annex i summary of product...

1

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

CIALIS 10 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10 mg tadalafil

For excipients, see 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.The 10 mg tablets are light yellow and almond shaped, marked "C 10" on one side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of erectile dysfunction.

In order for CIALIS to be effective, sexual stimulation is required.

CIALIS is not indicated for use by women.

4.2 Posology and method of administration

For oral use.

Use in adult menThe recommended dose is 10 mg taken prior to anticipated sexual activity and without regard to food.In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried. Itcan be taken from 30 minutes to 12 hours prior to sexual activity. Efficacy of tadalafil may persist upto 24 hours post-dose.The maximum recommended dosing frequency is once per day.Daily use of the medication is strongly discouraged because the long term safety after prolonged dailydosing has not been established. See section 4.4 Special warnings and special precautions for use, lastparagraph.

Use in elderly menDosage adjustments are not required in elderly patients.

Use in men with impaired renal functionThe recommended dose of CIALIS is 10 mg taken prior to anticipated sexual activity and withoutregard to food. There are no available data about the administration of doses higher than 10 mg oftadalafil to patients with renal impairment. (See sections 4.4 Special warnings and precautions for useand 5.2 Pharmacokinetic properties).

Use in men with impaired hepatic functionThe recommended dose of CIALIS is 10 mg taken prior to anticipated sexual activity and withoutregard to food. There are no available data about the administration of doses higher than 10 mg oftadalafil to patients with hepatic impairment. (See sections 4.4 Special warnings and precautions foruse and 5.2 Pharmacokinetic properties).

Use in men with diabetesDosage adjustments are not required in diabetic patients.

Use in children and adolescentsCIALIS should not be used in individuals below 18 years of age.

4.3 Contraindications

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.

Agents for the treatment of erectile dysfunction, including CIALIS, should not be used in men withcardiac disease for whom sexual activity is inadvisable. Physicians should consider the potentialcardiac 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 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 uncontrolled

hypertension,- patients with a stroke within the last 6 months.

CIALIS should not be used in patients with hypersensitivity to tadalafil or to any of the excipients.

4.4 Special warnings and special precautions for use

A medical history and physical examination should be undertaken to diagnose erectile dysfunction anddetermine potential underlying causes, before pharmacological treatment 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 5.1Pharmacodynamic properties) and as such potentiate the hypotensive effect of nitrates (see section 4.3Contraindications).

Serious cardiovascular events, including myocardial infarction, unstable angina pectoris, ventriculararrhythmia, strokes, and transient ischemic attacks occurred during clinical studies of CIALIS. Inaddition hypertension and hypotension (including postural hypotension) were also seen infrequently inclinical trials. Most of the patients in whom these events have been observed had pre-existingcardiovascular risk factors. However, it is not possible to definitively determine whether these eventsare related directly to these risk factors.

There is limited clinical data on the safety of CIALIS in the following groups; if prescribed, a carefulindividual benefit/risk evaluation should be undertaken by the prescribing physician:

- patients with severe renal insufficiency (creatinine clearance � 30 ml/min)- patients with severe hepatic insufficiency (Child-Pugh Class C)

Tadalafil 10 mg has been the highest dose studied in patients with mild (creatinine clearance = 51 to80 ml/min), and moderate (creatinine clearance = 31 to 50 ml/min) renal failure and in patients withend-stage renal failure undergoing haemodialysis.

Priapism was not reported in clinical trials with CIALIS. However, priapism has been reported withanother PDE5 inhibitor. 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 andpermanent loss of potency may result.

CIALIS should be used with caution in patients who have conditions that might predispose them topriapism (such as sickle cell anaemia, multiple myeloma, or leukaemia), or in patients with anatomicaldeformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease).

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 with spinal cord injuries and patients who have undergonepelvic surgery or radical non-nerve-sparing prostatectomy.

CIALIS should not be administered to patients with hereditary problems of galactose intolerance, theLapp lactase deficiency or glucose-galactose malabsorption.

The safety and efficacy of combinations of CIALIS and other treatments for erectile dysfunction havenot been studied. Therefore, the use of such combinations is not recommended.

In dogs given tadalafil daily for 6 to 12 months at doses of 25 mg/kg/day (resulting in at least a 3-foldgreater exposure [range 3.7 – 18.6] than seen in humans at a 20 mg single dose) and above, there wasregression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis insome dogs. Results from two 6 month studies in volunteers suggest that this effect is unlikely inhumans (see section 5.1 Pharmacodynamic properties). The effects of longer term daily dosing havenot been established. Therefore, daily use of the medication is strongly discouraged.

4.5 Interaction with other medicinal products and other forms of interaction

Many of the interaction studies were conducted with 10 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 medicinal products on tadalafil

Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole,increased tadalafil AUC by 107 %, relative to the AUC values for tadalafil alone (10 mg dose).Although specific interactions have not been studied, some protease inhibitors, such as ritonavir andsaquinavir, and other CYP3A4 inhibitors, such as erythromycin, clarithromycin, itraconazole andgrapefruit juice should be co-administered with caution as they would be expected to increase plasmaconcentrations of tadalafil. Consequently the incidence of the undesirable effects listed in section 4.8might be increased.

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

A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88 %, relative to the AUC values fortadalafil alone (10 mg dose). It can be expected that concomitant administration of other CYP3A4inducers such as phenobarbital, phenytoin and carbamazepine, will also decrease plasmaconcentrations of tadalafil.

Effects of tadalafil on other medicinal products

In clinical studies, tadalafil (10 mg) was shown to augment the hypotensive effects of nitrates.Therefore, administration of CIALIS to patients who are using any form of organic nitrate iscontraindicated (see section 4.3 Contraindications).

Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugsmetabolised by CYP450 isoforms. Studies have confirmed that tadalafil does not inhibit or induceCYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1 and CYP2C9.

Tadalafil (10 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) did not potentiate the increase in bleeding time caused by acetyl salicylic acid.

