Duloxetine Boehringer Ingelheim

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
DULOXETINE BOEHRINGER INGELHEIM 30 mg hard gastro-resistant capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each capsule contains 30 mg of duloxetine (as hydrochloride) 
 
Excipients: sucrose 8.6 mg. 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard gastro-resistant capsule. 
 
Opaque white body, imprinted with ‘30 mg’ and an opaque blue cap, imprinted with ‘9543’. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of diabetic peripheral neuropathic pain in adults. 
 
4.2 Posology and method of administration 
 
For oral use. 
 
Adults 
The starting and recommended maintenance dose is 60 mg daily with or without food. Dosages above 
60 mg once daily, up to a maximum dose of 120 mg per day administered in evenly divided doses, 
have been evaluated from a safety perspective in clinical trials.  The plasma concentration of 
duloxetine displays large inter-individual variability (see 5.2). Hence, some patients that respond 
insufficiently to 60 mg may benefit from a higher dose. 
 
Response to treatment should be evaluated after 2 months. In patients with inadequate initial response, 
additional response after this time is unlikely. 
 
The therapeutic benefit should be reassessed regularly (at least every three months) (see Section 5.1). 
 
Elderly 
No dosage adjustment is recommended for elderly patients solely on the basis of age. However, 
caution should be exercised when treating the elderly (see section 5.2). 
 
Children and adolescents 
There is no experience in children and adolescents (see section 4.4). 
 
Hepatic impairment 
DULOXETINE BOEHRINGER INGELHEIM should not be used in patients with liver disease 
resulting in hepatic impairment (see sections 4.3 and 5.2). 
 



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Renal insufficiency 
No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine 
clearance 30 to 80 ml/min). DULOXETINE BOEHRINGER INGELHEIM should not be used in 
patients with severe renal impairment (creatinine clearance <30 ml/min; see section 4.3).. 
 
Discontinuation of treatment 
Abrupt discontinuation should be avoided. When stopping treatment with DULOXETINE 
BOEHRINGER INGELHEIM the dose should be gradually reduced over a period of at least one to 
two weeks in order to reduce the risk of withdrawal reactions (see sections 4.4 and 4.8).If intolerable 
symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming 
the previously prescribed dose may be considered. Subsequently, the physician may continue 
decreasing the dose, but at a more gradual rate. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients. 
 
Concomitant use of DULOXETINE BOEHRINGER INGELHEIM with nonselective, irreversible 
Monoamine Oxidase Inhibitors (MAOIs) is contraindicated (see section 4.5). 
 
Liver disease resulting in hepatic impairment (see section 5.2). 
 
DULOXETINE BOEHRINGER INGELHEIM should not be used in combination with fluvoxamine, 
ciprofloxacin or enoxacine (i.e. potent CYP1A2 inhibitors) since the combination results in elevated 
plasma concentrations of duloxetine (see section 4.5). 
 
Severe renal impairment (creatinine clearance <30 ml/min) (see section 4.4). 
 
The initiation of treatment with DULOXETINE BOEHRINGER INGELHEIM is contraindicated in 
patients with uncontrolled hypertension that could expose patients to a potential risk of hypertensive 
crisis (see sections 4.4 and 4.8). 
 
4.4 Special warnings and precautions for use 
 
Mania and seizures 
DULOXETINE BOEHRINGER INGELHEIM should be used with caution in patients with a history 
of mania or a diagnosis of bipolar disorder, and/or seizures. 
 
Mydriasis 
Mydriasis has been reported in association with duloxetine, therefore, caution should be used when 
prescribing DULOXETINE BOEHRINGER INGELHEIM to patients with increased intraocular 
pressure, or those at risk of acute narrow-angle glaucoma. 
 
