Tadalafil Sigillata 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:
Zentiva k.s.
ATC-kod:
G04BE08
INN (International namn):
tadalafil
Dos:
5 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
tadalafil 5 mg Aktiv substans; natriumlaurilsulfat Hjälpämne; laktosmonohydrat Hjälpämne
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 14 tabletter; Blister, 28 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
55203
Tillstånd datum:
2017-07-13

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

27-11-2020

Produktens egenskaper Produktens egenskaper - engelska

27-11-2020

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

13-07-2017

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Package leaflet: Information for the user

Tadalafil Sigillata 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 Sigillata is and what it is used for

What you need to know before you take Tadalafil Sigillata

How to take Tadalafil Sigillata

Possible side effects

How to store Tadalafil Sigillata

Contents of the pack and other information

1.

What Tadalafil Sigillata is and what it is used for

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

phosphodiesterase type 5 inhibitors.

Tadalafil Sigillata 5 mg is used to treat adult men with:

erectile dysfunction

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

sexual activity. Tadalafil has been shown to significantly improve the ability of obtaining a hard

erect penis suitable for sexual activity. Following sexual stimulation tadalafil 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 will not help you if you do not have erectile

dysfunction. It is important to note that tadalafil for the treatment of erectile dysfunction does

not work if there is no sexual stimulation. You and your partner will need to engage in foreplay,

just as you would if you were not taking a medicine for erectile dysfunction.

urinary symptoms associated with a common condition called

benign prostatic hyperplasia

This is when the prostate gland gets bigger with age. Symptoms include difficulty in starting to

pass water, a feeling of not completely emptying the bladder and a more frequent need to pass

water even at night. Tadalafil improves blood flow to, and relaxes the muscles of, the prostate

and bladder which may reduce symptoms of benign prostatic hyperplasia. Tadalafil has been

shown to improve these urinary symptoms as early as 1-2 weeks after starting treatment.

2.

What you need to know before you take Tadalafil Sigillata

Do not take Tadalafil Sigillata:

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”). Tadalafil

Sigillata 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 Tadalafil Sigillata

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.

Since benign prostatic hyperplasia and prostatic cancer may have the same symptoms, your doctor will

check you for prostate cancer before starting treatment with Tadalafil Sigillata for benign prostatic

hyperplasia. Tadalafil Sigillata does not treat prostate cancer.

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 Sigillata 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 Sigillata 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 Sigillata and contact your doctor immediately.

Tadalafil Sigillata is not intended for use by women.

Children and adolescents

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

Other medicines and Tadalafil Sigillata

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

medicines.

Do not take Tadalafil Sigillata if you are already taking nitrates.

Some medicines may be affected by Tadalafil Sigillata or they may affect how well Tadalafil Sigillata

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 Sigillata with food, drink and alcohol

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

Sigillata 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 Tadalafil Sigillata in clinical studies have reported dizziness. Check carefully how

you react to the tablets before driving or using machines.

Tadalafil Sigillata 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 Sigillata

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

if you are not sure.

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

tablets can be taken with or without food.

Drinking alcohol may temporarily lower your blood pressure. If you have taken or are planning to take

Tadalafil Sigillata, avoid excessive drinking (blood alcohol level of 0.08% or greater), since this may

increase the risk of dizziness when standing up.

For the treatment of erectile dysfunction

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 Sigillata. This will

be given as a 2.5 mg tablet.

Do not take Tadalafil Sigillata more than once a day.

When taken once a day Tadalafil Sigillata allows you to obtain an erection, once sexually stimulated,

at any time point during the 24 hours of the day. Once a day dosing of Tadalafil Sigillata may be

useful to men who anticipate having sexual activity two or more times per week.

It is important to note that Tadalafil Sigillata 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.

For the treatment of benign prostatic hyperplasia

The dose is one 5 mg tablet taken once a day at approximately the same time of the day. If you have

benign prostatic hyperplasia and erectile dysfunction, the dose remains one 5 mg tablet taken once a

day.

Do not take Tadalafil Sigillata more than once a day.

If you take more Tadalafil Sigillata than you should

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

If you forget to take Tadalafil Sigillata

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 Sigillata more than once a day.

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

4.

Possible side effects

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

effects are normally mild to moderate in nature.

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

immediately:

allergic reactions including rashes (frequency uncommon).

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

priapism, a prolonged and possibly painful erection after taking Tadalafil Sigillata (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 Sigillata. 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 Sigillata 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 Sigillata. Diarrhoea has been reported more frequently in men over 65 years of age taking

Tadalafil Sigillata.