In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects ofantihypertensive agents was examined. Major classes of antihypertensive agents were studied,including calcium channel blockers (amlodipine), angiotensin converting enzyme (ACE) inhibitors(enalapril), beta-adrenergic receptor blockers (metoprolol), thiazide diuretics (bendrofluazide), andangiotensin 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 studieswith angiotensin II receptor blockers and amlodipine in which a 20 mg dose was applied) had noclinically significant interaction with any of these classes. Tadalafil (10 and 20 mg) had no clinicallysignificant effect on blood pressure changes due to tamsulosin, an alpha-adrenergic receptor blockingagent. In patients receiving concomitant antihypertensive medications, tadalafil 20 mg may induce ablood pressure decrease, which is, in general, minor and not likely to be clinically relevant. Analysis ofphase 3 clinical trial data showed no difference in adverse events in patients taking tadalafil with orwithout antihypertensive medications. However, appropriate clinical advice should be given to patientsregarding a possible decrease in blood pressure when they are treated with antihypertensivemedications.

Alcohol concentrations (mean maximum blood concentration 0.08 %) were not affected by co-administration with tadalafil (10 mg). The effect of alcohol on cognitive function was not augmentedby tadalafil (10 mg) nor was the effect of alcohol on blood pressure augmented by tadalafil (20 mg). Inaddition, no changes in tadalafil concentrations were seen 3 hours after co-administration with alcohol.

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

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 thesemedications.

Specific interaction studies with antidiabetic agents were not conducted.

4.6 Pregnancy and lactation

CIALIS is not indicated for use by women. There are no studies of tadalafil in pregnant women.

There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that receivedup to 1000 mg/kg/day.

4.7 Effects on ability to drive and use machines

CIALIS is expected to have no or negligible influence on the ability to drive and or use machines. Nospecific studies have been performed to evaluate a potential effect. Although the frequency of reportsof dizziness in placebo and tadalafil arms in clinical trials was similar, patients should be aware of howthey react to CIALIS, before driving or operating machinery.

4.8 Undesirable effects

The most commonly reported adverse reactions are headache and dyspepsia, see tables below.

Table 1

Very common adverse reactions (>1/10)

System Organ Class Adverse reaction

CIALIS10-20 mg

(%) N=724

Placebo

(%)N=379

Nervous System Headache 14.5 5.5Gastrointestinal Dyspepsia 12.3 1.8

Table 2

Common adverse reactions (>1/100, <1/10)


CIALIS10-20 mg

(%) N=724

Placebo

(%)N=379

Nervous System Dizziness 2.3 1.8Vascular Flushing 4.1 1.6Respiratory, thoracic, andmediastinal

Nasal Congestion 4.3 3.2

Musculoskeletal andconnective tissue

Back painMyalgia

6.55.7

4.21.8

Swelling of eyelids, sensations described as eye pain and conjunctival hyperaemia are uncommonadverse reactions.

The adverse events reported with tadalafil were transient, and generally mild or moderate.

Adverse event data are limited in patients over 75 years of age.

4.9 Overdose

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in erectile dysfunction (ATC Code G04B E).

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 absence of sexual stimulation.

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 other

phosphodiesterases. Tadalafil is > 10,000-fold more potent for PDE5 than for PDE1, PDE2, andPDE4, 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.

Two clinical studies were conducted in 571 patients in an at-home setting to define the period ofresponsiveness to CIALIS. CIALIS demonstrated statistically significant improvement in erectilefunction and the ability to have successful sexual intercourse up to 24 hours following dosing, as wellas patients’ ability to attain and maintain erections for successful intercourse compared to placebo asearly as 16 minutes following dosing. Sexual Encounter Profile (SEP) diary data collected in clinicalstudies supports this period of responsiveness and a statistically significant greater proportion ofsuccessful intercourse attempts associated with tadalafil treatment compared to placebo treatment up toand through the 12- to 14-hour interval following administration. In these studies patients were free tochoose the time interval between dose administration and the time of sexual attempts.

CIALIS 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. When tadalafil and certain oral antihypertensivemedications (including angiotensin II receptor blockers) were assessed in drug interaction studies,tadalafil did not result in clinically significant augmentation of the antihypertensive effects of thosemedications (see section 4.5 Interaction with other medicinal products and other forms of interaction).However, appropriate clinical advice should be given to patients regarding the possibility of a decreasein blood pressure when they are treated with antihypertensive medications. The administration ofCIALIS to patients who are using any form of organic nitrate is contraindicated.

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 withthe low affinity of tadalafil for PDE6 compared to PDE5. Across all clinical studies, reports of changesin colour vision were rare (< 0.1 %).

Two studies were conducted in men to assess the potential effect of CIALIS 10 mg and 20 mgadministered daily for 6 months on spermatogenesis. The results of these studies demonstrate nodifference from placebo with respect to the proportion of men showing a 50% or greater decrease insperm concentration. In addition, in comparison with placebo, there were no adverse effects observedwith respect to mean change in sperm count, sperm morphology, or sperm motility at either dose.However, in the study of 10 mg CIALIS taken daily for 6 months, results showed a decrease in meansperm concentration relative to placebo. This effect was not seen in the study where the higher dose,20 mg, CIALIS was taken daily for 6 months. In addition there was no effect on mean concentrationsof testosterone, luteinizing hormone or follicle stimulating hormone with either 10 or 20 mg ofCIALIS compared to placebo. The effects of longer term daily dosing have not been established. Seealso Sections 4.4 Special warnings and special precautions for use and 5.3 Preclinical safety data.

Tadalafil at doses of 2 to 100 mg has been evaluated in 16 clinical studies involving 3250 patients,including patients with erectile dysfunction of various severities (mild, moderate, severe), etiologies,ages (range 21-86 years), and ethnicities. Most patients reported erectile dysfunction of at least 1 yearin duration. In the primary efficacy studies of general populations, 81% of patients reported thatCIALIS improved their erections as compared to 35% with placebo. Also, patients with erectiledysfunction 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% withplacebo). In the primary efficacy studies, 75% of intercourse attempts were successful in CIALIStreated patients as compared to 32% with placebo.

