Treatment of erectile dysfunction in adult males.
In order for tadalafil to be effective for the treatment of erectile dysfunction, sexual
stimulation is required.
Treatment of the signs and symptoms of benign prostatic hyperplasia in adult males.
Tyra® 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 tadalafil (i.e., at least twice weekly) a once daily
regimen with the lowest doses of tadalafil 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 tadalafil once a day based on individual
tolerability.
The appropriateness of continued use of the daily regimen should be reassessed periodically.
Benign prostatic hyperplasia in adult men
The recommended dose is 5 mg, taken at approximately the same time every day with or
without food. For adult men being treated for both benign prostatic hyperplasia and erectile
dysfunction 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.
Men with Hepatic Impairment
For the treatment of erectile dysfunction using on-demand tadalafil the recommended dose of
tadalafil is 10 mg taken prior to anticipated sexual activity and with or without food. There is
limited clinical data on the safety of tadalafil 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.
Men with Diabetes
Dose adjustments are not required in diabetic patients.
Paediatric population
There is no relevant use of tadalafil in the paediatric population with regard to the treatment
of erectile dysfunction.
Method of administration
Tyra® 5 mg film-coated tablet is 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 Tyra® to patients who are using any form of organic nitrate is contraindicated. Tyra®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 preexisting 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. Tadalafil is contraindicated in patients who have loss of vision in one eye because of nonarteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure. 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.

Before treatment with Tyra®
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 and as such potentiates the hypotensive effect of nitrates.
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 tadalafil 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.
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 tadalafil, 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 tadalafil may lead
to symptomatic hypotension in some patients. 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
tadalafil 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 tadalafil and
consult a physician immediately.
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 (tadalafil 2.5 mg and 5 mg)
Due to increased tadalafil exposure (AUC), limited clinical experience and the lack of ability
to influence clearance by dialysis, once-a-day dosing of tadalafil is not recommended in
patients with severe renal impairment.
There is limited clinical data on the safety of single-dose administration of tadalafil in
patients with severe hepatic insufficiency (Child-Pugh Class C). Once-a-day administration
has not been evaluated in patients with hepatic insufficiency. If Tyra® is prescribed, a careful
individual benefit/risk evaluation should be undertaken by the prescribing physician.
Hepatic impairment (tadalafil 10 mg and 20 mg)
There is limited clinical data on the safety of single-dose administration of tadalafil in
patients with severe hepatic insufficiency (Child-Pugh Class C). If Tyra® 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.
Tadalafil, 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 tadalafil 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.
Tyra® and other treatments for erectile dysfunction
The safety and efficacy of combinations of tadalafil and other PDE5 inhibitors or other
treatments for erectile dysfunction have not been studied. The patients should be informed
not to take tadalafil in such combinations.
Lactose
Tyra® contains lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal
product.

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. 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 tadalafil to patients who are using any form of
organic nitrate is contraindicated. 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 tadalafil (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 of tadalafil 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.
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, calciumchannel
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-bloodpressure
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.
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 Swarfarin
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.

Tyra® is not indicated for use by women.
Pregnancy
Pregnancy Category: B
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. As a precautionary measure, it is
preferable to avoid the use of tadalafil 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. Tadalafil 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.

Tadalafil 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 tadalafil before driving or using machines.

Summary of the safety profile
The most commonly reported adverse reactions in patients taking tadalafil 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 tadalafil. The adverse
reactions reported were transient, and generally mild or moderate. The majority of headaches
reported with tadalafil 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 tadalafil 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).

Very common	Common	Uncommon	Rare
Immune system disorders
		Hypersensitivity reactions	Angioedema2
Nervous system disorders
	Headache	Dizziness	Stroke1 (including haemorrhagic events), Syncope, Transient ischaemic attacks1, Migraine2, Seizures2, Transient amnesia
Eye disorders
		Blurred vision, Sensations described as eye pain	Visual field defect, Swelling of eyelids, Conjunctival hyperaemia, Non-arteritic anterior ischaemic optic neuropathy (NAION)2, Retinal vascular occlusion2
Ear and labyrinth disorders
		Tinnitus	Sudden hearing loss
Cardiac disorders1
		Tachycardia, Palpitations	Myocardial infarction, Unstable angina pectoris2, Ventricular arrhythmia2
Vascular disorders
	Flushing	Hypotension3, Hypertension
Respiratory, thoracic and mediastinal disorders
	Nasal congestion	Dyspnoea, Epistaxis
Gastrointestinal disorders
	Dyspepsia	Abdominal pain, Vomiting, Nausea, Gastro-oesophageal reflux
Skin and subcutaneous tissue disorders
		Rash	Urticaria, Stevens-Johnson syndrome2, Exfoliative dermatitis2, Hyperhydrosis (sweating)
Musculoskeletal, connective tissue and bone disorders
	Back pain, Myalgia, Pain in extremity
Renal and urinary disorders
		Haematuria
Reproductive system and breast disorders
		Prolonged erections	Priapism, Penile haemorrhage, Haematospermia
General disorders and administration site conditions
		Chest pain1, Peripheral oedema, Fatigue	Facial oedema2, Sudden cardiac death1,2

(1) Most of the patients had pre-existing cardiovascular risk factors.

(2) Postmarketing 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.
To report any side effects:
• National Pharmacovigilance and Drug Safety Centre (NPC)
− Fax: + 966 112057662
− Call NPC at + 966 112038222, Exts: 2317-2356-2353-2354-2334-2340
− Toll free phone: 8002490000
− E-mail: npc.drug@sfda.gov.sa
− 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 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.
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
tadalafil 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 tadalafil 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 tadalafil improved their erections as compared to
35% with placebo. Also, patients with erectile dysfunction in all severity categories reported
improved erections whilst taking tadalafil (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 tadalafil -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 tadalafil 5mg, 50% on tadalafil 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 tadalafil 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 tadalafil 5mg once a day vs. placebo. The mean per-subject proportion of
successful sexual intercourse attempts was 68% for tadalafil patients compared to 52% for
patients on placebo.
Benign prostatic hyperplasia
Tadalafil 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 tadalafil 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 tadalafil 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 tadalafil 5 mg
compared to 1.8 and -3.8 with placebo, respectively. The mean per-subject proportion of
successful sexual intercourse attempts was 71.9% with tadalafil 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 tadalafil 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 doubleblind
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.

bsorption
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 tadalafil 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. Steadystate
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 tadalafil in patients with severe
hepatic insufficiency (Child-Pugh class C). If tadalafil is prescribed, a careful individual
benefit/risk evaluation should be undertaken by the prescribing physician. There are no
available data about the administration of once-a-day dosing of tadalafil to patients with
hepatic impairment. If tadalafil 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.

Lactose monohydrate
Croscarmellose sodium
Sodium laurilsulfate
Hypromellose
Microcrystalline cellulose
Magnesium stearate
Titanium dioxide
Triacetin
Iron oxide yellow (E172).

Not applicable

24 months.

Store below 30°C in the original package.

Immediate packaging	Outer packaging
PVC/PVDC/Aluminum Blister	Carton Leaflet

Tyra^® 5 mg film coated tablets are packed in aluminum blisters enclosed in a carton along with a leaflet. Tyra^® 5 mg is available in packs of 4 tablets (4 blisters each containing 1 tablet), and in packs of 28 tablets (2 blisters each containing 14 tablets).

Not all pack sizes may be marketed.

 

Medicines should not be disposed of via wastewater or household waste.