Summary of product characteristics for Cialis

From: http://www.medicines.org.uk/EMC/medicine/

1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
3. PHARMACEUTICAL FORM
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
4.2 Posology and method of administration
4.3 Contraindications
4.4 Special warnings and precautions for use
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Pregnancy and lactation
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
4.9 Overdose
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
5.3 Preclinical safety data
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
6.2 Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
6.6 Special precautions for disposal and other handling
7. MARKETING AUTHORISATION HOLDER
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT
LEGAL CATEGORY

1. NAME OF THE MEDICINAL PRODUCT

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

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 2.5mg tablet contains 2.5mg tadalafil.
Excipient: Each coated tablet contains 92mg lactose monohydrate.

Each 5mg tablet contains 5mg tadalafil.
Excipient: Each coated tablet contains 127mg lactose monohydrate.

Each 10mg tablet contains 10mg tadalafil.
Excipient: Each coated tablet contains 179mg lactose monohydrate.

Each 20mg tablet contains 20mg tadalafil.
Excipient: Each coated tablet contains 245mg lactose monohydrate.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).
The 2.5mg tablets are light orange-yellow and almond shaped, marked 'C 2 ½' on one side.
The 5mg tablets are light yellow and almond shaped, marked 'C 5' on one side.
The 10mg tablets are light yellow and almond shaped, marked 'C 10' on one side.
The 20mg 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 tadalafil 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. CIALIS is available as 2.5mg, 5mg, 10mg and 20mg film-coated tablets.

Use in Adult Men

In general, the recommended dose is 10mg taken prior to anticipated sexual activity and with or without food. In those patients in whom tadalafil 10mg does not produce an adequate effect, 20mg might be tried. It may be taken at least 30 minutes prior to sexual activity.
The maximum dose frequency is once per day.
Tadalafil 10mg and 20mg is intended for use prior to anticipated sexual activity and it is not recommended for continuous daily use.
In responder patients to on-demand regimen who anticipate a frequent use of CIALIS (i.e., at least twice weekly) a once daily regimen with the lowest doses of CIALIS might be considered suitable, based on patient choice and the physician's judgement.
In these patients, the recommended dose is 5mg taken once a day at approximately the same time of day. The dose may be decreased to 2.5mg once a day based on individual tolerability.
The appropriateness of continued use of the daily regimen should be reassessed periodically.

Use in Elderly Men

Dose adjustments are not required in elderly patients.
Use in Men with Impaired Renal Function
Dose adjustments are not required in patients with mild to moderate renal impairment. For patients with severe renal impairment, 10mg is the maximum recommended dose. Once-a-day dosing of tadalafil is not recommended in patients with severe renal impairment.

Use in Men with Impaired Hepatic Function

The recommended dose of CIALIS is 10mg taken prior to anticipated sexual activity and with or without food. There is limited clinical data on the safety of CIALIS in patients with severe hepatic impairment (Child-Pugh class C); if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of doses higher than 10mg of tadalafil to patients with hepatic impairment. Once-a-day dosing has not been evaluated in patients with hepatic impairment; therefore if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.

Use in Men with Diabetes

Dose adjustments are not required in diabetic patients.

Use in Children and Adolescents

CIALIS should not be used in individuals below 18 years of age.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

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

Agents for the treatment of erectile dysfunction, including CIALIS, must not be used in men with cardiac disease for whom sexual activity is inadvisable. Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease.

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

Patients with myocardial infarction within the last 90 days.
Patients with unstable angina or angina occurring during sexual intercourse.
Patients with New York Heart Association class 2 or greater heart failure in the last 6 months.
Patients with uncontrolled arrhythmias, hypotension (<90/50mmHg), or uncontrolled hypertension.
Patients with a stroke within the last 6 months.

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

4.4 Special warnings and precautions for use

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

Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Tadalafil has vasodilator properties, resulting in mild and transient decreases in blood pressure (see section 5.1), and as such potentiates the hypotensive effect of nitrates.

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

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

Visual defects and cases of NAION have been reported in connection with the intake of CIALIS and other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, he should stop taking CIALIS and consult a physician immediately.

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

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

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

Agents for the treatment of erectile dysfunction, including CIALIS, should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease) or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma, or leukaemia).

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

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

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 medicines are combined.