5.2 Pharmacokinetic properties

AbsorptionTadalafil 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.

DistributionThe 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.

BiotransformationTadalafil 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.

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

Linearity/non-linearityTadalafil 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.

Special Populations

ElderlyHealthy 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.

Renal insufficiencyIn a clinical pharmacology study in subjects with mild (creatinine clearance 51 to 80 ml/min) ormoderate (creatinine clearance 31 to 50 ml/min) renal impairment, tadalafil exposure (AUC) washigher than in healthy subjects after administration of a 10 mg dose. In another clinical pharmacologystudy in subjects with end-stage renal failure undergoing haemodialysis the tadalafil exposure (AUC)after a 10 mg dose was comparable to the exposure in healthy subjects.There are no available data about the administration of doses higher than 10 mg of tadalafil to patientswith renal impairment.

Hepatic insufficiencyTadalafil exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh ClassA and B) is comparable to exposure in healthy subjects when a dose of 10 mg is administered.There are no available data about the administration of doses higher than 10 mg of tadalafil to patientswith hepatic impairment.

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.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, genotoxicity, carcinogenic potential, and toxicity to reproduction.There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that receivedup to 1000 mg/kg/day. In a rat pre- and postnatal development study, the no observed effect dose was30 mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was approximately 18times 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 sections 4.4 Specialwarnings and special precautions for use and 5.1 Pharmacodynamic properties.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:lactose monohydrate,croscarmellose sodium,hydroxypropylcellulose,microcrystalline cellulose,sodium laurilsulfate,magnesium stearate.

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

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store in the original package.

6.5 Nature and contents of container

Aluminium/PVC/PE/Aclar blisters in cartons of 4 tablets 10 mg.

6.6 Instructions for use and handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Lilly ICOS Limited, 25 New Street Square, London, EC4A 3LN. United Kingdom.

8. MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT


CIALIS 20 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION


For excipients, see 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of erectile dysfunction.

In order for CIALIS to be effective, sexual stimulation is required.

CIALIS is not indicated for use by women.

4.2 Posology and method of administration

For oral use.

Use in adult menThe recommended dose is 10 mg taken prior to anticipated sexual activity and without regard to food.In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried. Itcan be taken from 30 minutes to 12 hours prior to sexual activity. Efficacy of tadalafil may persist upto 24 hours post-dose.The maximum recommended dosing frequency is once per day.Daily use of the medication is strongly discouraged because the long term safety after prolonged dailydosing has not been established. See section 4.4 Special warnings and special precautions for use, lastparagraph.

Use in elderly menDosage adjustments are not required in elderly patients.

Use in men with impaired renal functionThe recommended dose of CIALIS is 10 mg taken prior to anticipated sexual activity and withoutregard to food. There are no available data about the administration of doses higher than 10 mg oftadalafil to patients with renal impairment. (See sections 4.4 Special warnings and precautions for useand 5.2 Pharmacokinetic properties).

Use in men with impaired hepatic functionThe recommended dose of CIALIS is 10 mg taken prior to anticipated sexual activity and withoutregard to food. There are no available data about the administration of doses higher than 10 mg oftadalafil to patients with hepatic impairment. (See sections 4.4 Special warnings and precautions foruse and 5.2 Pharmacokinetic properties).

Use in men with diabetesDosage adjustments are not required in diabetic patients.

Use in children and adolescentsCIALIS should not be used in individuals below 18 years of age.

4.3 Contraindications

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.

Agents for the treatment of erectile dysfunction, including CIALIS, should not be used in men withcardiac disease for whom sexual activity is inadvisable. Physicians should consider the potentialcardiac 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 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 uncontrolled

hypertension,- patients with a stroke within the last 6 months.

CIALIS should not be used in patients with hypersensitivity to tadalafil or to any of the excipients.

4.4 Special warnings and special precautions for use

A medical history and physical examination should be undertaken to diagnose erectile dysfunction anddetermine potential underlying causes, before pharmacological treatment 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 5.1Pharmacodynamic properties) and as such potentiate the hypotensive effect of nitrates (see section 4.3Contraindications).

Serious cardiovascular events, including myocardial infarction, unstable angina pectoris, ventriculararrhythmia, strokes, and transient ischemic attacks occurred during clinical studies of CIALIS. Inaddition hypertension and hypotension (including postural hypotension) were also seen infrequently inclinical trials. Most of the patients in whom these events have been observed had pre-existingcardiovascular risk factors. However, it is not possible to definitively determine whether these eventsare related directly to these risk factors.

There is limited clinical data on the safety of CIALIS in the following groups; if prescribed, a carefulindividual benefit/risk evaluation should be undertaken by the prescribing physician:

- patients with severe renal insufficiency (creatinine clearance � 30 ml/min)- patients with severe hepatic insufficiency (Child-Pugh Class C)

Tadalafil 10 mg has been the highest dose studied in patients with mild (creatinine clearance = 51 to80 ml/min), and moderate (creatinine clearance = 31 to 50 ml/min) renal failure and in patients withend-stage renal failure undergoing haemodialysis.

Priapism was not reported in clinical trials with CIALIS. However, priapism has been reported withanother PDE5 inhibitor. Patients who experience erections lasting 4 hours or more should be instructedto seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage andpermanent loss of potency may result.

CIALIS should be used with caution in patients who have conditions that might predispose them topriapism (such as sickle cell anaemia, multiple myeloma, or leukaemia), or in patients with anatomicaldeformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease).

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 with spinal cord injuries and patients who have undergonepelvic surgery or radical non-nerve-sparing prostatectomy.

CIALIS should not be administered to patients with hereditary problems of galactose intolerance, theLapp lactase deficiency or glucose-galactose malabsorption.

The safety and efficacy of combinations of CIALIS and other treatments for erectile dysfunction havenot been studied. Therefore, the use of such combinations is not recommended.

