Package leaflet: Information for the user

YENTREVE 40 mg gastro-resistant hard capsules, 20 mg gastro-resistant hard capsules

duloxetine (as hydrochloride)
Please 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 questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not give it to others, even if they have the same symptoms as yours, because it could be harmful.
If you experience any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist.

Contents of this leaflet:

What YENTREVE is and what it is used for
What you need to know before taking YENTREVE
How to take YENTREVE
Possible side effects
How to store YENTREVE
Contents of the pack and other information

1. What YENTREVE is and what it is used for

YENTREVE contains the active substance duloxetine. YENTREVE increases the levels of serotonin and
noradrenaline in the nervous system.
YENTREVE is a medicine taken by mouth to treat Stress Urinary Incontinence (SUI) in women.
Stress urinary incontinence is a medical condition in which patients experience involuntary loss or
leakage of urine during physical exertion or activities such as laughing, coughing, sneezing,
lifting weights, or exercising.
YENTREVE is thought to work by increasing the strength of the muscles that control urine retention
when you laugh, sneeze, or engage in physical activities.
The effectiveness of YENTREVE is enhanced when combined with an exercise programme known as
Pelvic Floor Muscle Training (PFMT).

2. What you need to know before taking YENTREVE

Do NOT take YENTREVE if you

are allergic to duloxetine or to any of the other ingredients of this medicine (listed in section 6)
have liver disease
have severe kidney disease
are taking or have taken within the last 14 days another medicine known as a Monoamine Oxidase Inhibitor (MAOI) (see ‘Other medicines and YENTREVE’)
are taking fluvoxamine, which is commonly used to treat depression, or ciprofloxacin or enoxacin, which are used to treat certain infections.

Tell your doctor if you have high blood pressure or heart disease. Your doctor will advise you whether you can take YENTREVE.
Warnings and precautions
Reasons why YENTREVE may not be suitable for you include the following. Talk to your doctor before taking YENTREVE if:

you are taking medicines to treat depression (see ‘Other medicines and YENTREVE’)
you are taking St. John’s Wort (Hypericum perforatum), a herbal preparation
you have kidney disease
you have a history of seizures (epileptic fits)
you have experienced mania
you suffer from bipolar disorder
you have eye problems, such as certain types of glaucoma (increased pressure inside the eye)
you have a history of bleeding disorders (tendency to bruise easily), especially if you are pregnant (see “Pregnancy and breastfeeding”)
you are at risk of low sodium levels (e.g. if you are taking diuretics, particularly if you are elderly)
you are being treated with another medicine that may cause liver damage
you are taking other medicines containing duloxetine (see ‘Other medicines and YENTREVE’)

YENTREVE may cause a feeling of restlessness or inability to sit still. If this happens to you, inform your doctor.
You should also contact your doctor if you experience signs and symptoms such as restlessness, hallucinations, loss of coordination, rapid heartbeat, elevated body temperature, rapid changes in blood pressure, hyperactive reflexes, diarrhoea, coma, nausea, or vomiting, as you may be suffering from serotonin syndrome.
In its most severe form, serotonin syndrome may resemble neuroleptic malignant syndrome (NMS). Signs and symptoms of NMS may include a combination of fever, rapid heartbeat, sweating, severe muscle rigidity, confusion, and increased muscle enzymes (detected by a blood test).
Medicines such as YENTREVE (so-called selective serotonin and serotonin-noradrenaline reuptake inhibitors, SSRIs and SNRIs) may cause symptoms of sexual dysfunction (see section 4). In some cases, these symptoms have persisted after discontinuation of treatment.
Suicidal thoughts and worsening of depression and anxiety disorder
Although YENTREVE is not indicated for the treatment of depression, its active ingredient (duloxetine) is used as an antidepressant medicine. If you are depressed and/or have anxiety disorders, you may occasionally have thoughts of harming yourself or committing suicide. These thoughts may increase when you first start treatment with antidepressants, as these medicines require some time to become effective, usually about 2 weeks but sometimes longer.
You may be more likely to have such thoughts if you:

have previously had thoughts of suicide or self-harm
are a young adult. Clinical study data have shown an increased risk of suicidal behaviour in adults under 25 years of age with psychiatric disorders who were treated with an antidepressant.