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

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

4.5 Interaction with other medicinal products and other forms of interaction

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

Effects of Other Substances on Tadalafil

Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (200mg daily), increased tadalafil (10mg) exposure (AUC) 2-fold and Cmax by 15%, relative to the AUC and Cmax values for tadalafil alone. Ketoconazole (400mg daily) increased tadalafil (20mg) exposure (AUC) 4-fold and Cmax by 22%. Ritonavir, a protease inhibitor (200mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20mg) exposure (AUC) 2-fold with no change in Cmax. Although specific interactions have not been studied, other protease inhibitors, such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin, clarithromycin, itraconazole, and grapefruit juice, should be co-administered with caution, as they would be expected to increase plasma concentrations of tadalafil. Consequently, the incidence of the undesirable effects might be increased.

The role of transporters (for example, p-glycoprotein) in the disposition of tadalafil is not known. There is 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 for tadalafil alone (10mg). 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 Product

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

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

The co-administration of doxazosin (4 and 8 mg daily) and tadalafil (5 mg daily dose and 20 mg as a single dose) increases the blood pressure-lowering effect of this alpha-blocker in a significant manner. This effect lasts at least twelve hours and may be symptomatic, including syncope. Therefore, this combination is not recommended.

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

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

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

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

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

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

Specific interaction studies with antidiabetic agents were not conducted.

4.6 Pregnancy and lactation

CIALIS is not indicated for use by women.

For tadalafil, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

4.7 Effects on ability to drive and use machines

No studies on the effect of the ability to drive and use machines have been performed. Although the frequency of reports of dizziness in placebo and tadalafil arms in clinical trials was similar, patients should be aware of how they react to CIALIS before driving or operating machinery.

4.8 Undesirable effects

The most commonly reported adverse reactions were headache and dyspepsia. The adverse reactions reported were transient, and generally mild or moderate. Adverse reaction data are limited in patients over 75 years of age.

The table below lists the adverse reactions reported during placebo-controlled clinical trials for registration in patients treated with CIALIS on demand and daily dosing. Adverse reactions are also included that have been reported from post marketing surveillance in patients taking CIALIS on demand.

Adverse Reactions

Frequency estimate: Very common (1/10), Common (1/100 to <1/10), Uncommon (1/1000 to <1/100), Rare (1/10,000 to<1/1000), Very Rare (<1/10,000) and Not known (events not reported in registration trials cannot be estimated from post marketing spontaneous reports).

Very common (1/10)	Common (1/100 to <1/10)	Uncommon (1/1000 to <1/100)	Rare (1/10000 to <1/1000)	Not Known
System Organ Class: Immune system disorders
		Hypersensivity reactions
System Organ Class: Nervous system disorders
Headache	Dizziness		Stroke1 (including haemorrhagic events), Syncope, Transient ischaemic attacks1 , Migraine	Seizures, Transient amnesia
System Organ Class: Eye disorders
		Blurred vision, Sensations described as eye pain, Swelling of eyelids, Conjunctival hyperaemia	Visual field defect	Non-arteritic anterior ischaemic optic neuropathy (NAION), Retinal vascular occlusion
System Organ Class: Ear and labyrinth disorders
				Sudden deafness2
System Organ Class: Cardiac disorders1
	Palpitations	Tachycardia	Myocardial infarction	Unstable angina pectoris, Ventricular arrhythmia
System Organ Class: Vascular disorders
	Flushing	Hypotension (more commonly reported when tadalafil is given to patients who are already taking antihypertensive agents), Hypertension
System Organ Class: Respiratory, thoracic and mediastinal disorders
	Nasal congestion	Epistaxis
System Organ Class: Gastro-intestinal disorders
Dyspepsia	Abdominal pain, Gastro-oesophageal reflux
System Organ Class: Skin and subcutaneous tissue disorders
		Rash, Urticaria, Hyperhydrosis (sweating)		Stevens-Johnson syndrome, Exfoliative dermatitis
System Organ Class: Musculoskeletal, connective tissue and bone disorders
	Back pain, Myalgia
System Organ Class: Reproductive system and breast disorders
			Prolonged erections	Priapism
System Organ Class: General disorders and administration site conditions
		Chest pain1	Facial oedema	Sudden cardiac death1

1 Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors.
2 Sudden decrease or loss of hearing has been reported in a small number of post marketing and clinical trial cases with the use of all PDE5 inhibitors, including tadalafil.