In dogs given tadalafil daily for 6 to 12 months at doses of 25 mg/kg/day (resulting in at least a 3-foldgreater exposure [range 3.7 – 18.6] than seen in humans at a 20 mg single dose) and above, there wasregression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis insome dogs. Results from two 6 month studies in volunteers suggest that this effect is unlikely inhumans (see section 5.1 Pharmacodynamic properties). The effects of longer term daily dosing havenot been established. Therefore, daily use of the medication is strongly discouraged.

4.5 Interaction with other medicinal products and other forms of interaction

Many of the interaction studies were conducted with 10 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 medicinal products on tadalafil

Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole,increased tadalafil AUC by 107 %, relative to the AUC values for tadalafil alone (10 mg dose).Although specific interactions have not been studied, some protease inhibitors, such as ritonavir andsaquinavir, and other CYP3A4 inhibitors, such as erythromycin, clarithromycin, itraconazole andgrapefruit juice should be co-administered with caution as they would be expected to increase plasmaconcentrations of tadalafil. Consequently the incidence of the undesirable effects listed in section 4.8might be increased.

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

A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88 %, relative to the AUC values fortadalafil alone (10 mg dose). It can be expected that concomitant administration of other CYP3A4inducers such as phenobarbital, phenytoin and carbamazepine, will also decrease plasmaconcentrations of tadalafil.

Effects of tadalafil on other medicinal products

In clinical studies, tadalafil (10 mg) was shown to augment the hypotensive effects of nitrates.Therefore, administration of CIALIS to patients who are using any form of organic nitrate iscontraindicated (see section 4.3 Contraindications).

Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugsmetabolised by CYP450 isoforms. Studies have confirmed that tadalafil does not inhibit or induceCYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1 and CYP2C9.

Tadalafil (10 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) did not potentiate the increase in bleeding time caused by acetyl salicylic acid.

In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects ofantihypertensive agents was examined. Major classes of antihypertensive agents were studied,including calcium channel blockers (amlodipine), angiotensin converting enzyme (ACE) inhibitors(enalapril), beta-adrenergic receptor blockers (metoprolol), thiazide diuretics (bendrofluazide), andangiotensin 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 studieswith angiotensin II receptor blockers and amlodipine in which a 20 mg dose was applied) had noclinically significant interaction with any of these classes. Tadalafil (10 and 20 mg) had no clinicallysignificant effect on blood pressure changes due to tamsulosin, an alpha-adrenergic receptor blockingagent. In patients receiving concomitant antihypertensive medications, tadalafil 20 mg may induce ablood pressure decrease, which is, in general, minor and not likely to be clinically relevant. Analysis ofphase 3 clinical trial data showed no difference in adverse events in patients taking tadalafil with orwithout antihypertensive medications. However, appropriate clinical advice should be given to patientsregarding a possible decrease in blood pressure when they are treated with antihypertensivemedications.

Alcohol concentrations (mean maximum blood concentration 0.08 %) were not affected by co-administration with tadalafil (10 mg). The effect of alcohol on cognitive function was not augmentedby tadalafil (10 mg) nor was the effect of alcohol on blood pressure augmented by tadalafil (20 mg). Inaddition, no changes in tadalafil concentrations were seen 3 hours after co-administration with alcohol.

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

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 thesemedications.

Specific interaction studies with antidiabetic agents were not conducted.

4.6 Pregnancy and lactation

CIALIS is not indicated for use by women. There are no studies of tadalafil in pregnant women.

There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that receivedup to 1000 mg/kg/day.

4.7 Effects on ability to drive and use machines

CIALIS is expected to have no or negligible influence on the ability to drive and or use machines. Nospecific studies have been performed to evaluate a potential effect. Although the frequency of reportsof dizziness in placebo and tadalafil arms in clinical trials was similar, patients should be aware of howthey react to CIALIS, before driving or operating machinery.

4.8 Undesirable effects

The most commonly reported adverse reactions are headache and dyspepsia, see tables below.

Table 1

Very common adverse reactions (>1/10)


CIALIS10-20 mg

(%) N=724

Placebo

(%)N=379

Nervous System Headache 14.5 5.5Gastrointestinal Dyspepsia 12.3 1.8

Table 2

Common adverse reactions (>1/100, <1/10)


CIALIS10-20 mg

(%) N=724

Placebo

(%)N=379

Nervous System Dizziness 2.3 1.8Vascular Flushing 4.1 1.6Respiratory, thoracic, andmediastinal

Nasal Congestion 4.3 3.2

Musculoskeletal andconnective tissue

Back painMyalgia

6.55.7

4.21.8

Swelling of eyelids, sensations described as eye pain and conjunctival hyperaemia are uncommonadverse reactions.

The adverse events reported with tadalafil were transient, and generally mild or moderate.

Adverse event data are limited in patients over 75 years of age.

4.9 Overdose

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in erectile dysfunction (ATC Code G04B E).

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 absence of sexual stimulation.

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 other

phosphodiesterases. Tadalafil is > 10,000-fold more potent for PDE5 than for PDE1, PDE2, andPDE4, 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.

Two clinical studies were conducted in 571 patients in an at-home setting to define the period ofresponsiveness to CIALIS. CIALIS demonstrated statistically significant improvement in erectilefunction and the ability to have successful sexual intercourse up to 24 hours following dosing, as wellas patients’ ability to attain and maintain erections for successful intercourse compared to placebo asearly as 16 minutes following dosing. Sexual Encounter Profile (SEP) diary data collected in clinicalstudies supports this period of responsiveness and a statistically significant greater proportion ofsuccessful intercourse attempts associated with tadalafil treatment compared to placebo treatment up toand through the 12- to 14-hour interval following administration. In these studies patients were free tochoose the time interval between dose administration and the time of sexual attempts.

