CIALIS 5mg tablets medication leaflet

CIALIS 5 mg film-coated tablets

Each tablet contains 5 mg tadalafil.

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

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Light yellow and almond shaped tablets, marked 'C 5' 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 isrequired.

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 orwithout food.

In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried. Itmay 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 notrecommended for continuous daily use.

In patients who anticipate a frequent use of CIALIS (i.e., at least twice weekly) a once daily regimenwith the lowest doses of CIALIS might be considered suitable, based on patient choice and thephysician’s judgement.

In these patients the recommended dose is 5 mg taken once a day at approximately the same time ofday. The dose may be decreased to 2.5 mg 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

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 therecommended dose is also 5 mg taken at approximately the same time every day. Patients who areunable to tolerate tadalafil 5 mg for the treatment of benign prostatic hyperplasia should consider analternative therapy as the efficacy of tadalafil 2.5mg for the treatment of benign prostatic hyperplasiahas not been demonstrated.

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 patientswith severe renal impairment 10 mg is the maximum recommended dose for on-demand treatment.

Once-a-day dosing of 2.5 or 5 mg tadalafil both for the treatment of erectile dysfunction or benignprostatic hyperplasia is not recommended in patients with severe renal impairment (see sections 4. 4and 5.2).

Men with hepatic impairment

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

Once-a-day dosing of CIALIS both for the treatment of erectile dysfunction and benign prostatichyperplasia has not been evaluated in patients with hepatic impairment; therefore, if prescribed, acareful individual benefit/risk evaluation should be undertaken by the prescribing physician (seesections 4.4 and 5.2).

Men with diabetes

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 erectiledysfunction.

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 thoughtto 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 iscontraindicated (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-existingcardiovascular disease.

The following groups of patients with cardiovascular disease were not included in clinical trials andthe 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 uncontrolledhypertension,

- 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-arteriticanterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection ornot with previous PDE5 inhibitor exposure (see section 4.4).

The co-administration of PDE5 inhibitors, including tadalafil, with guanylate cyclase stimulators, suchas riociguat, is contraindicated as it may potentially lead to symptomatic hypotension (see section 4.5).

Before treatment with CIALIS

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

Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascularstatus of their patients, since there is a degree of cardiac risk associated with sexual activity. Tadalafilhas 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).

Prior to initiating treatment with tadalafil for benign prostatic hyperplasia patients should be examinedto rule out the presence of carcinoma of the prostate and carefully assessed for cardiovascularconditions (see section 4.3).

The evaluation of erectile dysfunction should include a determination of potential underlying causesand the identification of appropriate treatment following an appropriate medical assessment. It is notknown if CIALIS is effective in patients who have undergone pelvic surgery or radical non-nerve-sparing prostatectomy.

Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable anginapectoris, ventricular arrhythmia, stroke, transient ischemic attacks, chest pain, palpitations andtachycardia, have been reported either post marketing and/or in clinical trials. Most of the patients inwhom these events have been reported had pre-existing cardiovascular risk factors. However, it is notpossible 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.

In patients receiving concomitant antihypertensive medicinal products, tadalafil may induce a bloodpressure decrease. When initiating daily treatment with tadalafil, appropriate clinical considerationsshould be given to a possible dose adjustment of the antihypertensive therapy.

In patients who are taking alpha1 blockers, concomitant administration of CIALIS may lead tosymptomatic hypotension in some patients (see section 4.5). The combination of tadalafil anddoxazosin is not recommended.

Vision

Visual defects, including Central Serous Chorioretinopathy (CSCR), and cases of NAION have beenreported in connection with the intake of CIALIS and other PDE5 inhibitors. Most cases of CSCRresolved spontaneously after stopping tadalafil. Regarding NAION, analyses of observational datasuggest an increased risk of acute NAION in men with erectile dysfunction following exposure totadalafil or other PDE5 inhibitors. As this may be relevant for all patients exposed to tadalafil, thepatient should be advised that in case of sudden visual defect, visual acuity impairment and/or visualdistortion, he should stop taking CIALIS and consult a physician immediately (see section 4.3).

Decreased or sudden hearing loss

Cases of sudden hearing loss have been reported after the use of tadalafil. Although other risk factorswere 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 ofsudden decrease or loss of hearing.

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

There is limited clinical data on the safety of single-dose administration of CIALIS in patients withsevere hepatic insufficiency (Child-Pugh Class C). Once-a-day administration either for the treatmentof erectile dysfunction or benign prostatic hyperplasia has not been evaluated in patients with hepaticinsufficiency. If CIALIS is prescribed, a careful individual benefit/risk evaluation should beundertaken 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 immediatemedical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss ofpotency may result.