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

4.9 Overdose

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

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in erectile dysfunction. ATC code: G04BE.

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

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

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

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

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

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

Tadalafil at doses of 2.5mg, 5mg, and 10 mg taken once a day has been evaluated in 3 clinical studies involving 853 patients of various ages (range 21-82 years) and ethnicities, with erectile dysfunction of various severities (mild, moderate, severe) and etiologies. Most patients in all three studies were responders to previous on-demand treatment with PDE5 inhibitors. In the two primary efficacy studies of general populations, the mean per-subject proportion of successful attempts were 57 and 67% on CIALIS 5mg, 50% on CIALIS 2.5mg as compared to 31 and 37% with placebo. In the study in patients with erectile dysfunction secondary to diabetes, the mean per-subject proportion of successful attempts were 41 and 46% on CIALIS 5mg and 2.5mg, respectively, as compared to 28% with placebo.

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 year in duration. In the primary efficacy studies of general populations, 81% of patients reported that CIALIS improved their erections as compared to 35% with placebo. Also, patients with erectile dysfunction in all severity categories reported improved erections whilst taking CIALIS (86%, 83%, and 72% for mild, moderate, and severe, respectively, as compared to 45%, 42%, and 19% with placebo). In the primary efficacy studies, 75% of intercourse attempts were successful in CIALIS-treated patients as compared to 32% with placebo.

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

5.2 Pharmacokinetic properties

Absorption

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

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

Distribution

The mean volume of distribution is approximately 63 litres, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Protein binding is not affected by impaired renal function.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.

Biotransformation

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

Elimination

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

Linearity/Non-Linearity

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

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

Special Populations

Elderly

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

Renal Insufficiency

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

Hepatic Insufficiency

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

Patients with Diabetes

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

5.3 Preclinical safety data

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

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

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

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:
Lactose monohydrate
Croscarmellose sodium
Hydroxypropylcellulose
Microcrystalline cellulose
Sodium laurilsulfate
Magnesium stearate
2.5 mg Film-coat:
Lactose monohydrate
Hypromellose
Triacetin,
Titanium dioxide (E171)
Iron oxide yellow (E172)
Iron oxide red (E172)
Talc
5 mg, 10mg and 20mg Film-coat:
Lactose monohydrate
Hypromellose
Triacetin
Titanium dioxide (E171)
Iron oxide yellow (E172)
Talc

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store in the original package in order to protect from moisture. For Tadalafil 5mg - Do not store above 25°C. For Tadalafil 2.5mg, 10mg and 20mg - Do not store above 30°C.

6.5 Nature and contents of container

Aluminium/PVC/PE/ PCTFE blisters in cartons of 2, 4, 8, 10, 12, 14 and 28 film-coated tablets.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Eli Lilly Nederland B.V.
Grootslag 1-5, NL-3991 RA, Houten
The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/237/001
CIALIS 10mg x 4 film-coated tablets.
EU/1/02/237/002
CIALIS 20mg x 2 film-coated tablets.
EU/1/02/237/003
CIALIS 20mg x 4 film-coated tablets.
EU/1/02/237/004
CIALIS 20mg x 8 film-coated tablets.
EU/1/02/237/005
CIALIS 20mg x 12 film-coated tablets.
EU/1/02/237/006
CIALIS 2.5mg x 28 film-coated tablets.
EU/1/02/237/007
CIALIS 5mg x 14 film-coated tablets.
EU/1/02/237/008
CIALIS 5mg x 28 film-coated tablets.
EU/1/02/237/009
CIALIS 20mg x 10 film-coated tablets.

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first Authorisation:
12 November 2002
Date of last renewal:
12 November 2007

10. DATE OF REVISION OF THE TEXT

18 March 2010

LEGAL CATEGORY

POM
*CIALIS (tadalafil) is a trademark of Eli Lilly and Company.

Cialis tablets are available in 2.5mg, 5mg, 10mg and 20mg dosages and manufactured by Lilly who own the patent. Cheap generic Cialis is unlicensed, illegal and possibly dangerous to your health. Cialis is a prescription only medicine.

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