CIALIS 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. When tadalafil and certain oral antihypertensivemedications (including angiotensin II receptor blockers) were assessed in drug interaction studies,tadalafil did not result in clinically significant augmentation of the antihypertensive effects of thosemedications (see section 4.5 Interaction with other medicinal products and other forms of interaction).However, appropriate clinical advice should be given to patients regarding the possibility of a decreasein blood pressure when they are treated with antihypertensive medications. The administration ofCIALIS to patients who are using any form of organic nitrate is contraindicated.

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 withthe low affinity of tadalafil for PDE6 compared to PDE5. Across all clinical studies, reports of changesin colour vision were rare (< 0.1 %).

Two studies were conducted in men to assess the potential effect of CIALIS 10 mg and 20 mgadministered daily for 6 months on spermatogenesis. The results of these studies demonstrate nodifference from placebo with respect to the proportion of men showing a 50% or greater decrease insperm concentration. In addition, in comparison with placebo, there were no adverse effects observedwith respect to mean change in sperm count, sperm morphology, or sperm motility at either dose.However, in the study of 10 mg CIALIS taken daily for 6 months, results showed a decrease in meansperm concentration relative to placebo. This effect was not seen in the study where the higher dose,20 mg, CIALIS was taken daily for 6 months. In addition there was no effect on mean concentrationsof testosterone, luteinizing hormone or follicle stimulating hormone with either 10 or 20 mg ofCIALIS compared to placebo. The effects of longer term daily dosing have not been established. Seealso Sections 4.4 Special warnings and special precautions for use and 5.3 Preclinical safety data.

Tadalafil at doses of 2 to 100 mg has been evaluated in 16 clinical studies involving 3250 patients,including patients with erectile dysfunction of various severities (mild, moderate, severe), etiologies,ages (range 21-86 years), and ethnicities. Most patients reported erectile dysfunction of at least 1 yearin duration. In the primary efficacy studies of general populations, 81% of patients reported thatCIALIS improved their erections as compared to 35% with placebo. Also, patients with erectiledysfunction 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% withplacebo). In the primary efficacy studies, 75% of intercourse attempts were successful in CIALIStreated patients as compared to 32% with placebo.

5.2 Pharmacokinetic properties

AbsorptionTadalafil 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.

DistributionThe 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.

BiotransformationTadalafil 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.

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

Linearity/non-linearityTadalafil 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.

Special Populations

ElderlyHealthy 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.

Renal insufficiencyIn a clinical pharmacology study in subjects with mild (creatinine clearance 51 to 80 ml/min) ormoderate (creatinine clearance 31 to 50 ml/min) renal impairment, tadalafil exposure (AUC) washigher than in healthy subjects after administration of a 10 mg dose. In another clinical pharmacologystudy in subjects with end-stage renal failure undergoing haemodialysis the tadalafil exposure (AUC)after a 10 mg dose was comparable to the exposure in healthy subjects.There are no available data about the administration of doses higher than 10 mg of tadalafil to patientswith renal impairment.

Hepatic insufficiencyTadalafil exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh ClassA and B) is comparable to exposure in healthy subjects when a dose of 10 mg is administered.There are no available data about the administration of doses higher than 10 mg of tadalafil to patientswith hepatic impairment.

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.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, genotoxicity, carcinogenic potential, and toxicity to reproduction.There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that receivedup to 1000 mg/kg/day. In a rat pre- and postnatal development study, the no observed effect dose was30 mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was approximately 18times 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 sections 4.4 Specialwarnings and special precautions for use and 5.1 Pharmacodynamic properties.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:lactose monohydrate,croscarmellose sodium,hydroxypropylcellulose,microcrystalline cellulose,sodium laurilsulfate,magnesium stearate.

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

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store in the original package.

6.5 Nature and contents of container

Aluminium/PVC/PE/Aclar blisters in cartons of 2, 4 or 8 tablets 20 mg.

6.6 Instructions for use and handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Lilly ICOS Limited, 25 New Street Square, London, EC4A 3LN. United Kingdom.


9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT

ANNEX II

A. MANUFACTURING AUTHORISATION HOLDERRESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OF THE MARKETING AUTHORISATION

A MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCHRELEASE

Name and address of the manufacturer responsible for batch release Eli Lilly and Company LtdKingsclere RoadBasingstokeHampshire RG21 6XAUK B CONDITIONS OF THE MARKETING AUTHORISATION

� CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ONTHE MARKETING AUTHORISATION HOLDER

Medicinal product subject to medical prescription � OTHER CONDITIONS

The holder of this marketing authorisation must inform the European Commission about the marketingplans for the medicinal product authorised by this decision.

ANNEX III

LABELLING AND PACKAGE LEAFLET

A. LABELLING

PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NOOUTER PACKAGING, ON THE IMMEDIATE PACKAGING

OUTER CARTON TEXT


CIALIS 10 mg film-coated tabletstadalafil

2. STATEMENT OF ACTIVE SUBSTANCE(S)


3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

4 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

For oral use. Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUTOF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

Contains lactose monohydrate

8. EXPIRY DATE

Exp. {MM/YYYY}

9. SPECIAL STORAGE CONDITIONS

Store in the original package

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTSOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IFAPPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Lilly ICOS Limited25 New Street SquareLondonEC4A 3LNUnited Kingdom


EU/0/00/000/000

13. MANUFACTURER’S BATCH NUMBER

Lot.

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE


OUTER CARTON TEXT














8. EXPIRY DATE

Exp. {MM/YYYY}





Lilly ICOS Limited

25 New Street SquareLondonEC4A 3LNUnited Kingdom


EU/0/00/000/000


Lot.





OUTER CARTON TEXT














8. EXPIRY DATE

Exp. {MM/YYYY}





Lilly ICOS Limited



EU/0/00/000/000


Lot.





OUTER CARTON TEXT














8. EXPIRY DATE

Exp. {MM/YYYY}





Lilly ICOS Limited



EU/0/00/000/000


Lot.




MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS


CIALIS 10 mgtadalafil

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Lilly ICOS

3. EXPIRY DATE

Exp. {MM/YYYY}

4. BATCH NUMBER

Lot.

