

Tadalafil once daily exposure and compliance

The mean ± standard deviation of total treatment exposure time during period 1 and period 2 was 89.5 ± 11.7 days and 271.9 ± 18.6 days, respectively. By month 12, total exposure time was 332.5 ± 89.4 days. Total treatment compliance (taking 70%–100% of prescribed tablets) at month 12 was 86.0%.

Safety of tadalafil once daily

At the end of the 12-month treatment period, no deaths were reported. Serious adverse events (SAEs) included unstable angina, coronary artery disease, duodenal ulcer hemorrhage, osteoporosis, spouse pregnancy, ureterolithiasis, and sleep apnea syndrome, none of which were considered related to study drug. The study reported TEAEs in 172 (27.3%) of the patients who were mostly mild ( Table 2 ). The most frequent TEAEs (occurring in >1% of patients in any treatment group) at 3 months included nasopharyngitis, upper respiratory tract infection, headache, dizziness, alanine aminotransferase increased, and blood uric acid increased; in addition, at 12 months, chronic gastritis, abdominal pain upper, and dental caries were also reported ( Table 2 ). A total of 6 (1.0%) patients were discontinued from the study due to AEs of eye swelling, duodenal ulcer hemorrhage, chest discomfort, back pain, coronary artery disease, and hemoptysis (1 [0.2%] patient for each AE).

Table 2

Treatment-emergent adverse events during first 12-month treatment

At month 3, several statistically significant changes from baseline were measured for hematological and chemistry laboratory values, such as decreases in erythrocytes, hematocrit, hemoglobin, leukocytes, lymphocytes, and monocytes; decreases in albumin, alanine aminotransferase, aspartate aminotransferase/serum glutamic oxaloacetic transaminase, cholesterol, calcium, glucose, potassium, and sodium; and increases in creatinine and uric acid. However, all of the median changes in the laboratory values were within the normal range and were not considered clinically meaningful.

A median change from baseline in systolic blood pressure was detected at month 3 in the 5.0-mg treatment group (−1.0 mmHg; P = 0.003). At month 12, slight increases from baseline in heart rate were observed in the 2.5-mg to 5.0-mg (median change: 2.0 bpm; P = 0.014) and 5.0-mg (median change: 2.0 bpm; P = 0.012) treatment groups.

Overall, safety results at 1 year suggest similar AEs to the known safety profile of tadalafil. No new cardiovascular concerns were observed.

Effectiveness of tadalafil once daily

DISCUSSION

The safety and effectiveness of long-term tadalafil once-daily administration were assessed in the Chinese population. The results reported in this study are from a 1-year interim analysis; the full 2-year analysis will be conducted once all patients have completed this period. At the time of this analysis, 530 (83.5%) of the 635 Chinese men who entered randomization completed 1 year of treatment and demonstrated a high treatment compliance rate of 86.0%.

Extended treatment with 5.0 mg tadalafil up to 1 year did not unveil any new safety concerns in Chinese patients with ED. Long-term tadalafil once-daily dosing resulted in mostly mild AEs (total TEAE incidence of 27.3%), only six discontinuations due to AEs, and no clinically meaningful laboratory or vital sign changes. No deaths were reported, and SAEs that occurred were mostly present in patients with preexisting conditions and therefore considered not related to study drug. The primary objective of this trial regarding long-term safety was met and the safety profile was consistent with the tolerability reported previously.17

Consistent with previous studies,12,13,14,15,16 tadalafil once daily improved erectile function. Based on the IIEF-EF domain score assessments, effectiveness was notable as early as 1 month after tadalafil once-daily dosing at 2.5 mg and 5.0 mg. After 1 month of tadalafil once-daily dosing, erectile function had returned to normal (IIEF-EF ≥26) for 27.9% of patients. This effectiveness was maintained at 3 months and continued up to 12 months, with 43.7% of patients having an IIEF-EF score ≥26. Responses for the SEP questions after once-daily treatment similarly supported long-term effectiveness and, importantly, patient fulfillment. Both treatment doses, 2.5 mg and 5.0 mg, led to increases in penetration (SEP2) and intercourse (SEP3). Largely, the effectiveness and improvements seen at month 1 were maintained to month 3 and then to month 12, after tadalafil once-daily dosing.