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 Sigillata

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 Tadalafil Sigillata contains

The active substance is tadalafil. Each tablet contains 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 Sigillata looks like and contents of the pack

Tadalafil Sigillata 5 mg is a pale yellow, oval shaped, film-coated tablet (tablet), debossed with “5” on

one side and plain on the other side. The tablet is 10 mm x 6.0 mm in diameter and 3.3 – 3.9 mm in

thickness.

Pack sizes

Tadalafil Sigillata 5 mg is available in blister packs containing 14, 28 tablets.

Not all pack sizes may be marketed

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Sigillata Limited

Fourth Floor

20 Margaret Street

W1W 8 RS London

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

2020-11-26

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SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

Tadalafil Sigillata 5 mg film-coated tablets.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 5 mg tadalafil.

Excipient with known effect:

Each coated tablet contains 123 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet (tablet).

5 mg film-coated tablets are: Pale yellow, oval shape, film-coated tablets, debossed with “5” on one side

and plain on the other side. The tablet is 10 mm x 6.0 mm in diameter and 3.3 – 3.9 mm in thickness.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of erectile dysfunction in adult males.

In order for tadalafil to be effective, for the treatment of erectile dysfunction sexual stimulation is

required.

Treatment of the signs and symptoms of benign prostatic hyperplasia in adult males.

Tadalafil Sigillata is not indicated for use by women.

4.2

Posology and method of administration

Posology

Erectile dysfunction in adult men

In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or

without food.

In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried.

It may be taken at least 30 minutes prior to sexual activity.

The maximum dose frequency is once per day.

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

recommended for continuous daily use.

In patients who anticipate a frequent use of Tadalafil Sigillata (i.e., at least twice weekly) a once daily

regimen with the lowest doses of Tadalafil Sigillata 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.

Benign prostatic hyperplasia in adult men

The recommended dose is 5 mg, taken at approximately the same time every day with or without food.

For adult men being treated for both benign prostatic hyperplasia and erectile dysfunction the

recommended dose is also 5 mg taken at approximately the same time every day. Patients who are

unable to tolerate tadalafil 5 mg for the treatment of benign prostatic hyperplasia should consider an

alternative therapy as the efficacy of tadalafil 2.5 mg for the treatment of benign prostatic hyperplasia

has not been demonstrated.

Special populations

Elderly men

Dose adjustments are not required in elderly patients.

Men with renal impairment

Dose adjustments are not required in patients with mild to moderate renal impairment. For patients

with severe renal impairment 10 mg is the maximum recommended dose for on-demand treatment.

Once a day dosing of 2.5 or 5 mg tadalafil for both the treatment of erectile dysfunction or benign

prostatic hyperplasia is not recommended in patients with severe renal impairment (see sections 4.4

and 5.2).

Men with hepatic impairment

For the treatment of erectile dysfunction using on-demand Tadalafil Sigillata the recommended dose

of Tadalafil Sigillata is 10 mg taken prior to anticipated sexual activity and with or without food.

There is limited clinical data on the safety of tadalafil in patients with severe hepatic impairment

(Child-Pugh Class C); if prescribed, a careful individual benefit/risk evaluation should be undertaken

by the prescribing physician. There are no available data about the administration of doses higher than

10 mg of tadalafil to patients with hepatic impairment.

Once-a-day dosing of tadalafil both for the treatment of erectile dysfunction and benign prostatic

hyperplasia has not been evaluated in patients with hepatic impairment; therefore, if prescribed, a

careful individual benefit/risk evaluation should be undertaken by the prescribing physician (see

sections 4.4 and 5.2).

Men with diabetes

Dose adjustments are not required in diabetic patients.

Paediatric population

There is no relevant use of Tadalafil Sigillata 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 Sigillata to patients who are using any form of organic nitrate is

contraindicated (see section 4.5).

Tadalafil Sigillata 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 Sigillata 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 Sigillata

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

benign prostatic hyperplasia and determine potential underlying causes, before pharmacological

treatment is considered.

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

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

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

and as such potentiates the hypotensive effect of nitrates (see section 4.3).

Prior to initiating treatment with tadalafil for benign prostatic hyperplasia patients should be examined

to rule out the presence of carcinoma of the prostate and carefully assessed for cardiovascular

conditions (see section 4.3).

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 Sigillata 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 Sigillata, 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 Sigillata 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 are 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 either for the treatment

of erectile dysfunction or benign prostatic hyperplasia has not been evaluated in patients with hepatic

insufficiency. If Tadalafil Sigillata 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 Sigillata 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 Sigillata 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 Sigillata 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

Sigillata in such combinations.

Lactose

Tadalafil Sigillata contains lactose. Patients with rare hereditary problems of galactose intolerance,

total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

This medicine 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 C

. Although specific interactions have not been studied, other

protease inhibitors, such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin,

clarithromycin, itraconazole and grapefruit juice should be co-administered with caution as they would

be expected to increase plasma concentrations of tadalafil (see section 4.4). Consequently the

incidence of the adverse reactions listed in section 4.8 might be increased.

