10 mg: Each yellow, almond-shaped, film-coated tablet contains 10 mg of tadalafil and is marked with 'C10' on one side.

20 mg: Each yellow, almond-shaped, film-coated tablet contains 20 mg of tadalafil and is marked with 'C20' on one side.

Pharmacotherapeutic group: medicines used in erectile dysfunction. Tadalafil is a potent, 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 if there is no 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.

Two clinical studies were conducted in 571 patients in an at-home setting to define the period of responsiveness to CIALIS. CIALIS 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. Sexual Encounter Profile (SEP) diary data collected in clinical studies supports this period of responsiveness. In these studies patients were free to choose the time interval between dose administration and the time of sexual attempts.

CIALIS administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8 mm Hg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6 mm Hg, respectively), and no significant change in heart rate. When tadalafil and certain oral antihypertensive medications were assessed in medicine interaction studies, tadalafil did not result in clinically significant augmentation of the antihypertensive effects of those medications (see Interactions).

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. In addition, no effects were observed on visual acuity, electroretinograms, intraocular pressure, or pupillometry. Across all clinical studies, reports of changes in colour vision were rare (< 0.1%).

There were no clinically relevant effects on sperm concentration, sperm count, motility, or morphology in 103 men in a study of daily doses of 10 mg for 6 months or 111 men in a study of daily doses of 20 mg for 6 months. 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), aetiologies, 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. Also, patients with erectile dysfunction in all severity categories reported improved erections while taking CIALIS (86%, 83% and 72% for mild, moderate, and severe, respectively). In the primary efficacy studies, 75% of intercourse attempts were successful in CIALIS-treated patients.

Tadalafil is rapidly absorbed after oral administration and the mean maximum observed plasma concentration (Cmax) is achieved at a median time of 2 hours after dosing. Absolute bioavailability of tadalafil following oral dosing has not been determined. The rate and extent of absorption of tadalafil are not influenced by food, thus CIALIS may be taken with or without food. The time of dosing (morning versus evening) had no clinically relevant effects on the rate and extent of absorption.

The mean volume of distribution is approximately 63 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. Samples collected from healthy human subjects approximately 5 hours after dosing indicated that <0.0005% of the total dose of tadalafil is distributed to semen.

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

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

Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range of 2.5 to 20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasma concentrations are attained within 5 days of once-daily dosing. Pharmacokinetics determined with a population approach in patients with erectile dysfunction are similar to pharmacokinetics in subjects without erectile dysfunction.

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

In a clinical pharmacology study in subjects with mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min) renal impairment, tadalafil exposure (AUC) was higher than in healthy subjects after administration of a 10-mg dose. In another clinical pharmacology study 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, (see Warnings and Precautions)

Tadalafil exposure (AUC) in subjects with mild or moderate hepatic impairment (Child-Pugh Class A and B) is comparable to exposure in healthy subjects. No dose adjustment is required in these patients.

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.

Treatment of erectile dysfunction. In order for CIALIS to be effective, sexual stimulation is required.

CIALIS tablets are for oral use.

The recommended dose of CIALIS is 20 mg, taken prior to anticipated sexual activity. The maximum recommended dosing frequency is once per day. CIALIS may be taken between 30 minutes and 36 hours prior to anticipated sexual activity. Patients may initiate sexual activity at varying time points relative to dosing in order to determine their own optimal window of responsiveness. The dose may be lowered to 10 mg based on individual response and tolerability. CIALIS may be taken without regard to food.

Dosage adjustments are not required in elderly patients. Dosage recommendations described in "Use in adult men" apply to elderly men.

Dosage adjustments are not required in patients with renal impairment (see Warnings and Precautions).

Dosage adjustments are not required in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) (see Pharmacokinetics).

The presence of diabetes does not require a dose reduction.

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

In clinical studies, tadalafil (10 mg) was shown to augment the hypotensive effects of nitrates. This is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, administration of CIALIS to patients who are using any form of organic nitrate is contraindicated. CIALIS should not be used in patients with a known hypersensitivity to tadalafil or to any of the excipients.

Sexual activity carries a potential cardiac risk for patients with pre-existing cardiovascular disease. Therefore, treatments for erectile dysfunction, including CIALIS, should 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:

• 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.

Additionally, there is limited clinical trial data on the safety of CIALIS in the following groups; if prescribed, a careful individual 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 to 80 mL/min), and moderate (creatinine clearance 31 to 50 mL/min) renal failure and in patients with end stage renal failure undergoing haemodialysis.

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

CIALIS should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anaemia, multiple myeloma, or leukaemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease). The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following an appropriate medical assessment.

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.

