Treatment of erectile dysfunction in adult males.
In order for tadalafil to be effective for the treatment of erectile dysfunction, sexual stimulation is
required.
5 mg only: Treatment of the signs and symptoms of benign prostatic hyperplasia in adult males.
AVIALIS is not indicated for use by women.

Posology:
Erectile dysfunction in adult Men
In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or
without food.
In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried.
It may be taken at least 30 minutes prior to sexual activity.
The maximum dose frequency is once per day.
Tadalafil 10 and 20 mg is intended for use prior to anticipated sexual activity and it is not
recommended for continuous daily use.

In patients who anticipate a frequent use of AVIALIS (i.e., at least twice weekly) a once daily
regimen with the lowest doses of AVIALIS might be considered suitable, based on patient choice
and the physician's judgement.
In these patients, the recommended dose is 5mg taken once a day at approximately the same time of
day. The dose may be decreased to 2.5mg once a day based on individual tolerability.
The appropriateness of continued use of the daily regimen should be reassessed periodically. Benign
prostatic hyperplasia in adult men (tadalafil 5 mg only)
The recommended dose is 5 mg, taken at approximately the same time every day with or without
food. For adult men being treated for both benign prostatic hyperplasia and erectile dysfunction the
recommended dose is also 5 mg taken at approximately the same time every day. Patients who are
unable to tolerate tadalafil 5 mg for the treatment of benign prostatic hyperplasia should consider an
alternative therapy as the efficacy of tadalafil 2.5 mg for the treatment of benign prostatic
hyperplasia has not been demonstrated.

Special Populations:
Elderly Men:
Dose adjustments are not required in elderly patients.
Men with Renal Impairment:
Dose adjustments are not required in patients with mild to moderate renal impairment. For patients
with severe renal impairment, 10 mg is the maximum recommended dose.
Once-a-day dosing of 2.5 or 5 mg tadalafil both for the treatment of erectile dysfunction or benign
prostatic hyperplasia is not recommended in patients with severe renal impairment (see sections 4.4
and 5.2).
Men with Hepatic impairment:
For the treatment of erectile dysfunction using on-demand AVIALIS the recommended dose of
AVIALIS is 10 mg taken prior to anticipated sexual activity and with or without food. There is
limited clinical data on the safety of AVIALIS in patients with severe hepatic impairment (Child-
Pugh class C); if prescribed, a careful individual benefit/risk evaluation should be undertaken by the
prescribing physician. There are no available data about the administration of doses higher than
10mg of tadalafil to patients with hepatic impairment.
Once-a-day dosing both for the treatment of erectile dysfunction and benign prostatic hyperplasia
has not been evaluated in patients with hepatic impairment; therefore, if prescribed, a careful
individual benefit/risk evaluation should be undertaken by the prescribing physician (see sections 4.4
and 5.2).
Men with Diabetes:
Dose adjustments are not required in diabetic patients.
Paediatric population:
There is no relevant use of AVIALIS in the paediatric population w i t h r e g a r d t o t h e
t r e a t m e n t o f erectile dysfunction.

Method of Administration:
AVIALIS is available as 5, and 20 mg film-coated tablets for oral use.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. In clinical studies, tadalafil was shown to augment the hypotensive effects of nitrates. This is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, administration of AVIALIS to patients who are using an y f o r m o f o r g a n i c n i t r a t e i s contraindicated (see section 4.5). AVIALIS must not be used in men with cardiac disease for whom sexual activity is inadvisable. Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease. The following groups of patients with cardiovascular disease were not included in clinical trials and the use of tadalafil is therefore contraindicated:  patients with myocardial infarction within the last 90 days,  patients with unstable angina or angina occurring during sexual intercourse,  patients with New York Heart Association Class 2 or greater heart failure in the last 6 months,  patients with uncontrolled arrhythmias, hypotension (<90/50 mm Hg), or uncontrolled hypertension,  patients with a stroke within the last 6 months. AVIALIS is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure (see section 4.4). The co-administration of PDE5 inhibitors, including tadalafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension (see section 4.5).

Before treatment with AVIALIS
A medical history and physical examination should be undertaken to diagnose erectile dysfunction or
benign prostatic hyperplasia and determine potential underlying causes, before pharmacological treatment
is considered.
Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular
status of their patients, since there is a degree of cardiac risk associated with sexual activity. Tadalafil has
vasodilator properties, resulting in mild and transient decreases in blood pressure (see section 5.1) and as
such potentiates the hypotensive effect of nitrates (see section 4.3).