Transporters

The role of transporters (for example p-glycoprotein) in the disposition of tadalafil is not known.

Therefore there is the potential of drug interactions mediated by inhibition of transporters.

Cytochrome P450 inducers

A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88 %, relative to the AUC values for

tadalafil alone (10 mg). This reduced exposure can be anticipated to decrease the efficacy of tadalafil;

the magnitude of decreased efficacy is unknown. Other inducers of CYP3A4 such as phenobarbital,

phenytoin and carbamazepine, may also decrease plasma concentrations of tadalafil.

Effects of tadalafil on other medicinal products

Nitrates

In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of

nitrates. Therefore, administration of Tadalafil Sigillata 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

Sigillata (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 Sigillata

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 Sigillata 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 Sigillata 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 Sigillata 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.

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,

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

Very common

Common

Uncommon

Rare

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 treatment of erectile dysfunction in the absence of sexual

stimulation.

The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum is also observed in

the smooth muscle of the prostate, the bladder and their vascular supply. The resulting vascular

relaxation increases blood perfusion which may be the mechanism by which symptoms of benign

prostatic hyperplasia are reduced. These vascular effects may be complemented by inhibition of

bladder afferent nerve activity and smooth muscle relaxation of the prostate and bladder

Pharmacodynamic effects

Studies

in vitro

have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in

corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets,

kidney, lung, and cerebellum. The effect of tadalafil is more potent on PDE5 than on other

phosphodiesterases. Tadalafil is > 10,000-fold more potent for PDE5 than for PDE1, PDE2 and PDE4

enzymes which are found in the heart, brain, blood vessels, liver, and other organs. Tadalafil

is > 10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood

vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in

cardiac contractility. Additionally, tadalafil is approximately 700-fold more potent for PDE5 than for

PDE6, an enzyme which is found in the retina and is responsible for phototransduction. Tadalafil is

also > 10,000-fold more potent for PDE5 than for PDE7 through PDE10.

Clinical efficacy and safety

Tadalafil administered to healthy subjects produced no significant difference compared to placebo in

supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8 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

For tadalafil on demand, 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.

For once-a-day evaluation of tadalafil at doses of 2.5, 5, and 10 mg 3 clinical studies were initially

conducted involving 853 patients of various ages (range 21-82 years) and ethnicities, with erectile

dysfunction of various severities (mild, moderate, severe) and etiologies. In the two primary efficacy

studies of general populations, the mean per-subject proportion of successful intercourse attempts

were 57 and 67 % on tadalafil 5 mg, 50 % on tadalafil 2.5 mg as compared to 31 and 37 % with

placebo. In the study in patients with erectile dysfunction secondary to diabetes, the mean per-subject

proportion of successful attempts were 41 and 46 % on tadalafil 5 mg and 2.5 mg, respectively, as

compared to 28 % with placebo. Most patients in these three studies were responders to previous

on-demand treatment with PDE5 inhibitors. In a subsequent study, 217 patients who were

treatment-naïve to PDE5 inhibitors were 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.

Benign prostatic hyperplasia

Tadalafil was studied in 4 clinical studies of 12 weeks duration enrolling over 1500 patients with signs

and symptoms of benign prostatic hyperplasia. The improvement in the total international prostate

symptom score with tadalafil 5 mg in the four studies were -4.8, -5.6, -6.1 and -6.3 compared to -2.2, -

3.6, -3.8 and -4.2 with placebo. The improvements in total international prostate symptom score

occurred as early as 1 week. In one of the studies, which also included tamsulosin 0.4 mg as an active

comparator, the improvement in total international prostate symptom score with tadalafil 5 mg,

tamsulosin and placebo were -6.3, -5.7 and -4.2 respectively.

One of these studies assessed improvements in erectile dysfunction and signs and symptoms of benign

prostatic hyperplasia in patients with both conditions. The improvements in the erectile function

domain of the international index of erectile function and the total international prostate symptom

score in this study were 6.5 and -6.1 with tadalafil 5 mg compared to 1.8 and -3.8 with placebo,

respectively. The mean per-subject proportion of successful sexual intercourse attempts was 71.9 %

with tadalafil 5 mg compared to 48.3 % with placebo.

The maintenance of the effect was evaluated in an open-label extension to one of the studies, which

showed that the improvement in total international prostate symptom score seen at 12 weeks was

maintained for up to 1 additional year of treatment with tadalafil 5 mg.

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, 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.

Nature and contents of container

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

14, 28 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

Sigillata Limited

Fourth Floor

20 Margaret Street

W1W 8 RS London

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

2020-11-26

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