CIALIS, should be used with caution in patients with anatomical deformation of the penis (such asangulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which maypredispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia).

Use with CYP3A4 inhibitors

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 forerectile dysfunction have not been studied. The patients should be informed not to take CIALIS insuch combinations.

CIALIS contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactasedeficiency 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 regardto those interaction studies where only the 10 mg tadalafil dose was used, clinically relevantinteractions at higher doses cannot be completely ruled out.

Effects of other substances on tadalafil

Cytochrome P450 inhibitors

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), whichis 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 wouldbe 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.

Cytochrome P450 inducers

A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88 %, relative to the AUC values fortadalafil 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

Nitrates

In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects ofnitrates. Therefore, administration of CIALIS to patients who are using any form of organic nitrate iscontraindicated (see section 4.3). Based on the results of a clinical study in which 150 subjectsreceiving daily doses of tadalafil 20 mg for 7 days and 0.4 mg sublingual nitroglycerin at varioustimes, this interaction lasted for more than 24 hours and was no longer detectable when 48 hours hadelapsed 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 48hours should have elapsed after the last dose of CIALIS before nitrate administration is considered. Insuch circumstances, nitrates should only be administered under close medical supervision withappropriate 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 asingle 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 thiscombination is not recommended (see section 4.4).

In interaction studies performed in a limited number of healthy volunteers, these effects were notreported with alfuzosin or tamsulosin. However, caution should be exercised when using tadalafil inpatients treated with any alpha-blockers, and notably in the elderly. Treatments should be initiated atminimal dosage and progressively adjusted.

In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects ofantihypertensive medicinal products was examined. Major classes of antihypertensive medicinalproducts were studied, including calcium channel blockers (amlodipine), angiotensin convertingenzyme (ACE) inhibitors (enalapril), beta-adrenergic receptor blockers (metoprolol), thiazide diuretics(bendrofluazide), and angiotensin II receptor blockers (various types and doses, alone or incombination 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 dosewas applied) had no clinically significant interaction with any of these classes. In another clinicalpharmacology study tadalafil (20 mg) was studied in combination with up to 4 classes ofantihypertensives. In subjects taking multiple antihypertensives, the ambulatory-blood-pressurechanges appeared to relate to the degree of blood-pressure control. In this regard, study subjects whoseblood pressure was well controlled, the reduction was minimal and similar to that seen in healthysubjects. In study subjects whose blood pressure was not controlled, the reduction was greateralthough this reduction was not associated with hypotensive symptoms in the majority of subjects. Inpatients receiving concomitant antihypertensive medicinal products, tadalafil 20 mg may induce ablood pressure decrease, which (with the exception of alpha blockers -see above-) is, in general, minorand not likely to be clinically relevant. Analysis of phase 3 clinical trial data showed no difference inadverse events in patients taking tadalafil with or without antihypertensive medicinal products.

However, appropriate clinical advice should be given to patients regarding a possible decrease inblood pressure when they are treated with antihypertensive medicinal products.

Riociguat

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

5- alpha reductase inhibitors

In a clinical trial that compared tadalafil 5 mg coadministered with finasteride 5 mg to placebo plusfinasteride 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 reductaseinhibitors (5-ARIs) has not been performed, caution should be exercised when tadalafil is co-administered with 5-ARIs.

CYP1A2 substrates (e.g. theophylline)

When tadalafil 10 mg was administered with theophylline (a non-selective phosphodiesteraseinhibitor) in a clinical pharmacology study, there was no pharmacokinetic interaction. The onlypharmacodynamic effect was a small (3.5 bpm) increase in heart rate. Although this effect is minorand was of no clinical significance in this study, it should be considered when co-administering thesemedicinal products.

Ethinylestradiol and terbutaline

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

Alcohol

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 concentrationswere seen 3 hours after co-administration with alcohol. Alcohol was administered in a manner tomaximise 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 orapproximately 180 ml of 40 % alcohol [vodka] in an 80-kg male) but in some subjects, posturaldizziness and orthostatic hypotension were observed. When tadalafil was administered with lowerdoses of alcohol (0.6 g/kg), hypotension was not observed and dizziness occurred with similarfrequency 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 ofmedicinal products metabolised by CYP450 isoforms. Studies have confirmed that tadalafil does notinhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9 and

CYP2C19.