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS


CIALIS 20 mgtadalafil

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Lilly ICOS

3. EXPIRY DATE

Exp. {MM/YYYY}

4. BATCH NUMBER

Lot.

B. PACKAGE LEAFLET

PACKAGE LEAFLET

Read all of this leaflet carefully before you start taking this medicine.- Keep this leaflet. You may need to read it again.- If you have further questions, please ask your doctor or your pharmacist.- This medicine has been prescribed for you personally and you should not pass it on to others. It

may harm them, even if their symptoms are the same as yours. In this leaflet:1. What CIALIS is and what it is used for2. Before you take CIALIS3. How to take CIALIS4. Possible side effects5 Storing CIALIS6. Further information CIALIS 10 mg film-coated tablets

tadalafil The active substance is tadalafil. Each tablet of CIALIS contains 10 mg of tadalafil.The other ingredients are:Tablet core: lactose monohydrate, croscarmellose sodium, hydroxypropylcellulose, microcrystallinecellulose, sodium laurilsulfate, magnesium stearate.Film-coat: lactose monohydrate, hypromellose, triacetin, titanium dioxide (E171), iron oxide yellow(E172), talc. Marketing Authorisation Holder: Lilly ICOS Limited, 25 New Street Square, London, EC4A 3LN.United Kingdom. Manufacturer: Eli Lilly and Company Ltd., Kingsclere Road, Basingstoke, Hampshire, RG21 6XA.United Kingdom. 1. WHAT CIALIS IS AND WHAT IT IS USED FOR CIALIS comes as light yellow film-coated tablets. They are in the shape of almonds and have “C 10”marked on one side. These tablets are available in blister packs containing 4 tablets. CIALIS is a treatment for men with erectile dysfunction. This is when a man cannot get, or keep ahard, erect penis suitable for sexual activity. CIALIS belongs to a group of medicines called phosphodiesterase type 5 inhibitors. Following sexualstimulation CIALIS works by helping the blood vessels in your penis to relax, allowing the flow ofblood into your penis. The result of this is improved erectile function. CIALIS will not help you if youdo not have erectile dysfunction. It is important to note that CIALIS does not work if there is no sexual stimulation. You and yourpartner will need to engage in foreplay, just as you would if you were not taking a medicine forerectile dysfunction. 2. BEFORE YOU TAKE CIALIS Do not take CIALIS:

- if you are taking any form of organic nitrate or nitric oxide donors such as amyl nitrite. This is a

group of medicines (“nitrates”) used in the treatment of angina pectoris (“chest pain”). CIALIShas been shown to increase the effects of these drugs. If you are taking any form of nitrate or areunsure tell your doctor.

- if you have serious heart disease or have had a recent heart attack. - if you have had a recent stroke. - if you have low blood pressure or uncontrolled high blood pressure. - if you are (hypersensitive) allergic to tadalafil or any of the other ingredients of CIALIS. Take special care with CIALIS:

Sexual activity carries a possible risk to patients with heart disease because it puts an extra strain onyour heart. If you have a heart problem you should tell your doctor.

The following are reasons why CIALIS may also not be suitable for you. If any of them apply to you,talk to your doctor before you take the medicine:- You have sickle cell anaemia (an abnormality of red blood cells), multiple myeloma (cancer of the

bone marrow), leukaemia (cancer of the blood cells) or any deformation of your penis.- You have a serious liver or kidney problem.

Taking other medicines:As a general rule, always tell your doctor if you are taking or have recently taken any other medicine,even those not prescribed, because occasionally they might interact. This is particularly important ifyou are treated with nitrates as you should not take CIALIS if you are taking these medicines. Do nottake CIALIS with other medicines if your doctor tells you that you may not.

You should not use CIALIS together with any other treatments for erectile dysfunction. CIALIS is not intended for use by women or by children under the age of 18. Driving and using machines: As dizziness has been reported in men taking CIALIS in clinical studies, you should be aware of howyou react to CIALIS before you drive or operate machinery. Information for men intolerant of lactose, one of the ingredients of CIALIS: CIALIS contains lactose and should not be taken by patients with rare hereditary problems ofgalactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. 3. HOW TO TAKE CIALIS Always take CIALIS exactly as your doctor has instructed you. You should check with your doctor orpharmacist if you are unsure. The recommended starting dose is one 10 mg tablet before sexual activity. If the effect of this dose istoo weak your doctor may increase the dose to 20 mg. CIALIS tablets are for oral use. Swallow thetablet whole with some water. You may take CIALIS with or without food. You may take a CIALIS tablet at any point in time from 30 minutes to 12 hours before sexual activity.CIALIS may still be effective up to 24 hours after taking the tablet. It is important to note that CIALISdoes not work if there is no sexual stimulation. You and your partner will need to engage in foreplay,just as you would if you were not taking a medicine for erectile dysfunction.

You should NOT take CIALIS more than once a day. Daily use of CIALIS is strongly discouraged. If you take more CIALIS than you should: Tell your doctor. 4. POSSIBLE SIDE EFFECTS Like all medicines, CIALIS can have side effects. These effects are normally mild to moderate innature. The most common undesirable effects are headache and indigestion. Less commonly reported sideeffects are back pain, muscle aches, nasal congestion, facial flushing and dizziness. Uncommon effectsare swelling of the eyelids, eye pain and red eyes. If you have any of these side effects and they are troublesome, severe, or do not go away, tell yourdoctor. Allergic reactions (including skin rashes) could occur. In rare instances it is possible that a prolonged and possibly painful erection may occur after takingCIALIS. If you have such an erection, which lasts continuously for more than 4 hours, you shouldcontact a doctor immediately. In case of chest pain occurring during or after sexual activity you should NOT use nitrates but youshould seek immediate medical assistance. If you notice any side effects not mentioned in this leaflet, please inform your doctor or pharmacist. Heart attack, stroke, and irregular heart beats have been reported rarely in men taking CIALIS. Most,but not all of these men had known heart problems before taking this medicine. It is not possible todetermine whether these events were directly related to CIALIS. Effects were seen in one animal species that might indicate impairment of fertility. Subsequent studiesin man suggest that this effect is unlikely in humans. 5. STORING CIALIS Keep out of the reach and sight of children. Store in the original package. Do not use after the expiry date stated on the carton and blister.