In a clinical pharmacology study, administration of tadalafil (10 mg) to patients with moderate renal impairment (creatinine clearance 31 to 50 mL/min) was determined to be safe but appeared to be less well tolerated in terms of back pain than in patients with mild renal impairment (creatinine clearance 51 to 80 mL/min) and healthy subjects. Tadalafil 10 mg has been the highest dose studied in patients with mild (creatinine clearance 51 to 80 mL/min), and moderate (creatinine clearance 31 to 50 mL/min) renal failure and in patients with end stage renal failure undergoing haemodialysis. Tadalafil exposure was increased by 107% when co-administered (10 mg dose) with ketoconazole. Although specific interactions have not been studied, some protease inhibitors, such as ritonavir and saquinavir, and other CYP3A4 inhibitors, such as erythromycin and itraconazole, would also be likely to increase tadalafil exposure.

Tadalafil exposure was reduced by 88% when co-administered (10 mg dose) with rifampicin. It can be expected that concomitant administration of other CYP3A4 inducers will also decrease plasma concentrations of tadalafil.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential, and toxicity to reproduction.

There was no impairment of fertility in male and female rats. In dogs given tadalafil daily for 6 to 12 months at doses of 25 mg/kg/day and above, there were alterations to the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs. There were no clinically relevant effects on sperm concentration, sperm count, motility, or morphology in 103 men in a study of daily doses of 10 mg for 6 months or 111 men in a study of daily doses of 20 mg for 6 months. In men, tadalafil 10 or 20 mg given daily for 6 months had no significant effect compared to placebo on serum levels of testosterone, luteinising hormone, or follicle stimulating hormone.

CIALIS is not indicated for use in women. There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that received up to 1000 mg/kg/day. In a rat pre- and postnatal development study, the no observed effect dose was 30 mg/kg/day. In the pregnant rat, the AUC for calculated free drug at this dose was approximately 18 times the human AUC at a 20 mg dose. There are no studies of tadalafil in pregnant women.

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.

CIALIS was administered to over 4000 subjects (aged 19 to 86 years) during clinical trials worldwide. Over 230 patients were treated for longer than one year and over 720 patients were treated for over 6 months. In controlled phase 2/3 clinical trials, the discontinuation rate due to adverse effects in CIALIS-treated patients (1.7%) was not significantly different from placebo-treated patients (1.1%). In these studies, the adverse effects reported with CIALIS were generally mild or moderate, transient, and decreased with continued dosing.

In controlled phase 2/3 clinical trials, the following adverse effects were reported:

Table 1. Adverse effects reported in phase 2/3 clinical trials where the effect was reported by = 2% of patients treated with CIALIS and the frequency was greater than that reported in patients treated with placebo.

Effect	CIALIS (N=1561) (%)	Placebo (N=758) (%)
Headache	11	4
Dyspepsia	7	1
Back pain	4	3
Myalgia	4	1
Nasal congestion	4	2
Flushing	4	2

Additional reported adverse effects where a causal relationship is uncertain (but plausible) and which occurred in <2% of patients receiving CIALIS included dizziness (1.7%), swelling of eyelids (0.3%), sensations described as eye pain (0.3%), and conjunctival hyperaemia (0.3%). Across all clinical studies, reports of changes in colour vision were rare (<0.1%).

Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole, increased tadalafil AUC by 107% and a CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88%, relative to the AUC values for tadalafil (10 mg) alone (see Warnings and Precautions). Simultaneous administration of an antacid (magnesium hydroxide/aluminium hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil (10 mg). An increase in gastric pH resulting from administration of nizatidine, an H2 antagonist had no significant effect on tadalafil (10 mg) pharmacokinetics. 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 is contraindicated (see Contraindications). CIALIS is not expected to cause clinically significant inhibition or induction of the clearance of medicines metabolised by CYP450 isoforms. Studies have confirmed that tadalafil does not inhibit or induce CYP450 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 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 (10 mg except for studies with angiotensin II receptor blockers and amlodipine in which a 20 mg dose was applied) had no clinically significant interaction with any of these classes. Analysis of phase 3 clinical trial data also showed no difference in adverse events in patients taking tadalafil with or without antihypertensive medications.

Tadalafil (10 and 20 mg) had no clinically significant effect on blood pressure changes due to tamsulosin, an alpha-adrenergic receptor blocking agent.

Alcohol concentrations (mean maximum blood concentration 0.08%) were not affected by co-administration with tadalafil (10 mg). The effects of alcohol on cognitive function and on blood pressure were not augmented by tadalafil (20 mg). In addition, no changes in tadalafil concentrations were seen 3 hours after co-administration with alcohol. Tadalafil (10 mg) had no clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline, a CYP1A2 substrate.

Single doses of up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients. Adverse events were similar to those seen at lower doses. In cases of overdose, standard supportive measures should be adopted as required.

Store below 25°C. Store in the original package.

2 years.

No special requirements.

Prescription Medicine.

CIALIS 10 mg tablets are blister packed and are presented in cartons containing 4 tablets. CIALIS 20 mg tablets are blister packed and are presented in cartons containing 1, 2 or 4 tablets.