CYP2C9 substrates (e.g. R-warfarin)

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 bywarfarin.

Aspirin

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

Antidiabetic medicinal products

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 indicatedirect or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturitionor postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid theuse of CIALIS during pregnancy.

Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk. Arisk 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 studiessuggest that this effect is unlikely in humans, although a decrease in sperm concentration was seen insome men (see sections 5.1 and 5.3).

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

The most commonly reported adverse reactions in patients taking CIALIS for the treatment of erectiledysfunction or benign prostatic hyperplasia were headache, dyspepsia, back pain and myalgia, in whichthe 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 dosingare experienced within the first 10 to 30 days of starting treatment.

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 benignprostatic hyperplasia.

Frequency convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to<1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000) and not known (cannot be estimatedfrom the available data).

Very Common Uncommon Rare Not knowncommon

Hypersensitivity Angioedema2reactions

Headache Dizziness Stroke1 (includinghaemorrhagicevents), Syncope,

Transientischaemic attacks1,

Migraine2,

Seizures2,

Transient amnesia

Blurred vision, Visual field defect, Central serous

Sensations Swelling of chorioretinopathydescribed as eye eyelids,pain Conjunctivalhyperaemia, Non-arteritic anteriorischemic opticneuropathy(NAION)2,

Retinal vascularocclusion2

Ear and labyrinth disorders

Tinnitus Sudden hearingloss

Cardiac disorders1

Tachycardia, Myocardial

Palpitations infarction, Unstableangina pectoris2,

Ventriculararrhythmia2

Flushing Hypotension3,

Nasal congestion Dyspnoea,

Epistaxis

Dyspepsia Abdominal pain,

Vomiting, Nausea,

Gastro-oesophagealreflux

Rash Urticaria, Stevens-

Johnsonsyndrome2,

Exfoliativedermatitis2,

Hyperhydrosis(sweating)

Musculoskeletal, connective tissue and bone disorders

Back pain,

Myalgia, Pain inextremity

Haematuria

Prolonged Priapism, Penileerections haemorrhage,

Haematospermia

Chest pain1, Facial oedema2,

Peripheral oedema, Sudden cardiac

Fatigue death1, 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 clinicaltrials.(3) More commonly reported when tadalafil is given to patients who are already takingantihypertensive medicinal products.

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

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Single doses of up to 500 mg have been given to healthy subjects, and multiple daily doses up to100 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. Haemodialysiscontributes 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)-specificphosphodiesterase 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. Thisresults in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing anerection. Tadalafil has no effect in the treatment of erectile dysfunction in the absence of sexualstimulation.

The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum is also observed inthe smooth muscle of the prostate, the bladder and their vascular supply. The resulting vascularrelaxation increases blood perfusion which may be the mechanism by which symptoms of benignprostatic hyperplasia are reduced. These vascular effects may be complemented by inhibition ofbladder 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 incorpus 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 otherphosphodiesterases. 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 cardiaccontractility. 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 insupine 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 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 affinityof tadalafil for PDE6 compared to PDE5. Across all clinical studies, reports of changes in colour visionwere rare (< 0.1 %).

Three studies were conducted in men to assess the potential effect on spermatogenesis of CIALIS10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily. Intwo of these studies decreases were observed in sperm count and concentration related to tadalafiltreatment of unlikely clinical relevance. These effects were not associated with changes in otherparameters such as motility, morphology and FSH.

Erectile dysfunction

For CIALIS on demand, three clinical studies were conducted in 1054 patients in an at-home setting todefine the period of responsiveness. Tadalafil demonstrated statistically significant improvement inerectile 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 toplacebo as early as 16 minutes following dosing.

In a 12-week study performed in 186 patients (142 tadalafil, 44 placebo) with erectile dysfunctionsecondary to spinal cord injury, tadalafil significantly improved the erectile function leading to a meanper-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.

For once-a-day evaluation of tadalafil at doses of 2.5, 5, and 10 mg 3 clinical studies were initiallyconducted involving 853 patients of various ages (range 21-82 years) and ethnicities, with erectiledysfunction of various severities (mild, moderate, severe) and etiologies. In the two primary efficacystudies of general populations, the mean per-subject proportion of successful intercourse attempts were57 and 67 % on CIALIS 5 mg, 50 % on CIALIS 2.5 mg as compared to 31 and 37 % with placebo. Inthe study in patients with erectile dysfunction secondary to diabetes, the mean per-subject proportionof successful attempts were 41 and 46 % on CIALIS 5 mg and 2.5 mg, respectively, as compared to28 % with placebo. Most patients in these three studies were responders to previous on-demandtreatment with PDE5 inhibitors. In a subsequent study, 217 patients who were treatment-naïve to

PDE5 inhibitors were randomized to CIALIS 5 mg once a day vs. placebo. The mean per-subjectproportion of successful sexual intercourse attempts was 68 % for CIALIS patients compared to 52 %for patients on placebo.

