Telefil 10 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

30-10-2017

Produktens egenskaper Produktens egenskaper (SPC)

30-10-2017

Aktiva substanser:
tadalafil
Tillgänglig från:
Sigillata Ltd
ATC-kod:
G04BE08
INN (International namn):
tadalafil
Dos:
10 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
natriumlaurilsulfat Hjälpämne; laktosmonohydrat Hjälpämne; tadalafil 10 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Bemyndigande status:
Avregistrerad
Godkännandenummer:
52895
Tillstånd datum:
2017-03-30

Dokument på andra språk

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

30-03-2017

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Package leaflet: Information for the user

Telefil 10 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

What Telefil is and what it is used for

What you need to know before you take Telefil

How to take Telefil

Possible side effects

How to store Telefil

Contents of the pack and other information

1.

What Telefil is and what it is used for

Telefil is a treatment for adult men with erectile dysfunction. This is when a man cannot get, or keep a

hard, erect penis suitable for sexual activity. Telefil has been shown to significantly improve the

ability of obtaining a hard erect penis suitable for sexual activity.

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

phosphodiesterase type 5 inhibitors. Following sexual stimulation Telefil 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. Telefil will not help you if you do not have erectile dysfunction.

It is important to note that Telefil 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 Telefil

Do not take Telefil:

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

if you 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”). Telefil

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

or are unsure tell your doctor.

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

if you recently had a stroke within the last 6 months.

if you have low blood pressure or uncontrolled high blood pressure.

if you ever had loss of vision because of non-arteritic anterior ischemic optic neuropathy

(NAION), a condition described as “stroke of the eye”.

if you are taking riociguat. This drug 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 tadalafil, 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 Telefil

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 Telefil 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 Telefil 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 Telefil and contact your doctor immediately.

Telefil is not intended for use by women.

Children and adolescents

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

Other medicines and Telefil

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

Do not take Telefil if you are already taking nitrates.

Some medicines may be affected by Telefil or they may affect how well Telefil 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.

Telefil with drink and alcohol

Information on the effect of alcohol is in section 3. Grapefruit juice may affect how well Telefil 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 Telefil in clinical studies have reported dizziness. Check carefully how you react to

the tablets before driving or using machines.

Telefil contains lactose

If you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

3.

How to take Telefil

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

if you are not sure.

Telefil tablets are for oral use in men only. Swallow the tablet whole with some water. The tablets can

be taken with or without food.

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. Telefil tablets are for

oral use.

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

up to 36 hours after taking the tablet.

Do not take Telefil more than once a day. Telefil 10 mg and 20 mg is intended for use prior to

anticipated sexual activity and is not recommended for continuous daily use.

It is important to note that Telefil 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 Telefil, 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 Telefil than you should

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

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).

chest pain - do not use nitrates but seek immediate medical assistance (frequency uncommon).

priapism, a prolonged and possibly painful erection after taking Telefil (frequency rare). 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).

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 Telefil. 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 Telefil that were not seen in

clinical trials. 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 Telefil.

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

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 the national reporting system

listed in Appendix V. By reporting side effects you can help provide more information on the safety of

this medicine.

5.

How to store Telefil

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 ʻEXPʼ.

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 Telefil contains

The active substance is tadalafil. Each tablet contains 10 mg of tadalafil.

The other ingredients are:

Tablet core:

lactose monohydrate, pregelatinised starch, colloidal anhydrous silica,

croscarmellose sodium, sodium laurilsulfate, magnesium stearate.

Film-coat:

hypromellose, lactose monohydrate, titanium dioxide (E171), triacetin, talc (E553b),

iron oxide yellow (E172), iron oxide red (E172).

What Telefil looks like and contents of the pack

Telefil 10 mg is a pale yellow, oval shaped, film-coated tablet (tablet), debossed with ‘10’ on one side

and plain on the other side. The tablet is 11 mm x 6.6 mm in diameter and 3.9 – 4.5 mm in thickness.

Pack sizes

Telefil 10 mg is available in blister packs containing 4 tablets.

Not all pack sizes may be marketed

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

<[To be completed nationally]>

Manufacturer

<[To be completed nationally]>

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

names:

<{Name of the Member State}> <{Name of the medicinal product}>

<{Name of the Member State}> <{Name of the medicinal product}>

This leaflet was last revised in

30 October 2017

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1.

NAME OF THE MEDICINAL PRODUCT

Telefil 10 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10 mg tadalafil.

Excipient with known effect:

Each coated tablet contains 177 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet (tablet).

10 mg film-coated tablets are: Pale yellow, oval shape, film-coated tablets, debossed with ‘10’ on one

side and plain on the other side. The tablet is 11 mm x 6.6 mm in diameter and 3.9 – 4.5 mm in

thickness.

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.

Telefil is not indicated for use by women.

4.2

Posology and method of administration

Posology

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 Telefil (i.e., at least twice weekly) a once daily regimen

with the lowest doses of Telefil 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.

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

tadalafil is not recommended in patients with severe renal impairment (see sections 4.4 and 5.2)

Men with hepatic impairment

The recommended dose of Telefil 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 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 Telefil in the paediatric population with regard to the treatment of erectile

dysfunction.

Method of administration

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 Telefil to patients who are using any form of organic nitrate is

contraindicated (see section 4.5).

Telefil 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.

Telefil 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 Telefil

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

determine potential underlying causes, before pharmacological treatment is considered.

Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular

status of their patients, since there is a degree of cardiac risk associated with sexual activity. Tadalafil

has vasodilator properties, resulting in mild and transient decreases in blood pressure (see section 5.1)

and as such potentiates the hypotensive effect of nitrates (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 Telefil 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 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

Telefil, to sexual activity, or to a combination of these or other factors.

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 Telefil 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.

Hepatic 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). If Telefil 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.

Telefil 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 Telefil 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).

Telefil 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 Telefil in such

combinations.

Lactose

Telefil 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 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 Telefil 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 Telefil (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 Telefil 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 co-administered 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.

Antidiabetic medicinal products

Specific interaction studies with antidiabetic medicinal products were not conducted.

4.6

Fertility, pregnancy and lactation

Telefil 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 Telefil 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. Telefil 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 trials 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 list 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) 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

Very common

Common

Uncommon

Rare

occlusion

Ear and labyrinth disorders

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-oesophageal

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

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

Postmarketing surveillance reported adverse reactions not observed in placebo-controlled

clinical trials.

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 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 the national reporting system

listed in Appendix V.

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 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.

Erectile dysfunction

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 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 100 mg has been evaluated in 16 clinical studies involving 3250 patients,

including patients with erectile dysfunction of various severities (mild, moderate, severe), etiologies,

ages (range 21-86 years), and ethnicities. Most patients reported erectile dysfunction of at least 1 year

in duration. In the primary efficacy studies of general populations, 81 % of patients reported that

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.

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 with

tadalafil 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.

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). 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 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.

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, 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.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core:

lactose monohydrate,

pregelatinised starch,

colloidal anhydrous silica,

croscarmellose sodium,

sodium laurilsulfate,

magnesium stearate.

Film-coat:

hypromellose (E464),

lactose monohydrate,

titanium dioxide (E171),

triacetin,

talc (E553b),

iron oxide yellow (E172),

iron oxide red (E172).

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container

The tablets are packaged in PVC/PCTFE/Aluminium blisters.

4 film-coated tablets

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

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

requirements.

7.

MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

8.

MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<Date of first authorisation: {DD month YYYY}>

<Date of latest renewal: {DD month YYYY}>

<[To be completed nationally]>

10.

DATE OF REVISION OF THE TEXT

30 October 2017

<[To be completed nationally]>

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