The long-term safety and effectiveness results of tadalafil once daily may afford several benefits to Chinese men. The rapid improvements in erectile function demonstrated after only 1 month of tadalafil once-daily dosing suggest the ability to quickly increase sexual performance. In addition, as demonstrated by the month 12 safety results, the extended tolerability of tadalafil once-daily dosing will enable greater administration compliance as well as a more spontaneous, natural sex life for Chinese men.

This study presents some limitations. First, the study uses an open-labeled trial design with a focus on long-term safety results, instead of a randomized, controlled trial design. In addition, the current data are only interim analyses; the final analysis will be disclosed in the future.

CONCLUSION

The findings of this study in a Chinese population provide evidence for extended effectiveness and tolerability of tadalafil, demonstrating no new safety concerns, in this population and make once-daily tadalafil administration a viable option to improve sexual performance and satisfaction in Chinese men with ED.

AUTHOR CONTRIBUTIONS

HJ, LMZ, and YL participated in the study design. YL carried out the statistical analysis, interpretation of data, and revising the intellectual content. ZCZ and HCL played a critical role in coordinating study conduction and manuscript preparation. All other authors, including SY, JHL, ZHZ, YTD, and FBL, participated in the acquisition of data and revising the intellectual content. All authors read and approved the final version of the manuscript and agree with the order of presentation of the authors.

COMPETING INTERESTS

All authors declared no competing interests.

ACKNOWLEDGMENTS

The authors thank Meghan Greenwood, of inVentiv Health Clinical (Raleigh, NC, USA), for writing assistance, and Teri Tucker and Sarah Becker-Marrero, of inVentiv Health Clinical, for editing assistance. This work was sponsored by Eli Lilly and Company. Eli Lilly and Company paid no influence on the results and had no conflict of interests.

REFERENCES

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2. China Food and Drug Administration. Database of approved Active Pharmaceutical Ingredients (APIs) and API manufacturers in China. Tadalafil. [Last accessed on 2018 Jun 21]. Available from: http://app2.sfda.gov.cn/datasearchp/index1.do?tableId=36&tableName=TABLE36&tableView=??3&Id=16333 .

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Efficacy and safety of once-daily tadalafil in men with erectile dysfunction who reported no successful intercourse attempts at baseline

Introduction: Tadalafil is efficacious and well tolerated for erectile dysfunction (ED), but effects in men with “complete ED” are unclear.

Aim: To investigate effects of once-daily tadalafil in men with no successful intercourse attempts at baseline.

Methods: Through a post hoc, pooled-data analysis of four randomized, double-blind trials on the effects of tadalafil 2.5 or 5 mg (vs. placebo) in men with ED, we evaluated efficacy and safety in subjects with 0 “yes” responses to Sexual Encounter Profile question 3 (SEP3) during an initial 4-week treatment-free run-in period.

Main outcome measures: Changes from baseline in the SEP diary and the International Index of Erectile Function-erectile function (IIEF-EF) domain were subjected to analysis of covariance models.

Results: Five hundred ninety-five subjects with no successful attempts at baseline were included in the analysis. The mean (± standard deviation) age was 58.2 ± 10.7 years; and most subjects had ED for ≥ 1 year (95.0%). ED was severe in 61.5% and moderate in 26.4%. Approximately 45% had diabetes mellitus or hypertension. After 12 weeks, the mean per-patient SEP3 percentage increased from 0% to 32.4% with tadalafil 2.5 mg and to 46.4% with tadalafil 5 mg (each P < 0.001 vs. placebo). Corresponding data for successful penetration (SEP2) were increases from 21.1% to 48.2% with tadalafil 2.5 mg and from 24.4% to 66.2% with 5 mg (each P < 0.001 vs. placebo). Mean IIEF-EF increased from 9.7 to 15.7 with tadalafil 2.5 mg and from 10.7 to 19.2 with 5 mg (each P < 0.001 vs. placebo). Tadalafil also significantly improved the intercourse-satisfaction and overall-satisfaction domains (vs. placebo). Both doses of tadalafil were generally well tolerated, with adverse event rates similar to placebo.