Benign prostatic hyperplasia

CIALIS was studied in 4 clinical studies of 12 weeks duration enrolling over 1500 patients with signsand symptoms of benign prostatic hyperplasia. The improvement in the total international prostatesymptom 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 scoreoccurred as early as 1 week. In one of the studies, which also included tamsulosin 0.4 mg as an activecomparator, 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 benignprostatic hyperplasia in patients with both conditions. The improvements in the erectile functiondomain of the international index of erectile function and the total international prostate symptomscore 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, whichshowed that the improvement in total international prostate symptom score seen at 12 weeks wasmaintained 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 concurrentcorticosteroid therapy. The study included a 48-week double-blind period where patients wererandomised to tadalafil 0.3 mg/kg, tadalafil 0.6 mg/kg, or placebo daily. Tadalafil did not showefficacy 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 theplacebo group, compared with -64.7 m in the tadalafil 0.3 mg/kg group (p = 0.307) and -59.1 m in thetadalafil 0.6 mg/kg group (p = 0.538). In addition, there was no evidence of efficacy from any of thesecondary analyses performed in this study. The overall safety results from this study were generallyconsistent with the known safety profile of tadalafil and with adverse events (AEs) expected in apaediatric DMD population receiving corticosteroids.

The European Medicines Agency has waived the obligation to submit the results of studies in allsubsets of the paediatric population in the treatment of the erectile dysfunction. See section 4.2 forinformation on paediatric use.

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

The rate and extent of absorption of tadalafil are not influenced by food, thus CIALIS may be takenwith or without food. The time of dosing (morning versus evening) had no clinically relevant effectson the rate and extent of absorption.

The mean volume of distribution is approximately 63 l, indicating that tadalafil is distributed intotissues. At therapeutic concentrations, 94 % of tadalafil in plasma is bound to proteins. Protein bindingis 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 majorcirculating metabolite is the methylcatechol glucuronide. This metabolite is at least 13,000-fold lesspotent than tadalafil for PDE5. Consequently, it is not expected to be clinically active at observedmetabolite 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 doserange of 2.5 to 20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasmaconcentrations are attained within 5 days of once-daily dosing.

Pharmacokinetics determined with a population approach in patients with erectile dysfunction aresimilar 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 notclinically significant and does not warrant a dose adjustment.

In clinical pharmacology studies using single-dose tadalafil (5 to 20 mg), 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 diseaseon 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 islimited clinical data on the safety of CIALIS in patients with severe hepatic insufficiency (Child-Pugh

Class C). There are no available data about the administration of once-a-day dosing of tadalafil topatients with hepatic impairment. If CIALIS is prescribed once-a-day, a careful individual benefit/riskevaluation should be undertaken by the prescribing physician.

Patients with diabetes

Tadalafil exposure (AUC) in patients with diabetes was approximately 19 % lower than the AUCvalue 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 safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity toreproduction.

There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that receivedup to 1000 mg/kg/day tadalafil. In a rat prenatal and postnatal development study, the no observedeffect dose was 30 mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose wasapproximately 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 12months at doses of 25 mg/kg/day (resulting in at least a 3-fold greater exposure [range 3.7 - 18.6] thanseen in humans given a single 20 mg dose) and above, there was regression of the seminiferous tubularepithelium that resulted in a decrease in spermatogenesis in some dogs. See also section 5.1.

Tablet corelactose monohydrate,croscarmellose sodium,hydroxypropylcellulose,microcrystalline cellulose,sodium laurilsulfate,magnesium stearate.

Film-coatlactose monohydrate,hypromellose,triacetin,titanium dioxide (E171),iron oxide yellow (E172),talc.

Not applicable.

3 years.

Store in the original package in order to protect from moisture. Do not store above 25°C.

Aluminium/PVC blisters in cartons of 14, 28 or 84 film-coated tablets.

Not all packs sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Eli Lilly Nederland B.V.

Papendorpseweg 83, 3528 BJ Utrecht

The Netherlands

EU/1/02/237/007-008, 010

Date of first authorisation: 12 November 2002

Date of last renewal: 12 November 2012

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.