If at any time you have thoughts of harming yourself or committing suicide, contact your doctor or go to hospital immediately.
You may find it helpful to tell a relative or close friend that you are depressed or have an anxiety disorder, and ask them to read this leaflet. You may wish to ask them to inform you if they think your depression or anxiety is worsening, or if they are concerned about changes in your behaviour.
Children and adolescents under 18 years of age
YENTREVE must not be used in children and adolescents under 18 years of age. Furthermore, you should know that patients under 18 years of age who take this type of medicine have an increased risk of adverse effects such as suicide attempts, suicidal thoughts, and hostility (particularly aggressive behaviour, oppositional behaviour, and anger). In addition, the long-term effects of YENTREVE on growth, maturation, and cognitive and behavioural development have not yet been established in this age group.
Other medicines and YENTREVE
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those without a prescription.
The main component of YENTREVE, duloxetine, is found in other medicines for other conditions:

diabetic neuropathic pain, depression, anxiety, and urinary incontinence.
The simultaneous use of more than one of these medicines must be avoided. Check with your doctor if you are already taking medicines containing duloxetine.

Your doctor must decide whether you can take YENTREVE together with other medicines. Do not start or stop taking any medicine, including those bought without a prescription and herbal preparations, before consulting your doctor.
Also inform your doctor if you are taking any of the following medicines:
Monoamine Oxidase Inhibitors (MAOIs): You must not take YENTREVE if you are currently taking, or have recently taken (within the last 14 days) an antidepressant medicine called a monoamine oxidase inhibitor (MAOI). Examples of MAOI medicines include moclobemide (an antidepressant) and linezolid (an antibiotic). Taking an MAOI together with many prescription medicines, including YENTREVE, may cause serious or even life-threatening side effects. You must wait at least 14 days after stopping an MAOI before starting YENTREVE. In addition, you must wait at least 5 days after stopping YENTREVE before starting an MAOI.
Medicines that cause drowsiness: These include prescription medicines such as benzodiazepines, strong painkillers, antipsychotics, phenobarbital, and sedating antihistamines.
Medicines that increase serotonin levels: Triptans, tramadol, tryptophan, Selective Serotonin Reuptake Inhibitors (SSRIs) (such as paroxetine and fluoxetine), Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs) (such as venlafaxine), tricyclic antidepressants (such as clomipramine, amitriptyline), meperidine, St. John’s Wort (hypericum), and MAOIs (such as moclobemide and linezolid). These medicines increase the risk of side effects; if you experience any unusual symptoms while taking one of these medicines together with YENTREVE, you must consult your doctor.
Oral anticoagulants and antiplatelet agents: Medicines that thin the blood or prevent blood clots. These medicines may increase the risk of bleeding.
YENTREVE with food, drinks and alcohol
YENTREVE can be taken regardless of meals. You should be particularly cautious if you drink alcohol while taking YENTREVE.
Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, ask your doctor or pharmacist for advice before taking this medicine.

Inform your doctor if you become pregnant or are planning to become pregnant while taking YENTREVE. You should use YENTREVE only after discussing with your doctor the potential benefits and any possible risks to the unborn child.
Make sure your midwife and/or doctor knows that you are being treated with YENTREVE. When taken during pregnancy, similar medicines (SSRIs) may increase the risk of a serious condition in newborns called persistent pulmonary hypertension of the newborn (PPHN), which causes the baby to breathe rapidly and appear bluish. These symptoms usually occur within the first 24 hours after birth. If this happens to your newborn, contact your midwife or doctor immediately.
If you take YENTREVE near the end of pregnancy, the newborn may show some symptoms shortly after birth. These usually appear at birth or within a few days after birth. These symptoms may include floppy muscles, tremors, irritability, feeding difficulties, breathing problems, and seizures. If your newborn shows any of these symptoms after birth, or if you are concerned about your baby’s health, contact your doctor or midwife, who will be able to advise you.
If you take YENTREVE near the end of your pregnancy, there is an increased risk of excessive vaginal bleeding immediately after delivery, especially if you have a history of bleeding disorders. Your doctor or midwife should be informed that you are taking duloxetine so they can advise you.
Available data on the use of YENTREVE during the first three months of pregnancy do not show an overall increased risk of birth defects in the child. If YENTREVE is taken during the second half of pregnancy, there may be an increased risk that the baby will be born prematurely (6 additional premature births per 100 women taking YENTREVE in the second half of pregnancy), mostly between weeks 35 and 36 of pregnancy.
Inform your doctor if you are breastfeeding. The use of YENTREVE during breastfeeding is not recommended. Ask your doctor or pharmacist for advice.

