Tadalafil Teva B.V. 2,5 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

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Bipacksedel Bipacksedel (PIL)

22-04-2018

Produktens egenskaper Produktens egenskaper (SPC)

22-04-2018

Aktiva substanser:
tadalafil
Tillgänglig från:
Teva BV
ATC-kod:
G04BE08
INN (International namn):
tadalafil
Dos:
2,5 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
natriumlaurilsulfat Hjälpämne; tadalafil 2,5 mg Aktiv substans; laktosmonohydrat Hjälpämne
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 4 tabletter; Blister, 28 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
52886
Tillstånd datum:
2017-02-17

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

23-10-2020

Produktens egenskaper Produktens egenskaper - engelska

23-10-2020

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

28-02-2017

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Package leaflet: Information for the user

Tadalafil Teva B.V. 2.5 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 Tadalafil Teva B.V. is and what it is used for

What you need to know before you take Tadalafil Teva B.V.

How to take Tadalafil Teva B.V.

Possible side effects

How to store Tadalafil Teva B.V.

Contents of the pack and other information

1.

What Tadalafil Teva B.V. is and what it is used for

Tadalafil Teva B.V. 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. Tadalafil Teva B.V. has been shown to significantly

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

Tadalafil Teva B.V. contains the active substance tadalafil which belongs to a group of medicines called

phosphodiesterase type 5 inhibitors. Following sexual stimulation Tadalafil Teva B.V. 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. Tadalafil Teva B.V. will not help you if you do not have erectile dysfunction.

It is important to note that Tadalafil Teva B.V. 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 Tadalafil Teva B.V.

Do not take Tadalafil Teva B.V.:

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

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”). Tadalafil Teva B.V.

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 Teva B.V., have been shown

Tadalafil, SE/H/1532/001, 22.06.20

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 Tadalafil Teva B.V.

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 Tadalafil Teva B.V. 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 Tadalafil Teva B.V. 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

Tadalafil Teva B.V. and contact your doctor immediately.

Tadalafil Teva B.V. is not intended for use by women.

Children and adolescents

Tadalafil Teva B.V. is not intended for use by children and adolescents under the age of 18.

Other medicines and Tadalafil Teva B.V.

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

Do not take Tadalafil Teva B.V. if you are already taking nitrates.

Some medicines may be affected by Tadalafil Teva B.V. or they may affect how well Tadalafil Teva B.V.

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.

Tadalafil Teva B.V. with drink and alcohol

Information on the effect of alcohol is in section 3. Grapefruit juice may affect how well Tadalafil Teva B.V.

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

Tadalafil, SE/H/1532/001, 22.06.20

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 Tadalafil Teva B.V. in clinical studies have reported dizziness. Check carefully how you

react to the tablets before driving or using machines.

Tadalafil Teva B.V. contains lactose and sodium

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

taking this medicine.

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

‘sodium-free’.

3.

How to take Tadalafil Teva B.V.

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

are not sure.

Tadalafil Teva B.V. 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 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 Tadalafil Teva B.V.. This will be given

as a 2.5 mg tablet.

Do not take Tadalafil Teva B.V. more than once a day.

Once a day dosing of Tadalafil Teva B.V. may be useful to men who anticipate having sexual activity two or

more times per week.

When taken once a day Tadalafil Teva B.V. allows you to obtain an erection, when sexually stimulated, at

any time point during the 24 hours of the day.

It is important to note that Tadalafil Teva B.V. 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 Tadalafil Teva B.V., 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 Tadalafil Teva B.V. than you should

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

If you forget to take Tadalafil Teva B.V.

Take your dose as soon as you remember. Do not take a double dose to make up for a forgotten tablet. You

should not take Tadalafil Teva B.V. 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

Tadalafil, SE/H/1532/001, 22.06.20

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 Tadalafil Teva B.V. (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 Tadalafil Teva B.V.. 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 Teva B.V. 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 Tadalafil

Teva B.V.. Diarrhoea has been reported more frequently in men over 65 years of age taking Tadalafil Teva

B.V..

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 Tadalafil Teva B.V.

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.

Tadalafil, SE/H/1532/001, 22.06.20

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 Tadalafil Teva B.V. contains

The active substance is tadalafil. Each tablet contains 2.5 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 Tadalafil Teva B.V. looks like and contents of the pack

Each tablet contains 2.5 mg tadalafil.

Tadalafil Teva B.V. 2.5 mg is a light yellow, oval shaped, film-coated tablet (tablet), debossed with “2.5” on

one side and plain on the other side. The tablet is 9 mm x 5.2 mm in diameter and 2.7 – 3.3 mm in thickness.

Pack sizes

Tadalafil Teva B.V. 2.5 mg is available in blister packs containing 4 and 28 tablets.

Not all pack sizes may be marketed

Marketing Authorisation Holder and 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

10/2020

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Tadalafil Teva B.V. 2.5 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2.5 mg tadalafil.

Excipient with known effect

Each film-coated tablet contains 84 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet (tablet).

2.5 mg film-coated tablets are: Light yellow, oval shape, film-coated tablets, debossed with “2.5” on one side

and plain on the other side. The tablet is 9 mm x 5.2 mm in diameter and 2.7 – 3.3 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.

Tadalafil Teva B.V. 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 Tadalafil Teva B.V. (i.e., at least twice weekly) a once daily

regimen with the lowest doses of Tadalafil Teva B.V. 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 Tadalafil Teva B.V. 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 Tadalafil Teva B.V. 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 Tadalafil Teva B.V. to patients who are using any form of organic nitrate is contraindicated

(see section 4.5).

Tadalafil Teva B.V. 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.

Tadalafil Teva B.V. 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 Teva B.V.

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

Tadalafil Teva B.V. 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 Tadalafil Teva B.V., 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 Teva B.V. 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 Teva B.V. 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 Teva B.V. 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 Teva B.V. 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 Teva B.V. 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 Teva B.V.

in such combinations.

Excipients

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose

malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say

essentially ‘sodium-free’.

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

. 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 Teva B.V. 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 Teva B.V. (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 Teva B.V. 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

Tadalafil Teva B.V. 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 Teva

B.V. 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 Teva B.V. 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 or use machines. Although the frequency of reports

of dizziness in placebo and tadalafil arms in clinical trials was similar, patients should be aware of how they

react to tadalafil, before driving or using machines.

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 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

occlusion

Ear and labyrinth disorders

Tinnitus

Sudden hearing loss

Cardiac disorders

1

Tachycardia,

Myocardial infarction,

Very common

Common

Uncommon

Rare

palpitations

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, connective tissue and bone disorders

Back pain, myalgia,

pain in extremity

Renal and urinary disorders

Haematuria

Reproductive system and breast disorders

Prolonged erections

Priapism, Penile

haemorrhage,

Haematospermia

General disorders and administration site conditions

Chest 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

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

responsiveness to tadalafil on demand. Tadalafil demonstrated statistically significant improvement in

erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as

well as patients’ ability to attain and maintain erections for successful intercourse compared to placebo as

early as 16 minutes following dosing.

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.

Tadalafil at doses of 2.5, 5, and 10 mg taken once a day was initially evaluated in 3 clinical studies 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 randomized 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.

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.

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).

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 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 and 28 film-coated tablets

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special 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

[To be completed nationally]

10.

DATE OF REVISION OF THE TEXT

[To be completed nationally]

10/2020

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