6. FURTHER INFORMATION For any information about this medicinal product, please contact the local representative of theMarketing Authorisation Holder. België/Belgique/BelgienEli Lilly Benelux S.A.Rue de l’Etuve 52/1, StoofstraatB-1000 Bruxelles, Brussel.Tél: +32-(0) 2 548 84 84

Luxembourg/LuxemburgEli Lilly Benelux S.A.Rue de l’Etuve 52/1, StoofstraatB-1000 Bruxelles, Brussel.Tél: +32-(0) 2 548 84 84

DanmarkEli Lilly Danmark A/SNybrovej 1102800 LyngbyTlf: +45-45 26 60 00

NederlandEli Lilly Nederland B.V.,Grootslag 1-5, 3991 RA HoutenTel: + 31-(0) 30 60 25 800

DeutschlandLilly Deutschland GmbHSaalburgstrasse 153D-61350 Bad HomburgTel: + 49-(0) 6172 273 2222

NorgeEli Lilly Norge A.SPostboks 6090 EtterstadN-0601 OsloTlf: + 47 22 88 18 00

ΕλλάδαΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε150 χλµ Εθνικής Οδού Αθηνών-ΛαµίαςGR-145 64 ΚηφισιάΤηλ: + 30-(0) 10 629 4600

ÖsterreichEli Lilly Ges.m.b.HBarichgasse 40-42A-1030 WienTel: +43-(0) 1 711 780

EspañaLilly, S.A.Avda. de la Industria, 30E-28108 Alcobendas (Madrid)Tel: 91 663 50 00

PortugalLilly Farma Produtos Farmacêuticos, LdaRua Dr. António Loureiro Borges 4 – Piso 3Arquiparque – MirafloresP-1495 – 131 AlgésTel: +351 21 4126600

FranceLilly France S.A.S.,203 Bureaux de la colline,92213 Saint-Cloud.Tél.: +33-(0)1 49 11 34 34

Suomi/FinlandOy Eli Lilly Finland AbPL 16 / Box 16FIN-01641 Vantaa / VandaPuh/Tel: + 358-(0) 9 85 45 250

IrelandEli Lilly and Co. (Ireland) Ltd,Hyde House, 65 Adelaide Road, Dublin 2,Republic of IrelandTel: +353-(0) 1 661 4377

SverigeEli Lilly Sweden ABBox 30037S-104 25 StockholmTel: +46 (08) 737 88 00

ÍslandEli Lilly Danmark A/SÚtibú á Íslandi, Brautarholti 28IS-105 ReykjavíkTel: +354 520 3400

United KingdomEli Lilly and Company LimitedDextra Court, Chapel HillBasingstoke, Hampshire, RG21 5SY - UKTel: + 44-(0) 1256 315000

ItaliaEli Lilly Italia S.p.A.Via Gramsci 731/733I-50019 Sesto Fiorentino (FI)Tel: + 39-055 42571 This leaflet was last approved on {date}

PACKAGE LEAFLET

Read all of this leaflet carefully before you start taking this medicine.- Keep this leaflet. You may need to read it again.- If you have further questions, please ask your doctor or your pharmacist.- This medicine has been prescribed for you personally and you should not pass it on to others. It

may harm them, even if their symptoms are the same as yours. In this leaflet:1. What CIALIS is and what it is used for2. Before you take CIALIS3. How to take CIALIS4. Possible side effects5 Storing CIALIS6. Further information CIALIS 20 mg film-coated tablets tadalafil The active substance is tadalafil. Each tablet of CIALIS contains 20 mg of tadalafil.The other ingredients are:Tablet core: lactose monohydrate, croscarmellose sodium, hydroxypropylcellulose, microcrystallinecellulose, sodium laurilsulfate, magnesium stearate.Film-coat: lactose monohydrate, hypromellose, triacetin, titanium dioxide (E171), iron oxide yellow(E172), talc. Marketing Authorisation Holder: Lilly ICOS Limited, 25 New Street Square, London, EC4A 3LN.United Kingdom. Manufacturer: Eli Lilly and Company Ltd., Kingsclere Road, Basingstoke, Hampshire, RG21 6XA.United Kingdom. 1. WHAT CIALIS IS AND WHAT IT IS USED FOR CIALIS comes as yellow film-coated tablets. They are in the shape of almonds and have "C 20"marked on one side. These tablets are available in blister packs containing 2, 4 or 8 tablets. CIALIS is a treatment for men with erectile dysfunction. This is when a man cannot get, or keep ahard, erect penis suitable for sexual activity. CIALIS belongs to a group of medicines called phosphodiesterase type 5 inhibitors. Following sexualstimulation CIALIS works by helping the blood vessels in your penis to relax, allowing the flow ofblood into your penis. The result of this is improved erectile function. CIALIS will not help you if youdo not have erectile dysfunction. It is important to note that CIALIS does not work if there is no sexual stimulation. You and yourpartner will need to engage in foreplay, just as you would if you were not taking a medicine forerectile dysfunction. 2. BEFORE YOU TAKE CIALIS Do not take CIALIS:

- if you are taking any form of organic nitrate or nitric oxide donors such as amyl nitrite. This is agroup of medicines (“nitrates”) used in the treatment of angina pectoris (“chest pain”). CIALIShas been shown to increase the effects of these drugs. If you are taking any form of nitrate or areunsure tell your doctor.

- if you have serious heart disease or have had a recent heart attack. - if you have had a recent stroke. - if you have low blood pressure or uncontrolled high blood pressure. - if you are (hypersensitive) allergic to tadalafil or any of the other ingredients of CIALIS. Take special care with CIALIS:

Sexual activity carries a possible risk to patients with heart disease because it puts an extra strain onyour heart. If you have a heart problem you should tell your doctor.