Driving and using machines
YENTREVE may cause drowsiness or dizziness. Do not drive or operate tools or machinery until you know how YENTREVE affects you.
YENTREVE contains sucrose
YENTREVE contains sucrose. If your doctor has told you that you have an intolerance to certain sugars, contact him or her before taking this medicine.
YENTREVE contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per capsule, i.e. essentially ‘sodium-free’.

3. How to take YENTREVE

Take this medicine exactly as directed by your doctor or pharmacist. If
you have any doubts, consult your doctor or pharmacist.
YENTREVE is taken orally. Swallow the capsule without chewing, with a
glass of water.
The recommended dose of YENTREVE is 40 mg twice daily (in the morning and late afternoon
or evening). Your doctor may decide to start treatment with 20 mg twice daily for two
weeks before increasing the dose to 40 mg twice daily.
To help you remember to take YENTREVE, it may be easier to take it at the
same time each day.
Do not stop taking YENTREVE, or change the dose, without first discussing it with your doctor.
Appropriate treatment of the disorder is important to help you feel better. If left untreated, the
condition may not improve and may become worse and more difficult to treat.
If you take more YENTREVE than you should
Contact your doctor or pharmacist immediately if you have taken more YENTREVE
than prescribed. Symptoms of overdose include
drowsiness, coma, serotonin syndrome (a rare reaction that may cause feelings of extreme well-being, drowsiness, clumsiness, restlessness, feeling drunk, fever, sweating,
or muscle stiffness), seizures, vomiting, and rapid heartbeat.
If you forget to take YENTREVE
If you miss a dose, take it as soon as you remember. However, if it is almost time for your next
dose, skip the missed dose and take only your next single dose as usual. Do not take a double
dose to make up for a missed dose. Do not take more than the amount of
YENTREVE prescribed for one day.
If you stop taking YENTREVE
Even if you feel better, DO NOT stop taking the capsules without consulting your
doctor. If your doctor decides you no longer need YENTREVE, they will instruct you to gradually reduce the dose over a period of 2 weeks.
Some patients who stop taking YENTREVE suddenly after more than
1 week of treatment have experienced symptoms such as:

dizziness, tingling sensations like pins and needles or electric shock sensations (particularly in the head), sleep disturbances (vivid dreams, nightmares, inability to sleep), fatigue, drowsiness, feeling restless or agitated, feeling anxious, nausea or feeling unwell (vomiting), unsteadiness (tremor), headache, muscle pain, feeling irritable, diarrhoea, excessive sweating, or vertigo. These symptoms are usually not severe and disappear within a few days, but if you experience bothersome symptoms, you should consult your doctor.

If you have any questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them. Usually these effects are mild to moderate and often disappear after a short time.

Very common side effects (may affect more than 1 in 10 people)

feeling unwell (nausea), dry mouth, constipation
tiredness

Common side effects (may affect up to 1 in 10 people)

loss of appetite
difficulty falling asleep, feeling restless, reduced sexual desire, anxiety, trouble getting to sleep
headache, dizziness, feeling sluggish, drowsiness, tremor, numbness, including a sensation of tingling, prickling, or pins and needles in the skin
blurred vision
feeling dizzy or of "spinning" (vertigo)
increased blood pressure, hot flush
diarrhoea, stomach ache, retching (vomiting), heartburn or indigestion
increased sweating
weakness, trembling