Blood pressure and heart rate 
Duloxetine has been associated with an increase in blood pressure and clinically significant 
hypertension in some patients. This may be due to the noradrenergic effect of duloxetine. Cases of 
hypertensive crisis have been reported with duloxetine, especially in patients with pre-existing 
hypertension. Therefore,in patients with known hypertension and/or other cardiac disease, blood 
pressure monitoring is recommended, especially during the first month of treatment. Duloxetine 
should be used with caution in patients whose conditions could be compromised by an increased heart 
rate or by an increase in blood pressure. Caution should also be exercised when duloxetine is used 
with medicinal products that may impair its metabolism (see section 4.5). For patients who experience 
a sustained increase in blood pressure while receiving duloxetine either dose reduction or gradual 
discontinuation should be considered (see section 4.8). In patients with uncontrolled hypertension 
duloxetine should not be initiated (see section 4.3). 
 



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Renal impairment 
Increased plasma concentrations of duloxetine occur in patients with severe renal impairment on 
haemodialysis (creatinine clearance <30 ml/min).  For patients with severe renal impairment, see 
section 4.3. ee section 4.2 for information on patients with mild or moderate renal dysfunction. 
 
Use with antidepressants 
Caution should be exercised when using DULOXETINE BOEHRINGER INGELHEIM in 
combination with antidepressants. In particular the combination with selective reversible MAOIs is not 
recommended. 
 
St John’s wort 
Undesirable effects may be more common during concomitant use of DULOXETINE BOEHRINGER 
INGELHEIM and herbal preparations containing St John’s wort (Hypericum perforatum). 
 
Depression, suicidal ideation and behaviour 
Although DULOXETINE BOEHRINGER INGELHEIM is not indicated for the treatment of 
depression, its active ingredient (duloxetine) also exists as an antidepressant medication. Depression is 
associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). 
This risk persists until significant remission occurs. As improvement may not occur during the first 
few weeks or more of treatment, patients should be closely monitored until such improvement occurs. 
It is general clinical experience that the risk of suicide may increase in the early stages of recovery. 
Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal 
thoughts prior to commencement of treatment are known to be at a greater risk of suicidal thoughts or 
suicidal behaviour, and should receive careful monitoring during treatment. A meta-analysis of 
placebo-controlled clinical trials of antidepressant medicinal products in psychiatric disorders showed 
an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 
25 years old. 
Cases of suicidal thoughts and suicidal behaviours have been reported during duloxetine therapy or 
early after treatment discontinuation (see section 4.8). Physicians should encourage patients to report 
any distressing thoughts or feelings or depressive symptoms at any time. If while on DULOXETINE 
BOEHRINGER INGELHEIM therapy, the patient develops agitation or depressive symptoms, 
specialised medical advice should be sought, as depression is a serious medical condition. If a decision 
to initiate antidepressant pharmacological therapy is taken, the gradual discontinuation of 
DULOXETINE BOEHRINGER INGELHEIM is recommended (see section 4.2). 
 
Use in children and adolescents under 18 years of age 
No clinical trials have been conducted with duloxetine in paediatric populations. DULOXETINE 
BOEHRINGER INGELHEIM should not be used in the treatment of children and adolescents under 
the age of 18 years.  Suicide-related behaviours (suicide attempts and suicidal thoughts), and hostility 
(predominantly aggression, oppositional behaviour and anger), were more frequently observed in 
clinical trials among children and adolescents treated with antidepressants compared to those treated 
with placebo.  If, based on clinical need, a decision to treat is nevertheless taken, the patient should be 
carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in 
children and adolescents concerning growth, maturation and cognitive and behavioural development 
are lacking. 
 
Haemorrhage  
There have been reports of bleeding abnormalities, such as ecchymoses, purpura and gastrointestinal 
haemorrhage with selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline 
reuptake inhibitors (SNRIs). Caution is advised in patients taking anticoagulants and/or medicinal 
products known to affect platelet function, and in patients with known bleeding tendencies. 
 



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Hyponatremia 
Hyponatremia has been reported rarely, predominantly in the elderly, when administering 
DULOXETINE BOEHRINGER INGELHEIM. Caution is required in patients at increased risk for 
hyponatremia; such as elderly, cirrhotic, or dehydrated patients or patients treated with diuretics. 
Hyponatremia may be due to a syndrome of inappropriate anti-diuretic hormone secretion (SIADH). 
 
