Quator 10 mg Film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Tadalafil
Available from:
Rowex Ltd
ATC code:
G04BE; G04BE08
INN (International Name):
Tadalafil
Dosage:
10 milligram(s)
Pharmaceutical form:
Film-coated tablet
Therapeutic area:
Drugs used in erectile dysfunction; tadalafil
Authorization status:
Not marketed
Authorization number:
PA0711/293/001
Authorization date:
2019-07-19

Package leaflet: Information for the patient

Quator 10 mg Film-coated tablets

Quator 20 mg Film-coated tablets

tadalafil

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. See section 4.

What is in this leaflet

1. What Quator is and what it is used for

2. What you need to know before you take Quator

3. How to take Quator

4. Possible side effects

5. How to store Quator

6. Contents of the pack and other information

1. What Quator is and what it is used for

Quator contains the active substance tadalafil which belongs to a group of medicines called

phosphodiesterase type 5 inhibitors.

Quator 2.5 mg, 5 mg, 10 mg and 20 mg film-coated tablets are used to treat adult men with erectile

dysfunction. This is when a man cannot get, or keep a hard, erect penis suitable for sexual activity.

Quator has been shown to significantly improve the ability of obtaining a hard, erect penis suitable for

sexual activity.

Following sexual stimulation Quator works by helping the blood vessels in your penis to relax,

allowing the flow of blood into your penis. The result of this is improved erectile function. Quator will

not help you if you do not have erectile dysfunction. It is important to note that Quator for the

treatment of erectile dysfunction does not work if there is no sexual stimulation. You and your partner

will need to engage in foreplay, just as you would if you were not taking a medicine for erectile

dysfunction.

2. What you need to know before you take Quator

Do not take Quator if you:

are allergic to tadalafil or any of the other ingredients of this medicine (listed in section 6)

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

medicines (“nitrates”) used in the treatment of angina pectoris (“chest pain”). Tadalafil has been

shown to increase the effects of these medicines. If you are taking any form of nitrate or are

unsure tell your doctor.

have serious heart disease or recently had a heart attack within the last 90 days

recently had a stroke within the last 6 months

have low blood pressure or uncontrolled high blood pressure

ever had loss of vision because of non-arteritic anterior ischemic optic neuropathy (NAION), a

condition described as “stroke of the eye”

are taking riociguat. This medicine is used to treat pulmonary arterial hypertension (i.e. high blood

pressure in the lungs) and chronic thromboembolic pulmonary hypertension (i.e. high blood

pressure in the lungs secondary to blood clots). PDE5 inhibitors, such as Quator, have been shown

to increase the hypotensive effects of this medicine. If you are taking riociguat or are unsure tell

your doctor.

Warnings and precautions

Talk to your doctor before taking Quator.

Be aware that sexual activity carries a possible risk to patients with heart disease because it puts an

extra strain on your heart. If you have a heart problem, you should tell your doctor.

Before taking the tablets, tell your doctor if you have:

sickle cell anaemia (an abnormality of red blood cells)

multiple myeloma (cancer of the bone marrow)

leukaemia (cancer of the blood cells)

any deformation of your penis

a serious liver problem

a severe kidney problem.

It is not known if Quator is effective in patients who have had:

pelvic surgery

removal of all or part of the prostate gland in which nerves of the prostate are cut (radical non-

nerve-sparing prostatectomy).

If you experience sudden decrease or loss of vision, stop taking Quator and contact your doctor

immediately.

Decreased or sudden hearing loss has been noted in some patients taking tadalafil. Although it is not

known if the event is directly related to tadalafil, if you experience decreased or sudden hearing loss,

stop taking Quator and contact your doctor immediately.

Quator is not intended for use by women.

Children and adolescents

Quator is not intended for use by children and adolescents under the age of 18.

Other medicines and Quator

Tell your doctor if you are taking, have recently taken or might take any other medicines.

Do not take Quator if you are already taking nitrates.

Some medicines may be affected by Quator or they may affect how well Quator will work. Tell your

doctor or pharmacist if you are already taking:

an alpha-blocker (used to treat high blood pressure or urinary symptoms associated with benign

prostatic hyperplasia)

other medicines to treat high blood pressure

riociguat

a 5- alpha reductase inhibitor (used to treat benign prostatic hyperplasia)

medicines such as ketoconazole tablets (to treat fungal infections) and protease inhibitors for

treatment of AIDS or HIV infection

phenobarbital, phenytoin and carbamazepine (anticonvulsant medicines)

rifampicin, erythromycin, clarithromycin or itraconazole

other treatments for erectile dysfunction.

Quator with drink and alcohol

Information on the effect of alcohol is in section 3. Grapefruit juice may affect how well Quator will

work and should be taken with caution. Talk to your doctor for further information.

