Package leaflet: Information for the user

CYMBALTA 30 mg gastro-resistant hard capsules, 60 mg gastro-resistant hard capsules

duloxetine (as hydrochloride)
Read this leaflet carefully before 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 pass it on to other people, even if their symptoms are the same as yours, because it may be harmful.
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What Cymbalta is and what it is used for

Cymbalta contains the active substance duloxetine. Cymbalta increases the levels of serotonin and
noradrenaline in the nervous system.
Cymbalta is used in adults to treat:

depression
generalized anxiety disorder (chronic feelings of anxiety or nervousness)
diabetic neuropathic pain (often described as burning, sharp, stabbing, shooting, or crushing, or as an electric shock. The affected area may have reduced sensation, or sensations where touch, heat, cold or pressure can cause pain)

Cymbalta begins to be effective in most people with depression or anxiety within
two weeks of starting treatment, but it may take 2–4 weeks before you start to
feel better. Speak to your doctor if you do not start to feel better after this time. Your doctor may
continue to give you Cymbalta once you feel better to prevent depression or anxiety
from returning.
In people with diabetic neuropathic pain, it may take several weeks before you
start to feel better. Inform your doctor if you do not feel better after 2 months.

2. What you should know before taking Cymbalta

Do not take Cymbalta if you

are allergic to duloxetine or 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 Cymbalta’)
are taking fluvoxamine, which is commonly used to treat depression, or ciprofloxacin or enoxacin, which are used to treat certain infections
are taking other medicines containing duloxetine (see ‘Other medicines and Cymbalta’)
Tell your doctor if you have high blood pressure or heart disease. Your doctor will advise whether you can take Cymbalta.

Warnings and precautions
Reasons why Cymbalta may not be suitable for you include the following. Talk to your doctor before
taking Cymbalta if:

you are taking other medicines to treat depression (see ‘Other medicines and Cymbalta’)
you are taking St. John’s wort ( Hypericum perforatum ), a herbal preparation
you have kidney disease
you have had seizures (epileptic fits)
you have experienced a manic episode
you suffer from bipolar disorder
you have eye problems, including certain types of glaucoma (increased pressure inside the eye)
you have a history of blood clotting 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 Cymbalta’)

Cymbalta 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, sudden changes in blood pressure, overactive reflexes, diarrhoea, coma, nausea, 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 Cymbalta (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
If you are depressed and/or suffer from anxiety disorders, you may sometimes have thoughts about 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 these thoughts if you:

have previously had thoughts of suicide or self-harm
are a young adult. Clinical trial 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 could ask them to inform you if they believe your depression or anxiety is worsening, or if they are concerned about changes in your behaviour.

Children and adolescents under 18 years of age
Cymbalta is generally not intended for use in children and adolescents under 18 years of age.
Furthermore, you should be aware 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). Nevertheless, your doctor may prescribe Cymbalta to patients under 18 years if he/she considers it the best option for them. If your doctor has prescribed Cymbalta to a patient under 18 and you would like further clarification, speak to your doctor. You must inform the doctor if any of the symptoms listed above appear or worsen while patients under 18 years are taking Cymbalta. In addition, long-term effects of Cymbalta on growth, maturation, and cognitive and behavioural development have not yet been established in this age group.

Other medicines and Cymbalta
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 active ingredient in Cymbalta, duloxetine, is also found in other medicines used for other conditions:

diabetic neuropathic pain, depression, anxiety, and urinary incontinence
Concurrent 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 Cymbalta with other medicines. Do not start or stop
taking any medicine, including over-the-counter medicines and herbal preparations, without first
consulting your doctor .
Also inform your doctor if you are taking any of the following medicines:
Monoamine Oxidase Inhibitors (MAOIs) : You must not take Cymbalta if you are currently taking, or have recently taken (within the last 14 days), another 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 Cymbalta, may cause serious or even life-threatening side effects. You must wait at least 14 days after stopping an MAOI before starting Cymbalta. Likewise, you must wait at least 5 days after stopping Cymbalta before starting an MAOI.
Medicines that cause drowsiness : These include prescription medicines such as benzodiazepines, strong painkillers, antipsychotics, phenobarbital, and 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 adverse effects; if you experience any unusual symptoms while taking any of these medicines together with Cymbalta, you should 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.

Cymbalta with food, drinks and alcohol
Cymbalta can be taken regardless of meals. You should be cautious about drinking alcohol while being treated with Cymbalta.

Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, planning to become pregnant, or breastfeeding, consult your doctor or pharmacist before taking this medicine.