Discontinuation of treatment 
Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is 
abrupt (see section 4.8). In clinical trials adverse events seen on abrupt treatment discontinuation 
occurred in approximately 45% of patients treated with DULOXETINE BOEHRINGER INGELHEIM 
and 23% of patients taking placebo.  
The risk of withdrawal symptoms seen with SSRI’s and SNRI’s may be dependent on several factors 
including the duration and dose of therapy and the rate of dose reduction. The most commonly 
reported reactions are listed in section 4.8. Generally these symptoms are mild to moderate, however, 
in some patients they may be severe in intensity.  They usually occur within the first few days of 
discontinuing treatment, but there have been very rare reports of such symptoms in patients who have 
inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 
weeks, though in some individuals they may be prolonged (2-3 months or more).  It is therefore 
advised that duloxetine should be gradually tapered when discontinuing treatment over a period of no 
less than 2 weeks, according to the patient’s needs (see section 4.2). 
 
Akathisia/psychomotor restlessness 
The use of duloxetine has been associated with the development of akathisia, characterised by a 
subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability 
to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who 
develop these symptoms, increasing the dose may be detrimental. 
 
Medicinal products containing duloxetine 
Duloxetine is used under different trademarks in several indications (treatment of diabetic neuropathic 
pain, major depressive episodes as well as stress urinary incontinence). The use of more than one of 
these products concomitantly should be avoided. 
 
Hepatitis/increased liver enzymes  
Cases of liver injury, including severe elevations of liver enzymes (>10 times upper limit of normal), 
hepatitis and jaundice have been reported with duloxetine (see section 4.8). Most of them occurred 
during the first months of treatment. The pattern of liver damage was predominantly hepatocellular. 
Duloxetine should be used with caution in patients treated with other medicinal products associated 
with hepatic injury. 
 
Sucrose 
DULOXETINE BOEHRINGER INGELHEIM gastro-resistant capsules contain sucrose. Patients with 
rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-
isomaltase insufficiency should not take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
CNS medicinal products: the risk of using duloxetine in combination with other CNS-active medicinal 
products has not been systematically evaluated, except in the cases described in this section. 
Consequently, caution is advised when DULOXETINE BOEHRINGER INGELHEIM is taken in 
combination with other centrally acting medicinal products and substances including alcohol and 
sedative medicinal products (e.g. benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, 
sedative antihistamines). 
 
Monoamine Oxidase Inhibitors (MAOIs): due to the risk of serotonin syndrome, DULOXETINE 
BOEHRINGER INGELHEIM should not be used in combination with nonselective irreversible 
monoamine oxidase inhibitors (MAOIs), or within at least 14 days of discontinuing treatment with an 



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MAOI. Based on the half-life of duloxetine, at least 5 days should be allowed after stopping 
DULOXETINE BOEHRINGER INGELHEIM before starting an MAOI (see section 4.3). 
 
For selective, reversible MAOIs, like moclobemide, the risk of serotonin syndrome is lower. However, 
the concomitant use of DULOXETINE BOEHRINGER INGELHEIM with selective, reversible 
MAOIs is not recommended (see section 4.4). 
 
Serotonin syndrome: in rare cases, serotonin syndrome has been reported in patients using SSRIs (e.g. 
paroxetine, fluoxetine) concomitantly with serotonergic medicinal products. Caution is advisable if 
DULOXETINE BOEHRINGER INGELHEIM is used concomitantly with serotonergic 
antidepressants like SSRIs, tricyclics like clomipramine or amitriptyline, St John’s wort (Hypericum 
perforatum), venlafaxine or triptans, tramadol, pethidine and tryptophan. 
 