Fertility

When dogs were treated there was reduced sperm development in the testes. A reduction in sperm was

seen in some men. These effects are unlikely to lead to a lack of fertility.

Driving and using machines

Some men taking Quator in clinical studies have reported dizziness. Check carefully how you react to

the tablets before driving or using machines.

Quator contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor

before taking this medicine.

Quator contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-

free’.

3. How to take Quator

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist

if you are not sure.

Quator tablets are for oral use in men only. Swallow the tablet whole with some water. Quator 20 mg

tablets can be divided into equal doses.

The tablets can be taken with or without food.

Flexible-dose, on demand, using 10 mg or 20 mg film-coated tablets:

The recommended starting dose is one 10 mg tablet before sexual activity. If the effect of this dose

is too weak your doctor may increase the dose to 20 mg. Quator tablets are for oral use.

You may take a Quator tablet at least 30 minutes before sexual activity. Quator may still be

effective up to 36 hours after taking the tablet.

Quator 10 mg and 20 mg is intended for use prior to anticipated sexual activity and is not

recommended for continuous daily use.

Once a day dosing, using 2.5 mg or 5 mg film-coated tablets:

The recommended dose is one 5 mg tablet taken once a day at approximately the same time of the

day. Your doctor may adjust the dose to 2.5 mg based on your response to Quator. This will be

given as a 2.5 mg tablet.

When taken once a day Quator allows you to obtain an erection, when sexually stimulated, at any

time point during the 24 hours of the day. Once a day dosing of Quator may be useful to men who

anticipate having sexual activity two or more times per week.

Do not take Quator more than once a day.

It is important to note that Quator does not work if there is no sexual stimulation. You and your

partner will need to engage in foreplay, just as you would if you were not taking a medicine for

erectile dysfunction.

Drinking alcohol may affect your ability to get an erection and may temporarily lower your blood

pressure. If you have taken or are planning to take Quator, avoid excessive drinking (blood alcohol

level of 0.08% or greater), since this may increase the risk of dizziness when standing up.

If you take more Quator than you should

Contact your doctor. You may experience side effects described in section 4.

If you forget to take Quator

If you have a once a day dosing of Quator, take your dose as soon as you remember but do not take a

double dose to make up for a forgotten dose. You should not take Quator more than once a day.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. These

effects are normally mild to moderate in nature.

If you experience any of the following side effects stop using the medicine and seek medical help

immediately:

allergic reactions including rashes (frequency uncommon, may affect up to 1 in 100 people)

chest pain - do not use nitrates but seek immediate medical assistance (frequency uncommon, may

affect up to 1 in 100 people)

priapism, a prolonged and possibly painful erection after taking tadalafil (frequency rare, may

affect up to 1 in 1,000 people)

If you have such an erection, which lasts continuously for more than 4 hours you should contact a

doctor immediately.

sudden loss of vision (frequency rare, may affect up to 1 in 1,000 people).

Other side effects have been reported:

Common (may affect up to 1 in 10 people)

headache, back pain, muscle aches, pain in arms and legs, facial flushing, nasal congestion and

indigestion.

Uncommon (may affect up to 1 in 100 people)

dizziness, stomach ache, feeling sick, being sick (vomiting), reflux, blurred vision, eye pain,

difficulty in breathing, presence of blood in urine, prolonged erection, pounding heartbeat

sensation, a fast heart rate, high blood pressure, low blood pressure, nose bleeds, ringing in the ears,

swelling of the hands, feet or ankles and feeling tired.

Rare (may affect up to 1 in 1,000 people)

fainting, seizures and passing memory loss, swelling of the eyelids, red eyes, sudden decrease or

loss of hearing, hives (itchy red welts on the surface of the skin), penile bleeding, presence of blood

in semen and increased sweating.

Heart attack and stroke have also been reported rarely in men taking tadalafil. Most of these men had

known heart problems before taking this medicine.

Partial, temporary, or permanent decrease or loss of vision in one or both eyes has been rarely reported.

Some additional rare side effects have been reported in men taking tadalafil that were not seen in

clinical studies. These include:

migraine, swelling of the face, serious allergic reaction which causes swelling of the face or throat,

serious skin rashes, some disorders affecting blood flow to the eyes, irregular heartbeats, angina

and sudden cardiac death.

The side effect dizziness has been reported more frequently in men over 75 years of age taking

tadalafil. Diarrhoea has been reported more frequently in men over 65 years of age taking tadalafil.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not

listed in this leaflet. You can also report side effects directly via HPRA Pharmacovigilance; website:

www.hpra.ie. By reporting side effects you can help provide more information on the safety of this

medicine.

5. How to store Quator

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The

expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Quator contains

The active substance is tadalafil.

Each film-coated tablet contains 10 mg of tadalafil.