The evaluation of erectile dysfunction should include a determination of potential underlying causes and
the identification of appropriate treatment following an appropriate medical assessment. It is not known if
AVIALIS is effective in patients who have undergone pelvic surgery or radical non-nerve-sparing
prostatectomy.
Tadalafil 5 mg - Prior to initiating treatment with tadalafil for benign prostatic hyperplasia patients should
be examined to rule out the presence of carcinoma of the prostate and carefully assessed for
cardiovascular conditions (see section 4.3).
Cardiovascular
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
AVIALIS, to sexual activity, or to a combination of these or other factors.
Tadalafil 2.5 mg and 5 mg - In patients receiving concomitant antihypertensive medicinal products,
tadalafil may induce a blood pressure decrease. When initiating daily treatment with tadalafil, appropriate
clinical considerations should be given to a possible dose adjustment of the antihypertensive therapy.
In patients who are taking alpha1 blockers, concomitant administration of AVIALIS may lead to
symptomatic hypotension in some patients (see section 4.5). The combination of tadalafil and doxazosin
is not recommended.
Vision
Visual defects and cases of NAION have been reported in connection with the intake of AVIALIS and
other PDE5 inhibitors. Analyses of observational data suggest an increased risk of acute NAION in
men with erectile dysfunction following exposure to tadalafil or other PDE5 inhibitors. As this may be
relevant for all patients exposed to tadalafil, the patient should be advised that in case of sudden visual
defect, he should stop taking AVIALIS and consult a physician immediately (see section 4.3).
Decreased or sudden hearing loss
Cases of sudden hearing loss have been reported after the use of tadalafil. Although other risk factors
were present in some cases (such as age, diabetes, hypertension and previous hearing loss history)
patients should be advised to stop taking tadalafil and seek prompt medical attention in the event of
sudden decrease or loss of hearing.
Renal and hepatic impairment (tadalafil2.5mg and5mg)
Due to increased tadalafil exposure (AUC), limited clinical experience and the lack of ability to
influence clearance by dialysis, once-a-day dosing of AVIALISis not recommended in patients with
severe renal impairment.
There is limited clinical data on the safety of single-dose administration of AVIALIS in patients with
severe hepatic insufficiency (Child-Pugh Class C). Once-a-day administration has not been evaluated in patients with hepatic insufficiency. If AVIALIS is prescribed, a careful individual benefit/risk
evaluation should be undertaken by the prescribing physician.
Hepatic impairment (tadalafil10mg and20mg)
There is limited clinical data on the safety of single-dose administration of AVIALIS in patients
with severe hepatic insufficiency (Child-Pugh Class C). If AVIALIS is prescribed, a careful
individual benefit/risk evaluation should be undertaken by the prescribing physician.
Priapism and anatomical deformation of the penis
Patients who experience erections lasting 4 hours or more should be instructed to seek immediate medical
assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency
may result.
AVIALIS, 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).
Use with CYP3A4 inhibitors
Caution should be exercised when prescribing AVIALIS to patients using potent CYP3A4
inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, and erythromycin), as increased
tadalafil exposure (AUC) has been observed if the medicinal products are combined (see section
4.5).
AVIALIS and other treatments for erectile dysfunction
The safety and efficacy of combinations of AVIALIS and other PDE5 inhibitors or other treatments for
erectile dysfunction have not been studied. The patients should be informed not to takeAVIALIS in
such combinations.
Lactose
AVIALIS contains lactose. 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 10 mg and/or 20 mg tadalafil, as indicated below. With regard to
those interaction studies where only the 10 mg tadalafil dose was used, clinically relevant interactions at
higher doses cannot be completely ruled out.
Effects of Other Substances on Tadalafil
 Cytochrome P450 inhibitors
Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (200 mg
daily), increased tadalafil (10 mg) exposure (AUC) 2-fold and Cmax by 15%, relative to the AUC and
Cmax values for tadalafil alone. Ketoconazole (400 mg daily) increased tadalafil (20 mg) exposure
(AUC) 4-fold and Cmax by 22%. Ritonavir, a protease inhibitor (200 mg twice daily), which is an
inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg) exposure (AUC)
2-fold with no change in Cmax. Although specific interactions have not been studied, other protease
inhibitors, such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin, clarithromycin,
itraconazole, and grapefruit juice, should be co-administered with caution, as they would be expected to increase plasma concentrations of tadalafil (see section 4.4). Consequently, the incidence of the adverse
reactions listed in section 4.8 might be increased.
 Transporters
The role of transporters (for example, p-glycoprotein) in the disposition of tadalafil is not known.
Therefore, there is the potential of drug interactions mediated by inhibition of transporters.
 Cytochrome P450 inducers
A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88%, relative to the AUC values for tadalafil
alone (10 mg). This reduced exposure can be anticipated to decrease the efficacy of tadalafil; the
magnitude of decreased efficacy is unknown. Other inducers of CYP3A4, such as phenobarbital,
phenytoin, and carbamazepine, may also decrease plasma concentrations of tadalafil.
Effects of Tadalafil on Other Medicinal Products
 Nitrates
In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of nitrates.