Inform your doctor if you are pregnant or planning to become pregnant while taking Cymbalta. You should use Cymbalta only after discussing with your doctor the potential benefits and any potential risks to the unborn child.
Ensure that your midwife and/or doctor knows that you are taking Cymbalta. 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 Cymbalta near the end of pregnancy, the newborn may experience certain symptoms shortly after birth. These symptoms usually appear at birth or within a few days after birth. These 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 for advice.
If you take Cymbalta 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 provide appropriate advice.

Available data on the use of Cymbalta during the first three months of pregnancy do not show an increased overall risk of birth defects in the baby. If Cymbalta 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 Cymbalta in the second half of pregnancy), mostly between weeks 35 and 36 of pregnancy.

Inform your doctor if you are breastfeeding. The use of Cymbalta during breastfeeding is not recommended. Seek advice from your doctor or pharmacist.

Driving and using machines
Cymbalta may cause drowsiness or dizziness. Do not drive or operate tools or machinery until you know how Cymbalta affects you.

Cymbalta contains sucrose
Cymbalta contains sucrose . If your doctor has told you that you have an intolerance to certain sugars, contact him before taking this medicine.

Cymbalta contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per capsule, i.e. essentially ‘sodium-free’.

3. How to take Cymbalta

Take this medicine exactly as your doctor or pharmacist has told you. If you are unsure, consult your doctor or pharmacist.
Cymbalta is taken orally. Swallow the capsule whole, without chewing, with a glass of water.

For depression and diabetic neuropathic pain:
The usual dose of Cymbalta is 60 mg once daily. However, your doctor will prescribe the dose that is right for you.

For generalized anxiety disorder:
The usual starting dose of Cymbalta is 30 mg once daily. Most patients will then be increased to 60 mg once daily, but your doctor will determine the dose that is right for you.
The dose may be adjusted up to a maximum of 120 mg per day, depending on your response to Cymbalta.

To help you remember to take Cymbalta, it may be easier to take it at the same time each day.
Talk to your doctor about how long you should continue taking Cymbalta. Do not stop taking Cymbalta or change the dose without first discussing it with your doctor. Appropriate treatment of your condition is important to help you feel better. If left untreated, your condition may not improve and may become worse and more difficult to treat.

If you take more Cymbalta than you should
Contact your doctor or pharmacist immediately if you have taken more Cymbalta than prescribed. Symptoms of overdose may include drowsiness, coma, serotonin syndrome (a rare reaction that may cause feelings of intense well-being, drowsiness, clumsiness, restlessness, sensation of drunkenness, fever, sweating, or muscle rigidity), seizures, vomiting, and rapid heartbeat.

If you forget to take Cymbalta
If you forget 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 scheduled dose as usual. Do not take a double dose to make up for the missed one. Do not take more than the amount of Cymbalta prescribed for one day.

If you stop taking Cymbalta
Even if you feel better, DO NOT stop taking the capsules without first talking to your doctor. If your doctor decides that you no longer need Cymbalta, they will ask you to gradually reduce the dose over a period of at least 2 weeks before stopping treatment completely.

Some patients who stop taking Cymbalta suddenly 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), tremor, headache, muscle pain, feeling irritable, diarrhoea, excessive sweating, or vertigo.
These symptoms are usually not severe and tend to go away within a few days. However, if you experience bothersome symptoms, consult your doctor.

If you have any questions about how to use this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them. Normally, these effects are mild to moderate and often disappear after a few weeks.

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

headache, drowsiness
feeling unwell (nausea), dry mouth

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

loss of appetite
difficulty in falling asleep, feeling restless, reduced sexual desire, anxiety, difficulty or inability to reach orgasm, unusual dreams
dizziness, feeling sluggish, tremor, numbness, including a sensation of tingling, prickling, or skin tingling
blurred vision
tinnitus (perception of sound in the ear in the absence of an external sound stimulus)
awareness of heartbeat (palpitations)
increased blood pressure, hot flush
increased yawning
constipation, diarrhoea, stomach ache, retching (vomiting), heartburn, indigestion, gas accumulation in the intestine
increased sweating, skin rash (pruritic)
muscle pain, muscle spasm
painful urination, frequent urination
difficulty achieving an erection, ejaculation disorders
falls (especially in elderly people), fatigue
weight loss

Children and adolescents under 18 years of age with depression treated with this medicine have experienced some weight loss when first starting treatment. After 6 months of treatment, weight increased to be comparable to that of other children and adolescents of the same age and sex.