Conclusions: The posttreatment intercourse success rate was 32% and 46% for tadalafil 2.5 mg and 5 mg, respectively, in men with no successful intercourse attempts at baseline.

Trial registration: ClinicalTrials.gov NCT00381732 NCT00422734 NCT00547183.

© 2012 International Society for Sexual Medicine.

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Cialis 2.5mg film-coated tablets

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  • 1. Name of the medicinal product
  • 2. Qualitative and quantitative composition
  • 3. Pharmaceutical form
  • 4. Clinical particulars
  • 4.1 Therapeutic indications
  • 4.2 Posology and method of administration
  • 4.3 Contraindications
  • 4.4 Special warnings and precautions for use
  • 4.5 Interaction with other medicinal products and other forms of interaction
  • 4.6 Fertility, pregnancy and lactation
  • 4.7 Effects on ability to drive and use machines
  • 4.8 Undesirable effects
  • 4.9 Overdose
  • 5. Pharmacological properties
  • 5.1 Pharmacodynamic properties
  • 5.2 Pharmacokinetic properties
  • 5.3 Preclinical safety data
  • 6. Pharmaceutical particulars
  • 6.1 List of excipients
  • 6.2 Incompatibilities
  • 6.3 Shelf life
  • 6.4 Special precautions for storage
  • 6.5 Nature and contents of container
  • 6.6 Special precautions for disposal and other handling
  • 7. Marketing authorisation holder
  • 8. Marketing authorisation number(s)
  • 9. Date of first authorisation/renewal of the authorisation
  • 10. Date of revision of the text

This information is intended for use by health professionals

CIALIS ® 2.5 mg, 5 mg, 10 mg and 20 mg film-coated tablets.

Each 2.5 mg tablet contains 2.5 mg tadalafil.

Each coated tablet contains 87 mg of lactose (as monohydrate).

Each 5 mg tablet contains 5 mg tadalafil.

Each coated tablet contains 121 mg of lactose (as monohydrate).

Each 10 mg tablet contains 10 mg tadalafil.

Each coated tablet contains 170 mg of lactose (as monohydrate).

Each 20 mg tablet contains 20 mg tadalafil.

Each coated tablet contains 233 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

The 2.5 mg tablets are light orange-yellow and almond shaped tablets, marked ‘C 2 ½’ on one side.

The 5 mg tablets are light yellow and almond shaped tablets, marked ‘C 5’ on one side.

The 10 mg tablets are light yellow and almond shaped tablets, marked ‘C 10’ on one side.

The 20 mg tablets are yellow and almond shaped tablets, marked ‘C 20’ on one side.

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.

CIALIS is not indicated for use by women.

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 CIALIS (i.e., at least twice weekly) a once daily regimen with the lowest doses of CIALIS 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.

Dose adjustments are not required in elderly patients.

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 (see sections 4.4 and 5.2).

For the treatment of erectile dysfunction using on-demand CIALIS the recommended dose of CIALIS is 10 mg taken prior to anticipated sexual activity and with or without food. There is limited clinical data on the safety of CIALIS 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 (see sections 4.4 and 5.2).

Dose adjustments are not required in diabetic patients.

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

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

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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 CIALIS to patients who are using any form of organic nitrate is contraindicated (see section 4.5).

CIALIS 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 (

– patients with a stroke within the last 6 months.

CIALIS 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 (see section 4.4).

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 (see section 4.5).

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 (see section 5.1) and as such potentiates the hypotensive effect of nitrates (see section 4.3).

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 CIALIS 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 (see section 4.3).

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 CIALIS, 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 CIALIS may lead to symptomatic hypotension in some patients (see section 4.5). The combination of tadalafil and doxazosin is not recommended.