Therefore, administration of AVIALIS to patients who are using any form of organic nitrate is
contraindicated (see section 4.3). Based on the results of a clinical study in which 150 subjects receiving
daily doses of tadalafil 20 mg for 7 days and 0.4 mg sublingual nitroglycerin at various times, this
interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed after
the last tadalafil dose. Thus, in a patient prescribed any dose of AVIALIS (2.5 mg- 20 mg), where nitrate
administration is deemed medically necessary in a life-threatening situation, at least 48 hours should have
elapsed after the last dose ofAVIALIS before nitrate administration is considered. In such circumstances,
nitrates should only be administered under close medical supervision with appropriate haemodynamic
monitoring.
 Anti-hypertensives (including calcium channel blockers)
The co-administration of doxazosin (4 and 8 mg daily) and tadalafil (5 mg daily dose and 20 mg as a
single dose) increases the blood pressure-lowering effect of this alpha-blocker in a significant manner.
This effect lasts at least twelve hours and may be symptomatic, including syncope. Therefore, this
combination is not recommended (see section 4.4).
In interaction studies performed in a limited number of healthy volunteers, these effects were not reported
with alfuzosin or tamsulosin. However, caution should be exercised when using tadalafil in patients
treated with any alpha-blockers, and notably in the elderly. Treatments should be initiated at minimal
dosage and progressively adjusted.
In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects of
antihypertensive medicinal products was examined. Major classes of antihypertensive medicinal products
were studied, including calcium- channel blockers (amlodipine), angiotensin converting enzyme (ACE)
inhibitors (enalapril), beta-adrenergic receptor blockers (metoprolol), thiazide diuretics (bendrofluazide),
and angiotensin II receptor blockers (various types and doses, alone or in combination with thiazides,
calcium-channel blockers, beta-blockers, and/or alpha-blockers). Tadalafil (10 mg, except for studies with
angiotensin II receptor blockers and amlodipine in which a 20 mg dose was applied) had no clinically
significant interaction with any of these classes. In another clinical pharmacology study, tadalafil (20 mg)
was studied in combination with up to 4 classes of antihypertensives. In subjects taking multiple
antihypertensives, the ambulatory-blood-pressure changes appeared to relate to the degree of blood pressure control. In this regard, study subjects whose blood pressure was well controlled, the reduction
was minimal and similar to that seen in healthy subjects. In study subjects whose blood pressure was not
controlled, the reduction was greater, although this reduction was not associated with hypotensive
symptoms in the majority of subjects. In patients receiving concomitant antihypertensive medicinal
products, tadalafil 20 mg may induce a blood pressure decrease, which (with the exception of
alpha-blockers - see above) is, in general, minor and not likely to be clinically relevant. Analysis of Phase
3 clinical trial data showed no difference in adverse events in patients taking tadalafil with or without
antihypertensive medicinal products. However, appropriate clinical advice should be given to patients
regarding a possible decrease in blood pressure when they are treated with antihypertensive medicinal
products.
 Riociguat
Preclinical studies showed an additive systemic blood pressure lowering effect when PDE5 inhibitors
were combined with riociguat. In clinical studies, riociguat has been shown to augment the hypotensive
effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the combination in the
population studied. Concomitant use of riociguat with PDE5 inhibitors, including tadalafil, is
contraindicated (see section 4.3).
 5- alpha reductase inhibitors
In a clinical trial that compared tadalafil 5 mg coadministered with finasteride 5 mg to placebo plus
finasteride 5 mg in the relief of BPH symptoms, no new adverse reactions were identified. However, as a
formal drug-drug interaction study evaluating the effects of tadalafil and 5-alpha reductase inhibitors
(5-ARIs) has not been performed, caution should be exercised when tadalafil is co-administered with
5-ARIs.
 CYP1A2 substrates (e.g. theophylline)
When tadalafil 10 mg was administered with theophylline (a non-selective phosphodiesterase inhibitor) in
a clinical pharmacology study, there was no pharmacokinetic interaction. The only pharmacodynamic
effect was a small (3.5 bpm) increase in heart rate. Although this effect is minor and was of no clinical
significance in this study, it should be considered when co-administering these medicinal products.
 Ethinylestradiol and terbutaline
Tadalafil has been demonstrated to produce an increase in the oral bioavailability of ethinylestradiol; a
similar increase may be expected with oral administration of terbutaline, although the clinical
consequence of this is uncertain.
 Alcohol
Alcohol concentrations (mean maximum blood concentration 0.08%) were not affected by
co-administration with tadalafil (10 mg or 20 mg). In addition, no changes in tadalafil concentrations
were seen 3 hours after co-administration with alcohol. Alcohol was administered in a manner to
maximise the rate of alcohol absorption (overnight fast with no food until 2 hours after alcohol). Tadalafil
(20 mg) did not augment the mean blood pressure decrease produced by alcohol
(0.7 g/kg or approximately 180 ml of 40% alcohol [vodka] in an 80 kg male) but, in some subjects,
postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with
lower doses of alcohol (0.6 g/kg), hypotension was not observed and dizziness occurred with similar
frequency to alcohol alone. The effect of alcohol on cognitive function was not augmented by tadalafil
(10 mg).