Uncommon side effects (may affect up to 1 in 100 people)

inflammation of the throat causing hoarseness
allergic reactions
reduced activity of the thyroid gland which may cause tiredness or weight gain
dehydration
grinding or forcefully clenching teeth, feeling disoriented, lack of motivation, difficulty or inability to reach orgasm, unusual dreams
feeling nervous, difficulty concentrating, changes in taste sensation, poor quality of sleep
dilation of the pupils (the dark centre of the eye), visual disturbances, dry eyes
tinnitus (perception of sound in the ear in the absence of external auditory stimuli), ear pain
awareness of heartbeat in the chest, accelerated or irregular heartbeat
fainting
increased yawning
vomiting blood, or passing black, tar-like stools, gastroenteritis, inflammation of the mouth, belching, difficulty swallowing, gas accumulation in the intestine, bad breath
liver inflammation which may cause abdominal pain and yellowing of the skin or whites of the eyes
skin rash (with itching), night sweats, hives, cold sweats, increased tendency to bruise
muscle pain, muscle stiffness, muscle spasm, contraction of the muscles of the mouth
difficulty starting urination, painful urination, need to urinate during the night, frequent urination, altered odour of urine
abnormal vaginal bleeding, menopausal symptoms
chest pain, feeling cold, thirst, feeling hot
weight loss, weight gain
YENTREVE may cause effects you may not be aware of, such as increases in liver enzymes or blood levels of potassium, creatine phosphokinase, blood sugar, or cholesterol

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

severe allergic reaction causing breathing difficulties or dizziness with swelling of the tongue and lips
low levels of sodium in the blood (especially in elderly people; symptoms may include dizziness, feeling weak, confused, drowsy, or very tired, or having nausea or feeling like vomiting; more severe symptoms include loss of consciousness, seizures, or falls), syndrome of inappropriate antidiuretic hormone secretion (SIADH)
suicidal behaviour, suicidal thoughts, mania (hyperactivity, racing thoughts, reduced need for sleep), hallucinations, aggressive behaviour and anger
"Serotonin syndrome" (a rare reaction which may cause feelings of extreme well-being, drowsiness, clumsiness, restlessness, feeling drunk, fever, sweating, or muscle rigidity), seizures, sudden and involuntary muscle spasms or contractions, feeling restless or unable to sit still or remain still, difficulty controlling movements such as lack of coordination or involuntary muscle movements, restless legs syndrome
increased pressure inside the eye (glaucoma)
dizziness, feeling of emptiness in the head or impending faint when standing, cold sensation in fingers of hands and/or feet
tightness in the throat, nosebleeds
cough, wheezing and shortness of breath possibly accompanied by fever
presence of bright red blood in stools, inflammation of the large intestine (colon) (causing diarrhoea)
liver failure, yellowing of the skin or whites of the eyes (jaundice)
Stevens-Johnson syndrome (a serious illness with blistering of the skin, mouth, eyes and genitals), severe allergic reaction causing swelling of the face and throat (angioedema), sensitivity to sunlight
muscle contraction
difficulty or inability to urinate, need to urinate more than normal, reduced urinary flow
abnormal menstrual cycles, including heavy, painful, irregular or prolonged periods, unusually light or absent periods, abnormal production of breast milk
excessive vaginal bleeding immediately after childbirth (post-partum haemorrhage)
falls (especially in elderly people), abnormal gait

Very rare side effects (may affect up to 1 in 10,000 people)

inflammation of blood vessels in the skin (cutaneous vasculitis)

Frequency not known (cannot be estimated from the available data)

signs and symptoms of a condition called "stress cardiomyopathy" which may include chest pain, shortness of breath, dizziness, fainting, and irregular heartbeat.

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store YENTREVE

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the pack.
Store in the original packaging to protect from moisture. Do not store above 30 °C.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What YENTREVE contains
The active substance is duloxetine.
Each capsule contains 20 or 40 mg of duloxetine (as hydrochloride).
The other components are:
Capsule contents: hypromellose, hypromellose acetate succinate, sucrose, sugar spheres,
talc, titanium dioxide (E171), triethyl citrate.
(See end of section 2 for further information on sucrose).
Capsule shell: gelatin, sodium lauryl sulfate, titanium dioxide (E171), indigo carmine
(E132), red iron oxide and yellow iron oxide, edible black ink.
Edible ink: synthetic black iron oxide (E172), propylene glycol, shellac.

Description of the appearance of YENTREVE and contents of the pack
YENTREVE is a gastro-resistant hard capsule.
Each YENTREVE capsule contains duloxetine hydrochloride granules with a coating designed
to protect them from the acidity of the stomach.
YENTREVE is available in two strengths: 20 and 40 mg.
The 40 mg capsules are orange and blue, marked with '40 mg' and the code '9545'.
The 20 mg capsules are blue, marked with '20 mg' and the code '9544'.
YENTREVE 40 mg is available in packs of 28, 56, 98, 140 and 196 capsules (2 x 98).
YENTREVE 20 mg is available in packs of 28, 56 and 98 capsules.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands.
Manufacturer: Lilly S.A., Avda. De la Industria 30, 28108 Alcobendas, Madrid, Spain.