The following are reasons why CIALIS may also not be suitable for you. If any of them apply to you,talk to your doctor before you take the medicine:- You have sickle cell anaemia (an abnormality of red blood cells), multiple myeloma (cancer of the

bone marrow), leukaemia (cancer of the blood cells) or any deformation of your penis.- You have a serious liver or kidney problem.

Taking other medicines:As a general rule, always tell your doctor if you are taking or have recently taken any other medicine,even those not prescribed, because occasionally they might interact. This is particularly important ifyou are treated with nitrates as you should not take CIALIS if you are taking these medicines. Do nottake CIALIS with other medicines if your doctor tells you that you may not.

You should not use CIALIS together with any other treatments for erectile dysfunction. CIALIS is not intended for use by women or by children under the age of 18. Driving and using machines: As dizziness has been reported in men taking CIALIS in clinical studies, you should be aware of howyou react to CIALIS before you drive or operate machinery. Information for men intolerant of lactose, one of the ingredients of CIALIS: CIALIS contains lactose and should not be taken by patients with rare hereditary problems ofgalactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. 3. HOW TO TAKE CIALIS Always take CIALIS exactly as your doctor has instructed you. You should check with your doctor orpharmacist if you are unsure. The recommended starting dose is one 10 mg tablet before sexual activity. If the effect of this dose istoo weak your doctor may increase the dose to 20 mg. CIALIS tablets are for oral use. Swallow thetablet whole with some water. You may take CIALIS with or without food. You may take a CIALIS tablet at any point in time from 30 minutes to 12 hours before sexual activity.CIALIS may still be effective up to 24 hours after taking the tablet. It is important to note that CIALISdoes not work if there is no sexual stimulation. You and your partner will need to engage in foreplay,just as you would if you were not taking a medicine for erectile dysfunction.

You should NOT take CIALIS more than once a day. Daily use of CIALIS is strongly discouraged. If you take more CIALIS than you should: Tell your doctor. 4. POSSIBLE SIDE EFFECTS Like all medicines, CIALIS can have side effects. These effects are normally mild to moderate innature. The most common undesirable effects are headache and indigestion. Less commonly reported sideeffects are back pain, muscle aches, nasal congestion, facial flushing and dizziness. Uncommon effectsare swelling of the eyelids, eye pain and red eyes. If you have any of these side effects and they are troublesome, severe, or do not go away, tell yourdoctor. Allergic reactions (including skin rashes) could occur. In rare instances it is possible that a prolonged and possibly painful erection may occur after takingCIALIS. If you have such an erection, which lasts continuously for more than 4 hours, you shouldcontact a doctor immediately. In case of chest pain occurring during or after sexual activity you should NOT use nitrates but youshould seek immediate medical assistance. If you notice any side effects not mentioned in this leaflet, please inform your doctor or pharmacist. Heart attack, stroke, and irregular heart beats have been reported rarely in men taking CIALIS. Most,but not all of these men had known heart problems before taking this medicine. It is not possible todetermine whether these events were directly related to CIALIS. Effects were seen in one animal species that might indicate impairment of fertility. Subsequent studiesin man suggest that this effect is unlikely in humans. 5. STORING CIALIS Keep out of the reach and sight of children. Store in the original package. Do not use after the expiry date stated on the carton and blister.

6. FURTHER INFORMATION For any information about this medicinal product, please contact the local representative of theMarketing Authorisation Holder. België/Belgique/BelgienEli Lilly Benelux S.A.Rue de l’Etuve 52/1, StoofstraatB-1000 Bruxelles, Brussel.Tél: +32-(0) 2 548 84 84

Luxembourg/LuxemburgEli Lilly Benelux S.A.Rue de l’Etuve 52/1, StoofstraatB-1000 Bruxelles, Brussel.Tél: +32-(0) 2 548 84 84

DanmarkEli Lilly Danmark A/SNybrovej 1102800 LyngbyTlf: +45-45 26 60 00

NederlandEli Lilly Nederland B.V.,Grootslag 1-5, 3991 RA HoutenTel: + 31-(0) 30 60 25 800

DeutschlandLilly Deutschland GmbHSaalburgstrasse 153D-61350 Bad HomburgTel: + 49-(0) 6172 273 2222

NorgeEli Lilly Norge A.SPostboks 6090 EtterstadN-0601 OsloTlf: + 47 22 88 18 00

ΕλλάδαΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε150 χλµ Εθνικής Οδού Αθηνών-ΛαµίαςGR-145 64 ΚηφισιάΤηλ: + 30-(0) 10 629 4600

ÖsterreichEli Lilly Ges.m.b.HBarichgasse 40-42A-1030 WienTel: +43-(0) 1 711 780

EspañaLilly, S.A.Avda. de la Industria, 30E-28108 Alcobendas (Madrid)Tel: 91 663 50 00

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Suomi/FinlandOy Eli Lilly Finland AbPL 16 / Box 16FIN-01641 Vantaa / VandaPuh/Tel: + 358-(0) 9 85 45 250

IrelandEli Lilly and Co. (Ireland) Ltd,Hyde House, 65 Adelaide Road, Dublin 2,Republic of IrelandTel: +353-(0) 1 661 4377

SverigeEli Lilly Sweden ABBox 30037S-104 25 StockholmTel: +46 (08) 737 88 00

ÍslandEli Lilly Danmark A/SÚtibú á Íslandi, Brautarholti 28IS-105 ReykjavíkTel: +354 520 3400

United KingdomEli Lilly and Company LimitedDextra Court, Chapel HillBasingstoke, Hampshire, RG21 5SY - UKTel: + 44-(0) 1256 315000

ItaliaEli Lilly Italia S.p.A.Via Gramsci 731/733I-50019 Sesto Fiorentino (FI)Tel: + 39-055 42571 This leaflet was last approved on {date}

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