 Cytochrome P450 metabolised medicinal products
Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of
medicinal products metabolised by CYP450 isoforms. Studies have confirmed that tadalafil does not
inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9 and
CYP2C19.
 CYP2C9 substrates (e.g. R-warfarin)
Tadalafil (10 mg and 20 mg) had no clinically significant effect on exposure (AUC) to S-warfarin or
R-warfarin (CYP2C9 substrate), nor did tadalafil affect changes in prothrombin time induced by warfarin.
 Aspirin
Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic
acid.
 Antidiabetic medicinal products
Specific interaction studies with antidiabetic medicinal products were not conducted.

AVIALIS is not indicated for use by women.
Pregnancy:
There are limited data from the use of tadalafil in pregnant women. Animal studies do not indicate
direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development,
parturition or postnatal development (see section 5.3). As a precautionary measure, it is preferable to
avoid the use of AVIALIS during pregnancy.
Breastfeeding:
Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk.
A risk to the suckling child cannot be excluded. AVIALIS should not be used during breast feeding.
Fertility:
Effects were seen in dogs that might indicate impairment of fertility. Two subsequent clinical studies
suggest that this effect is unlikely in humans, although a decrease in sperm concentration was seen in
some men (see sections 5.1 and 5.3).

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

Summary of the safety profile
The most commonly reported adverse reactions in patients taking AVIALIS for the treatment of
erectile dysfunction or benign prostatic hyperplasia were headache, dyspepsia, back pain and
myalgia, in which the incidences increase with increasing dose of AVIALIS. The adverse reactions
reported were transient, and generally mild or moderate. The majority of headaches reported with
AVIALIS once-a-day dosing are experienced within the first 10 to 30 days of starting treatment.

Tabulated summary of adverse reactions
The table below lists the adverse reactions observed from spontaneous reporting and
in placebo-controlled clinical trials (comprising a total of 8022 patients on AVIALIS and 4422
patients on placebo) for on-demand and once-a-day treatment of erectile dysfunction and the
once-a-day treatment of benign prostatic hyperplasia.
Frequency convention: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to
<1/100), Rare (≥1/10,000 to <1/1,000), Very Rare (<1/10,000) and Not known (cannot be estimated
from the available data).

1) Most of the patients had pre-existing cardiovascular risk factors (see section 4.4).
2) Post-marketing surveillance reported adverse reactions not observed in
placebo-controlled clinical trials.
3) More commonly reported when tadalafil is given to patients who are already taking
antihypertensive medicinal products.