Each film-coated tablet contains 20 mg of tadalafil.

The other excipients are:

Tablet core:

Lactose monohydrate, sodium laurilsulfate (E487), povidone K-12 (E1201), crospovidone (Type B)

(E1202), sodium stearyl fumarate. See section 2 Quator contains lactose.

Film-coating:

Polyvinyl alcohol (E1203), macrogol 3350 (E1521), titanium dioxide (E171), talc (E553b), iron oxide

yellow (E172).

What Quator looks like and contents of the pack

Quator 10 mg film-coated tablets

Ochre to yellow, oval shaped film-coated tablet of approximately 11 x 6 mm. On one side, debossed

with “10”. The other side of the tablet is plain.

Quator 20 mg film-coated tablets

Ochre to yellow, oval shaped film-coated tablet of approximately 15 x 9 mm. On one side, debossed

with “20”. The other side of the tablet is bi-scored. The tablet can be divided into equal halves and/or

quarters.

Alu- Alu (Al-OPA/Al/PVC) blisters

PVC/ACLAR/PVC - Alu blisters

PVC/ACLAR/PVdC/PVC – Alu blisters

Pack sizes:

10 mg: 4, 12, 24, 36, 48 tablets

20 mg: 2, 4, 8, 12, 14, 24, 28, 36, 48 tablets

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturers

Marketing Authorisation Holder

Rowex Ltd., Bantry, Co. Cork, Ireland.

Manufacturers

PLIVA Hrvatska d.o.o., (PLIVA Croatia Ltd.), Prilaz baruna Filipovica 25, Zagreb 10000, Croatia.

Teva Pharma S.L.U., n. 4, Poligono Industrial Malpica, 50016 Zaragoza, Spain.

This medicinal product is authorised in the Member States of the EEA under the following

names:

Austria

Quator 2,5 mg – Filmtabletten

Quator 5 mg – Filmtabletten

Quator 10 mg – Filmtabletten

Quator 20 mg – Filmtabletten

Belgium

Quator 2,5 mg filmomhulde tabletten

Quator 5 mg filmomhulde tabletten

Quator 10 mg filmomhulde tabletten

Quator 20 mg filmomhulde tabletten

Denmark

Quator

Estonia

Quator

France

Quator 2,5 mg, comprimé pelliculé

Quator 5 mg, comprimé pelliculé

Quator 10 mg, comprimé pelliculé

Quator 20 mg, comprimé pelliculé

Germany

Quator 2,5 mg Filmtabletten

Quator 5 mg Filmtabletten

Quator 10 mg Filmtabletten

Quator 20 mg Filmtabletten

Greece

Quator 5 mg επικαλυμμένα με λεπτό υμένιο δισκία

Quator 10 mg επικαλυμμένα με λεπτό υμένιο δισκία

Quator 20 mg επικαλυμμένα με λεπτό υμένιο δισκία

Ireland

Quator 10 mg Film-coated tablets

Quator 20 mg Film-coated tablets

Latvia

Quator 5 mg apvalkotās tabletes

Quator 10 mg apvalkotās tabletes

Quator 20 mg apvalkotās tabletes

Lithuania

Quator 5 mg plėvele dengtosd tabletės

Quator 10 mg plėvele dengtosd tabletės

Quator 20 mg plėvele dengtosd tabletės

Portugal

Quator

Slovakia

Quator 5 mg

Quator 10 mg

Slovenia

Quator 5 mg filmsko obložene tablete

Quator 10 mg filmsko obložene tablete

Quator 20 mg filmsko obložene tablete

The Netherlands

Quator 2,5 mg, filmomhulde tabletten

Quator 5 mg, filmomhulde tabletten

Quator 10 mg, filmomhulde tabletten

Quator 20 mg, filmomhulde tabletten

This leaflet was last revised in 02/2020.

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Quator 10 mg Film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 10 mg tadalafil.

Excipient(s) with known effect

Each tablet contains 177 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Ochre to yellow, oval shaped film-coated tablet of approximately 11 x 6 mm. On one side debossed with "10". The other side of

the tablet is plain.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Treatment of erectile dysfunction in adult males. In order for tadalafil to be effective, sexual stimulation is required.

Quator is not indicated for use by women.

4.2 Posology and method of administration

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 5 mg taken once a day at approximately the same time of day. The dose may be

decreased to 2.5 mg once a day based on individual tolerability.

The appropriateness of continued use of the daily regimen should be reassessed periodically.

Special populations

Elderly men

Dose adjustments are not required in elderly patients.

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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 for on-demand treatment.

Once-a-day dosing of 2.5 or 5 mg tadalafil for the treatment of erectile dysfunction 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 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 10 mg of tadalafil to

patients with hepatic impairment.