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

throat inflammation causing hoarseness
suicidal thoughts, difficulty falling asleep, teeth grinding or clenching, feeling disoriented, lack of motivation
sudden and involuntary muscle spasms or contractions, feeling restless or unable to sit still, feeling nervous, difficulty concentrating, changes in taste sensation, difficulty controlling movements such as lack of coordination or involuntary muscle movements, restless legs syndrome, poor sleep quality
pupil dilation (the dark centre of the eye), visual disturbances
feeling dizzy or lightheaded (vertigo), ear pain
rapid or irregular heartbeat
fainting, dizziness, feeling of emptiness in the head or impending faint when standing up, cold sensation in fingers and/or toes
tightness in the throat, nosebleeds
vomiting blood or passing black, tar-like stools, gastroenteritis, belching, difficulty swallowing
liver inflammation which may cause abdominal pain and yellowing of the skin or whites of the eyes (jaundice)
night sweats, hives, cold sweats, sensitivity to sunlight, increased tendency to bruise
muscle stiffness, muscle contraction
difficulty or inability to urinate, difficulty starting urination, need to urinate during the night, need to urinate more than usual, reduced urine flow
abnormal vaginal bleeding, abnormal menstrual cycles, including heavy, painful, irregular or prolonged periods, unusually light or absent periods, testicular or scrotal pain
chest pain, feeling cold, thirst, trembling, feeling hot, abnormal gait
weight gain
Cymbalta may cause effects you may not be aware of, such as increases in liver enzymes, blood potassium levels, creatine phosphokinase, blood sugar, or cholesterol levels

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, allergic reactions
reduced activity of the thyroid gland which may cause tiredness or weight gain
dehydration, low sodium levels in the blood (especially in elderly people; symptoms may include dizziness, weakness, confusion, drowsiness, or extreme fatigue, nausea, or feeling like vomiting; more severe symptoms include loss of consciousness, seizures, or falls), syndrome of inappropriate antidiuretic hormone secretion (SIADH)
suicidal behaviour, 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, drunkenness-like sensations, fever, sweating, or muscle stiffness), seizures
increased pressure inside the eye (glaucoma)
cough, wheezing, and shortness of breath, possibly accompanied by fever
mouth inflammation, presence of bright red blood in stools, bad breath, 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 condition with blistering of the skin, mouth, eyes, and genitals), severe allergic reaction causing swelling of the face or throat (angioedema)
contraction of the muscles of the mouth
altered odour of urine
menopausal symptoms, abnormal production of breast milk in men and women
excessive vaginal bleeding immediately after childbirth (postpartum haemorrhage)

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, 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 Cymbalta

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton.
Store in the original packaging to protect it from moisture. Do not store above 30 °C.
Do not dispose of any medicine 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 Cymbalta contains
The active substance is duloxetine.
Each capsule contains 30 or 60 mg of duloxetine (as hydrochloride).
The other components are:
Capsule contents: hypromellose, hypromellose acetate succinate, sucrose, sugar granules,
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),
iron oxide yellow (E172) (only for 60 mg), and green edible ink (30 mg) or white edible ink (60 mg).
Green edible ink: synthetic black iron oxide (E172), synthetic yellow iron oxide (E172),
propylene glycol, shellac.
White edible ink: titanium dioxide (E171), propylene glycol, shellac, povidone.

Description of the appearance of Cymbalta and package contents
Cymbalta is a gastro-resistant hard capsule. Each Cymbalta capsule contains granules of
duloxetine hydrochloride with a coating to protect them from stomach acid.
Cymbalta is available in two strengths: 30 mg and 60 mg.
The 30 mg capsules are blue and white, printed with '30 mg' and the code '9543'.
The 60 mg capsules are blue and green, printed with '60 mg' and the code '9542'.
Cymbalta 30 mg is available in packs of 7, 28 and 98 gastro-resistant hard capsules.
Cymbalta 60 mg is available in packs of 28, 56, 84 and 98 gastro-resistant hard capsules, and in
multiple packs of 100 (5 packs of 20) and 500 (25 packs of 20) gastro-resistant hard capsules.
Not all pack sizes may be marketed.

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

For further information about this medicinal product, please contact the local representative of the Marketing Authorization 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 6817 280 Tlf: + 47 22 88 18 00

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

España Polska
Dista 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
Tηλ: +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 OF THE TERMS OF THE
MARKETING AUTHORISATION

Scientific conclusions
Taking into account the evaluation by the Pharmacovigilance Risk Assessment Committee (PRAC) of the Periodic Safety Update Report (PSUR) for duloxetine, the PRAC's scientific conclusions are as follows:
In light 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 its overall conclusions and the rationale behind the recommendation.

Grounds for the variation of the terms of the marketing authorisation
Based on the scientific conclusions on 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.