Description of selected adverse reactions
A slightly higher incidence of ECG abnormalities, primarily sinus bradycardia, has been reported in
patients treated with tadalafil once a day as compared with placebo. Most of these ECG
abnormalities were not associated with adverse reactions.
Other special populations
Data in patients over 65 years of age receiving tadalafil in clinical trials, either for the treatment of
erectile dysfunction or the treatment of benign prostatic hyperplasia, are limited. In clinical trials
with tadalafil taken on demand for the treatment of erectile dysfunction, diarrhoea was reported more
frequently in patients over 65 years of age. In clinical trials with tadalafil 5 mg taken once a day for
the treatment of benign prostatic hyperplasia, dizziness and diarrhoea were reported more frequently
in patients over 75 years of age.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via

The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
o Toll free phone: 8002490000
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc

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

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction. ATC code: G04BE08.
Mechanism of action
Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific
phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide,
inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This results
in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection.
Tadalafil has no effect in the treatment of erectile dysfunction in the absence of sexual stimulation.
Tadalafil 5 mg - The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum is also
observed in the smooth muscle of the prostate, the bladder and their vascular supply. The resulting
vascular relaxation increases blood perfusion which may be the mechanism by which symptoms of benign
prostatic hyperplasia are reduced. These vascular effects may be complemented by inhibition of bladder
afferent nerve activity and smooth muscle relaxation of the prostate and bladder.
Pharmacodynamic effects
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 phosphor
diesterases. 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 photo transduction. Tadalafil is also >10,000-fold more potent for PDE5 than
for PDE7 through PDE10.
Clinical efficacy and safety
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 AVIALIS
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.

Erectile dysfunction
Three clinical studies were conducted in 1054 patients in an at-home setting to define the period of
responsiveness to AVIALIS on demand. Tadalafil demonstrated statistically significant improvement in
erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as
well as patients' ability to attain and maintain erections for successful intercourse compared to placebo as
early as 16 minutes following dosing.
In a 12-week study performed in 186 patients (142 tadalafil, 44 placebo) with erectile dysfunction
secondary to spinal cord injury, tadalafil significantly improved the erectile function leading to a mean
per-subject proportion of successful attempts in patients treated with tadalafil 10 or 20 mg (flexible-dose,
on demand) of 48% as compared to 17% with placebo.
Tadalafil at doses of 2 to 100mg has been evaluated in 16 clinical studies involving 3250 patients,
including patients with erectile dysfunction of various severities (mild, moderate, severe), etiologies, ages
(range 21-86 years), and ethnicities. Most patients reported erectile dysfunction of at least 1 year in
duration. In the primary efficacy studies of general populations, 81% of patients reported that AVIALIS
improved their erections as compared to 35% with placebo. Also, patients with erectile dysfunction in all
severity categories reported improved erections whilst taking AVIALIS (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 AVIALIS-treated patients as compared
to 32% with placebo.
For once-a-day evaluation of tadalafil at doses of 2.5, 5, and 10 mg 3 clinical studies were initially
conducted involving 853 patients of various ages (range 21-82 years) and ethnicities, with erectile
dysfunction of various severities (mild, moderate, severe) and etiologies. In the two primary efficacy
studies of general populations, the mean per-subject proportion of successful intercourse attempts were
57 and 67% on AVIALIS 5mg, 50% on AVIALIS 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% onAVIALIS 5mg and 2.5mg, respectively, as compared to 28%
with placebo. Most patients in these three studies were responders to previous on-demand treatment with
PDE5 inhibitors. In a subsequent study, 217 patients who were treatment-naive to PDE5 inhibitors were
randomised to AVIALIS 5mg once a day vs. placebo. The mean per-subject proportion of successful
sexual intercourse attempts was 68% for AVIALIS patients compared to 52% for patients on placebo.
Benign prostatic hyperplasia
AVIALIS was studied in 4 clinical studies of 12 weeks duration enrolling over 1500 patients with signs
and symptoms of benign prostatic hyperplasia. The improvement in the total international prostate
symptom score with AVIALIS 5mg in the four studies were -4.8, -5.6, -6.1 and -6.3 compared to -2.2,
-3.6, -3.8 and -4.2 with placebo. The improvements in total international prostate symptom score occurred
as early as 1 week. In one of the studies, which also included Tamsulosin 0.4 mg as an active comparator,
the improvement in total international prostate symptom score with AVIALIS 5mg, Tamsulosin and
placebo were -6.3, -5.7 and -4.2 respectively.
One of these studies assessed improvements in erectile dysfunction and signs and symptoms of benign
prostatic hyperplasia in patients with both conditions. The improvements in the erectile function domain
of the international index of erectile function and the total international prostate symptom score in this
study were 6.5 and -6.1 with AVIALIS 5 mg compared to 1.8 and -3.8 with placebo, respectively. The
mean per-subject proportion of successful sexual intercourse attempts was 71.9% withAVIALIS 5 mg
compared to 48.3% with placebo.