Visual defects and cases of NAION have been reported in connection with the intake of CIALIS 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 CIALIS and consult a physician immediately (see section 4.3).

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 CIALIS is not recommended in patients with severe renal impairment.

There is limited clinical data on the safety of single-dose administration of CIALIS in patients with severe hepatic insufficiency (Child-Pugh Class C). Once-a-day administration has not been evaluated in patients with hepatic insufficiency. If CIALIS 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 CIALIS in patients with severe hepatic insufficiency (Child-Pugh Class C). If CIALIS 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.

CIALIS, 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).

Caution should be exercised when prescribing CIALIS 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 (see section 4.5).

CIALIS and other treatments for erectile dysfunction

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

CIALIS contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Interaction studies were conducted with 10 mg and/or 20 mg tadalafil, as indicated below. With regard to those interaction studies where only the 10 mg tadalafil dose was used, clinically relevant interactions at higher doses cannot be completely ruled out.

Effects of Other Substances on Tadalafil

Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (200 mg daily), increased tadalafil (10 mg) 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) exposure (AUC) 4-fold and Cmax by 22%. Ritonavir, a protease inhibitor (200 mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg) exposure (AUC) 2-fold with no change in Cmax. Although specific interactions have not been studied, other protease inhibitors, such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin, clarithromycin, itraconazole, and grapefruit juice, should be co-administered with caution, as they would be expected to increase plasma concentrations of tadalafil (see section 4.4). Consequently, the incidence of the adverse reactions listed in section 4.8 might be increased.

The role of transporters (for example, p-glycoprotein) in the disposition of tadalafil is not known. Therefore, there is the potential of drug interactions mediated by inhibition of transporters.

A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88%, relative to the AUC values for tadalafil alone (10 mg). This reduced exposure can be anticipated to decrease the efficacy of tadalafil; the magnitude of decreased efficacy is unknown. Other inducers of CYP3A4, such as phenobarbital, phenytoin, and carbamazepine, may also decrease plasma concentrations of tadalafil.

Effects of Tadalafil on Other Medicinal Products

In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of nitrates. Therefore, administration of CIALIS to patients who are using any form of organic nitrate is contraindicated (see section 4.3). Based on the results of a clinical study in which 150 subjects receiving daily doses of tadalafil 20 mg for 7 days and 0.4 mg sublingual nitroglycerin at various times, this interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed after the last tadalafil dose. Thus, in a patient prescribed any dose of CIALIS (2.5 mg- 20 mg), where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should have elapsed after the last dose of CIALIS before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate haemodynamic monitoring.

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).

In interaction studies performed in a limited number of healthy volunteers, these effects were not reported with alfuzosin or tamsulosin. However, caution should be exercised when using tadalafil in patients treated with any alpha-blockers, and notably in the elderly. Treatments should be initiated at minimal dosage and progressively adjusted.

In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects of antihypertensive medicinal products was examined. Major classes of antihypertensive medicinal products were studied, including calcium-channel blockers (amlodipine), angiotensin converting enzyme (ACE) inhibitors (enalapril), beta-adrenergic receptor blockers (metoprolol), thiazide diuretics (bendrofluazide), and angiotensin II receptor blockers (various types and doses, alone or in combination with thiazides, calcium-channel blockers, beta-blockers, and/or alpha-blockers). Tadalafil (10 mg, except for studies with angiotensin II receptor blockers and amlodipine in which a 20 mg dose was applied) had no clinically significant interaction with any of these classes. In another clinical pharmacology study, tadalafil (20 mg) was studied in combination with up to 4 classes of antihypertensives. In subjects taking multiple antihypertensives, the ambulatory-blood-pressure changes appeared to relate to the degree of blood pressure control. In this regard, study subjects whose blood pressure was well controlled, the reduction was minimal and similar to that seen in healthy subjects. In study subjects whose blood pressure was not controlled, the reduction was greater, although this reduction was not associated with hypotensive symptoms in the majority of subjects. In patients receiving concomitant antihypertensive medicinal products, tadalafil 20 mg may induce a blood pressure decrease, which (with the exception of alpha-blockers – see above) is, in general, minor and not likely to be clinically relevant. Analysis of Phase 3 clinical trial data showed no difference in adverse events in patients taking tadalafil with or without antihypertensive medicinal products. However, appropriate clinical advice should be given to patients regarding a possible decrease in blood pressure when they are treated with antihypertensive medicinal products.