For further information on this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
Eli Lilly Benelux S.A./N.V. Eli Lilly Lietuva
Tél/Tel: + 32-(0)2 548 84 84 Tel. +370 (5) 2649600

България Luxembourg/Luxemburg
ТП "Ели Лили Недерланд" Б.В. - България Eli Lilly Benelux S.A./N.V.
тел. + 359 2 491 41 40 Tél/Tel: + 32-(0)2 548 84 84

Česká republika Magyarország
Eli Lilly ČR, s.r.o. Lilly Hungária Kft.
Tel: + 420 234 664 111 Tel: + 36 1 328 5100

Danmark Malta
Eli Lilly Danmark A/S Charles de Giorgio Ltd.
Tlf: +45 45 26 60 00 Tel: + 356 25600 500

Deutschland Nederland
Lilly Deutschland GmbH Eli Lilly Nederland B.V.
Tel. + 49-(0) 6172 273 2222 Tel: + 31-(0) 30 60 25 800

Eesti Norge
Eli Lilly Nederland B.V Eli Lilly Norge A.S
Tel: + 372 6 817 280 Tlf: +47 22 88 18 00

Ελλάδα Österreich
ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.B.E. Eli Lilly Ges.m.b.H.
Τηλ: +30 210 629 4600 Tel: + 43-(0) 1 711 780

España Polska
Spaly Bioquímica, S.A. Eli Lilly Polska Sp. z o.o.
Tel: + 34-91-663 50 00 Tel: +48 22 440 33 00

France Portugal
Lilly France Lilly Portugal - Produtos Farmacêuticos, Lda
Tél: +33-(0) 1 55 49 34 34 Tel: + 351 21-4126600

Hrvatska România
Eli Lilly Hrvatska d.o.o. Eli Lilly România S.R.L.
Tel: +385 1 2350 999 Tel: + 40 21 4023000

Ireland Slovenija
Eli Lilly and Company (Ireland) Limited Eli Lilly farmacevtska družba, d.o.o.
Tel: +353-(0) 1 661 4377 Tel: +386 (0)1 580 00 10

Ísland Slovenská republika
Icepharma hf. Eli Lilly Slovakia s.r.o.
Sími + 354 540 8000 Tel: + 421 220 663 111

Italia Suomi/Finland
Eli Lilly Italia S.p.A. Oy Eli Lilly Finland Ab
Tel: + 39- 055 42571 Puh/Tel: +358-(0) 9 85 45 250

Κύπρος Sverige
Phadisco Ltd Eli Lilly Sweden AB
Τηλ: +357 22 715000 Tel: + 46-(0)8 7378800

Latvija United Kingdom (Northern Ireland)
Eli Lilly (Suisse) S.A Pārstāvniecība Latvijā Eli Lilly and Company (Ireland) Limited
Tel: + 371 67364000 Tel: + 353-(0) 1 661 4377

More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION

Scientific conclusions
Taking into account the assessment by the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Report (PSUR) for duloxetine, the PRAC's scientific conclusions are as follows:
In view of available literature data on neuroleptic malignant syndrome (NMS) and stress cardiomyopathy (Takotsubo cardiomyopathy), including spontaneous reports with, in some cases, a close temporal relationship, a positive de-challenge and/or re-challenge, and considering the plausible mechanism of action, the PRAC considers that a causal relationship between duloxetine and NMS and stress cardiomyopathy (Takotsubo cardiomyopathy) is at least a reasonable possibility. The PRAC concluded that the product information for medicinal products containing duloxetine should be amended accordingly.

Having reviewed the PRAC's recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the general conclusions and the rationale of the recommendation.

Grounds for the variation to the terms of the marketing authorisation
Based on the scientific conclusions regarding duloxetine, the CHMP considers that the benefit-risk balance of the medicinal product containing duloxetine remains unchanged, subject to the proposed amendments to the product information.
The CHMP recommends a variation to the terms of the marketing authorisation.

Yentreve