Once-a-day dosing of 2.5 or 5 mg tadalafil for the treatment of erectile dysfunction 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 tadalafil in the paediatric population with regard to the treatment of erectile dysfunction.

Method of administration

Quator is available as 2.5, 5, 10 and 20 mg film-coated tablets for oral use.

4.3 Contraindications

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 tadalafil to patients

who are using any form of organic nitrate is contraindicated (see section 4.5).

Tadalafil 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 studies 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 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).

4.4 Special warnings and precautions for use

Before treatment with tadalafil

A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potential

underlying causes, before pharmacological treatment is considered.

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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 tadalafil is effective in patients who have

undergone pelvic surgery or radical non-nerve- sparing prostatectomy.

Cardiovascular

Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular

arrhythmia, stroke, transient ischemic attacks, chest pain, palpitations and tachycardia, have been reported either post

marketing and/or in clinical studies. 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.

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 alpha

blockers, concomitant administration of tadalafil 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 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 (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

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 tadalafil 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 (see section 4.5).

Tadalafil 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.

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Lactose

Quator contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or

glucose-galactose malabsorption should not take this medicine.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interactions

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 C

by 15 %, relative to the AUC and C

values for tadalafil alone. Ketoconazole (400 mg

daily) increased tadalafil (20 mg) exposure (AUC) 4-fold and C

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 C

. 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 tadalafil 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 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 (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 dose 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

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(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 study 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 study 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 acetyl salicylic acid.

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Antidiabetic medicinal products

Specific interaction studies with antidiabetic medicinal products were not conducted.

4.6 Fertility, pregnancy and lactation

Quator 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 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 (see sections 5.1 and 5.3).

4.7 Effects on ability to drive and use machines

Tadalafil has negligible influence on the ability to drive and use machines. Although the frequency of reports of dizziness in

placebo and tadalafil arms in clinical studies was similar, patients should be aware of how they react to tadalafil, before driving

or using machines.

4.8 Undesirable effects

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 studies

(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) and 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

Angioedema

Nervous system

disorders

Headache

Dizziness

Stroke

(including haemorrhagic events), Syncope, Transient ischaemic

attacks

, Migraine

, Seizures

, Transient amnesia

Eye disorders

Blurred vision,

Sensations

described as

eye pain

Visual field defect, Swelling of eyelids, Conjunctival hyperaemia, Non

arteritic anterior ischemic optic neuropathy (NAION)

, Retinal vascular

occlusion

Ear and

labyrinth

disorders

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Tinnitus

Sudden hearing loss

Cardiac

disorders

1

Tachycardia,

Palpitations

Myocardial infarction, Unstable angina pectoris

, Ventricular arrhythmia

Vascular

disorders

Flushing

Hypotension

Hypertension

Respiratory,

thoracic and

mediastinal

disorders

Nasal

congestion

Dyspnoea,

Epistaxis

Gastrointestinal

disorders

Dyspepsia

Abdominal pain,

Vomiting,

Nausea,

Gastro-oesopha

geal reflux

Skin and

subcutaneous

tissue disorders

Rash

Urticaria, Stevens-Johnson syndrome

, Exfoliative dermatitis

, Hyperhydrosis

(sweating)

Musculoskeletal

and connective

tissue 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 pain

Peripheral

oedema,

Fatigue

Facial oedema

, Sudden cardiac death

(1) Most of the patients had pre-existing cardiovascular risk factors (see section 4.4).

(2) Postmarketing surveillance reported adverse reactions not observed in placebo-controlled clinical studies.

(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.

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Other special populations

Data in patients over 65 years of age receiving tadalafil in clinical studies, either for the treatment of erectile dysfunction or the

treatment of benign prostatic hyperplasia, are limited. In clinical studies 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 studies with

tadalafil 5mg 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 HPRA Pharmacovigilance: Website: www.hpra.ie;

4.9 Overdose

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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.

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 1.6/0.8 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.

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 10 mg (one 6-month study)

and 20 mg (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.

Three clinical studies were conducted in 1054 patients in an at-home setting to define the period of responsiveness to tadalafil.

Tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful sexual

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intercourse up to 36 hours following dosing, as well as patients' ability to attain and maintain erections for successful

intercourse compared to placebo as early as 16 minutes following dosing.

Tadalafil 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 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.

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.

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 5 mg, 50 % on tadalafil 2.5 mg 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 5 mg and 2.5 mg, 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- naïve to PDE5 inhibitors were randomised to tadalafil 5 mg 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.

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.

5.2 Pharmacokinetic properties

Absorption

Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration (C

) 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.

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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 20 mg), 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, C

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). 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.

Patients with diabetes

Tadalafil exposure (AUC) in patients with diabetes was approximately 19 % lower than the AUC value for healthy subjects. This

difference in exposure does not warrant a dose adjustment.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, 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 active substance 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.

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