Preclinical studies showed an additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment the hypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including tadalafil, is contraindicated (see section 4.3).

In a clinical trial that compared tadalafil 5 mg coadministered with finasteride 5 mg to placebo plus finasteride 5 mg in the relief of BPH symptoms, no new adverse reactions were identified. However, as a formal drug-drug interaction study evaluating the effects of tadalafil and 5-alpha reductase inhibitors (5-ARIs) has not been performed, caution should be exercised when tadalafil is co-administered with 5-ARIs.

When tadalafil 10 mg was administered with theophylline (a non-selective phosphodiesterase inhibitor) in a clinical pharmacology study, there was no pharmacokinetic interaction. The only pharmacodynamic effect was a small (3.5 bpm) increase in heart rate. Although this effect is minor and was of no clinical significance in this study, it should be considered when co-administering these medicinal products.

Tadalafil has been demonstrated to produce an increase in the oral bioavailability of ethinylestradiol; a similar increase may be expected with oral administration of terbutaline, although the clinical consequence of this is uncertain.

Alcohol concentrations (mean maximum blood concentration 0.08%) were not affected by co-administration with tadalafil (10 mg or 20 mg). In addition, no changes in tadalafil concentrations were seen 3 hours after co-administration with alcohol. Alcohol was administered in a manner to maximise the rate of alcohol absorption (overnight fast with no food until 2 hours after alcohol). Tadalafil (20 mg) did not augment the mean blood pressure decrease produced by alcohol (0.7 g/kg or approximately 180 ml of 40% alcohol [vodka] in an 80 kg male) but, in some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed and dizziness occurred with similar frequency to alcohol alone. The effect of alcohol on cognitive function was not augmented by tadalafil (10 mg).

Cytochrome P450 metabolised medicinal products

Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of medicinal products metabolised by CYP450 isoforms. Studies have confirmed that tadalafil does not inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9 and CYP2C19.

Tadalafil (10 mg and 20 mg) had no clinically significant effect on exposure (AUC) to S-warfarin or R-warfarin (CYP2C9 substrate), nor did tadalafil affect changes in prothrombin time induced by warfarin.

Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid.

Specific interaction studies with antidiabetic medicinal products were not conducted.

CIALIS is not indicated for use by women.

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 CIALIS during pregnancy.

Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk. A risk to the suckling child cannot be excluded. CIALIS should not be used during breast feeding.

Effects were seen in dogs that might indicate impairment of fertility. Two subsequent clinical studies 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).

CIALIS 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 CIALIS before driving or using machines.

The most commonly reported adverse reactions in patients taking CIALIS 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 CIALIS. The adverse reactions reported were transient, and generally mild or moderate. The majority of headaches reported with CIALIS 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 CIALIS 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.

Stroke 1 (including haemorrhagic events), Syncope, Transient ischaemic attacks 1 , Migraine 2 , Seizures 2 , Transient amnesia

Blurred vision, Sensations described as eye pain

Visual field defect, Swelling of eyelids, Conjunctival hyperaemia, Non-arteritic anterior ischaemic optic neuropathy (NAION) 2 , Retinal vascular occlusion 2

Myocardial infarction, Unstable angina pectoris 2 , Ventricular arrhythmia 2

Respiratory, thoracic and mediastinal disorders

Abdominal pain, Vomiting, Nausea, Gastro-oesophageal reflux

Skin and subcutaneous tissue disorders

Urticaria, Stevens-Johnson syndrome 2 , Exfoliative dermatitis 2 , Hyperhydrosis (sweating)

Musculoskeletal, connective tissue and bone disorders

Reproductive system and breast disorders

Priapism, Penile haemorrhage, Haematospermia

General disorders and administration site conditions

Chest pain 1, Peripheral oedema, Fatigue

Facial oedema 2 , Sudden cardiac death 1,2

(1) Most of the patients had pre-existing cardiovascular risk factors (see section 4.4).