The maintenance of the effect was evaluated in an open-label extension to one of the studies, which
showed that the improvement in total international prostate symptom score seen at 12 weeks was
maintained for up to 1 additional year of treatment with AVIALIS 5mg.
Paediatric population
A single study has been performed in paediatric patients with Duchenne Muscular Dystrophy (DMD) in
which no evidence of efficacy was seen. The randomised, double–blind, placebo–controlled, parallel,
3–arm study of tadalafil was conducted in 331 boys aged 7–14 years with DMD receiving concurrent
corticosteroid therapy. The study included a 48– week double-blind period where patients were
randomised to tadalafil 0.3 mg/kg, tadalafil 0.6 mg/kg, or placebo daily. Tadalafil did not show efficacy
in slowing the decline in ambulation as measured by the primary 6 minute walk distance (6MWD)
endpoint: least squares (LS) mean change in 6MWD at 48 weeks was –51.0 meters (m) in the placebo
group, compared with –64.7 m in the tadalafil 0.3 mg/kg group (p = 0.307) and –59.1 m in the tadalafil
0.6 mg/kg group (p = 0.538). In addition, there was no evidence of efficacy from any of the secondary
analyses performed in this study. The overall safety results from this study were generally consistent with
the known safety profile of tadalafil and with adverse events (AEs) expected in a paediatric DMD
population receiving corticosteroids.
The European Medicines Agency has waived the obligation to submit the results of studies in all subsets
of the paediatric population in the treatment of the erectile dysfunction. See section 4.2 for information on
paediatric use.

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 AVIALIS 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 l, indicating that tadalafil is distributed into tissues.
At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Protein binding is not
affected by impaired renal function.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
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
The mean oral clearance for tadalafil is 2.5 l/h and the mean half-life is 17.5 hours in healthy subjects.

Tadalafil is excreted predominantly as inactive metabolites, mainly in the faeces (approximately 61% of
the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Linearity/Non-Linearity
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.
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 (5 to 20mg), tadalafil exposure (AUC)
approximately doubled in subjects with mild (creatinine clearance 51 to 80 ml/min) or moderate
(creatinine clearance 31 to 50 ml/min) renal impairment and in subjects with end-stage renal disease on
dialysis. In haemodialysis patients, Cmax was 41% higher than that observed in healthy subjects.
Haemodialysis contributes negligibly to tadalafil elimination.
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 10 mg is administered. There is
limited clinical data on the safety of AVIALISin patients with severe hepatic insufficiency (Child-
Pugh class C). If AVIALIS is prescribed, a careful individual benefit/risk evaluation should be
undertaken by the prescribing physician. There are no available data about the administration of oncea-
day dosing of tadalafil to patients with hepatic impairment. If AVIALIS is prescribed once-a- day, a
careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are
no available data about the administration of doses higher than 10 mg of tadalafil to patients with
hepatic impairment.
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.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.
There was no evidence of teratogenicity, embryotoxicity, or foetotoxicity in rats or mice that received up
to 1000 mg/kg/day tadalafil. In a rat prenatal and postnatal development study, the no observed effect
dose was 30 mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was
approximately 18-times the human AUC at a 20 mg dose.
There was no impairment of fertility in male and female rats. In dogs given tadalafil daily for 6 to 12
months at doses of 25 mg/kg/day (resulting in at least a 3-fold greater exposure [range 3.7-18.6] than seen in humans given a single 20 mg dose) and above, there was regression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs. See also section 5.1.

Tablet core:
 Lactose Monohydrate (Pharmatose-200 M)
 Crosscarmellose Sodium (ACDISOL)
 Hydroxypropyl cellulose (Klucel EXF)
 Sodium Lauryl Sulphate (Empicol LZ / N)
 Microcrystalline Cellulose PH-102 (Avicel PH-102)
 Magnesium Stearate (Parteck LUB MST)
5 mg Film-coat:
 Opadry Yellow 32K220032
20 mg Film-coat:
 Opadry Yellow 32K220033

Not applicable.

2 years.

Store below 30°C.

The immediate packaging material is Aluminum–PVC/PVdC (250/60GSM) Blister.
The primary packed product is attached to leaflet and inserted into a carton of 28 film-coated tablets
for 5 mg, and 1 and 4 film-coated tablets for 20 mg.

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