(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.

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, Website: www.hpra.ie, , Malta: ADR Reporting, website: www.medicinesauthority.gov.mt/adrportal or United Kingdom: 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.

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

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.

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.

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 CIALIS 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.

For CIALIS on demand, three clinical studies were conducted in 1054 patients in an at-home setting to define the period of responsiveness. 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 CIALIS improved their erections as compared to 35% with placebo. Also, patients with erectile dysfunction in all severity categories reported improved erections whilst taking CIALIS (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 CIALIS-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 CIALIS 5mg, 50% on CIALIS 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 CIALIS 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 CIALIS 5mg once a day vs. placebo. The mean per-subject proportion of successful sexual intercourse attempts was 68% for CIALIS patients compared to 52% for patients on placebo.

CIALIS 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 CIALIS 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 CIALIS 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 CIALIS 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 CIALIS 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 CIALIS 5mg.

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. See section 4.2 for information on paediatric use.

Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration (Cmax) 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 CIALIS 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.

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.

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.

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).

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.

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.

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, Cmax was 41% higher than that observed in healthy subjects. Haemodialysis contributes negligibly to tadalafil elimination.

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 CIALIS in patients with severe hepatic insufficiency (Child-Pugh class C). If CIALIS 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 CIALIS 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.

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.

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. See also section 5.1.

Tadalafil dosed once a day in men with erectile dysfunction: a randomized, double-blind, placebo-controlled study in the US

The efficacy and safety of tadalafil, dosed once a day for the treatment of erectile dysfunction, was assessed in a randomized, double-blind, placebo-controlled, parallel-design study at 15 US centers. Following a 4-week treatment-free run-in period, patients ( ⩾ 18 years of age) were randomly assigned to 24 weeks treatment with tadalafil 2.5 mg, tadalafil 5 mg or placebo. Primary efficacy endpoints were change at 24 weeks in International Index of Erectile Function Erectile Function (EF) Domain score and mean per-patient percentage ‘yes’ responses to Sexual Encounter Profile diary questions 2 and 3. Tadalafil significantly improved erectile function compared with placebo for all three co-primary efficacy endpoints. Few patients discontinued because of adverse events (2.1%, placebo; 6.3%, tadalafil 2.5 mg; 4.1%, tadalafil 5 mg). Common treatment-emergent adverse events ( ⩾ 5%) were nasopharyngitis, influenza, viral gastroenteritis and back pain. Tadalafil 2.5 mg and 5 mg, dosed once a day for 24 weeks, was well tolerated and significantly improved erectile function.

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Acknowledgements

We acknowledge the additional study investigators: Stephen Auerbach, MD; Bradley Davis, MD; Eugene Dula, MD; Robert Feldman, MD; Darrell N. Fiske, MD; Michael Gambla, MD; Joel Kaufman, MD; Ira Klimberg, MD; Gary Ruoff, MD; David R Talley, MD; and Jay Young, MD. We thank Kate Loughney, PhD, ICOS Corporation for help in preparation of the manuscript and Steven D Watts, MS, Eli Lilly and Company for statistical analyses.

Author information

Authors and Affiliations

  1. Division of Urology, Harbor-UCLA Medical Center, Torrance, CA, USA J Rajfer
  2. Center for Urologic Research of Western New York, LLC, Williamsville, NY, USA P J Aliotta
  3. Northeast Indiana Research, LLC, Ft Wayne, IN, USA C P Steidle
  4. Urology Consultants, PA, San Antonio, TX, USA W P Fitch III
  5. Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA Y Zhao
  6. ICOS Corporation, Bothell, WA, USA A Yu