Effect of duloxetine on other medicinal products 
Medicinal products metabolised by CYP1A2: The pharmacokinetics of theophylline, a CYP1A2 
substrate, were not significantly affected by co-administration with duloxetine (60 mg twice daily).  
Medicinal products metabolised by CYP2D6: Duloxetine is a moderate inhibitor of CYP2D6. When 
duloxetine was administered at a dose of 60 mg twice daily with a single dose of desipramine, a 
CYP2D6 substrate, the AUC of desipramine increased 3-fold. The co-administration of duloxetine (40 
mg twice daily) increases steady state AUC of tolterodine (2 mg twice daily) by 71 %, but does not 
affect the pharmacokinetics of its active 5-hydroxyl metabolite and no dosage adjustment is 
recommended. Caution is advised if DULOXETINE BOEHRINGER INGELHEIM is co-administered 
with medicinal products that are predominantly metabolised by CYP2D6 (risperidone, tricyclic 
antidepressants [TCAs] such as nortriptyline, amitriptyline, and imipramine) particularly if they have a 
narrow therapeutic index (such as flecainide, propafenone and metoprolol). 
 
Oral contraceptives and other steroidal agents: results of in vitro studies demonstrate that duloxetine 
does not induce the catalytic activity of CYP3A. Specific in vivo drug interaction studies have not 
been performed. 
 
Anticoagulants and antiplatelet agents: Caution should be exercised when duloxetine is combined 
with oral anticoagulants or antiplatelet agents due to a potential increased risk of bleeding attributable 
to a pharmacodynamic interaction. Furthermore, increases in INR values have been reported when 
duloxetine was co-administered to patients treated with warfarin. However, concomitant 
administration of duloxetine with warfarin under steady state conditions, in healthy volunteers, as part 
of a clinical pharmacology study, did not result in a clinically significant change in INR from baseline 
or in the pharmacokinetics of R- or S-warfarin. 
 
Effects of other medicinal products on duloxetine 
Antacids and H2 antagonists: co-administration of duloxetine with aluminium- and magnesium-
containing antacids or duloxetine with famotidine had no significant effect on the rate or extent of 
duloxetine absorption after administration of a 40 mg oral dose. 
 
Inhibitors of CYP 1A2: because CYP1A2 is involved in duloxetine metabolism, concomitant use of 
duloxetine with potent inhibitors of CYP1A2 is likely to result in higher concentrations of duloxetine. 
Fluvoxamine (100 mg once daily), a potent inhibitor of CYP1A2, decreased the apparent plasma 
clearance of duloxetine by about 77% and increased AUCo-t 6-fold. Therefore DULOXETINE 
BOEHRINGER INGELHEIM should not be administered in combination with potent inhibitors of 
CYP1A2 like fluvoxamine (see section 4.3). 
 
Inducers of CYP1A2: Population pharmacokinetic analyses have shown that smokers have almost 50% 
lower plasma concentrations of duloxetine compared with non-smokers. 
 



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4.6 Pregnancy and lactation 
 
Pregnancy  
There are no data on the use of duloxetine in pregnant women. Studies in animals have shown 
reproductive toxicity at systemic exposure levels (AUC) of duloxetine lower than the maximum 
clinical exposure (see section 5.3).  
The potential risk for humans is unknown. As with other serotonergic medicinal products, 
discontinuation symptoms may occur in the neonate after maternal duloxetine use near term. 
DULOXETINE BOEHRINGER INGELHEIM should be used in pregnancy only if the potential 
benefit justifies the potential risk to the foetus. Women should be advised to notify their physician if 
they become pregnant, or intend to become pregnant, during therapy.  
 
Breast feeding 
Duloxetine is very weakly excreted into human milk based on a study of 6 lactating patients, who did  
not breast feed their children . The estimated daily infant dose on a mg/kg basis is approximately 
0.14% of the maternal dose (see section 5.2). As the safety of duloxetine in infants is not known, the 
use of DULOXETINE BOEHRINGER INGELHEIM while breast-feeding is not recommended.  
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed. 
DULOXETINE BOEHRINGER INGELHEIM may be associated with sedation and dizziness. 
Patients should be instructed that if they experience sedation or dizziness they should avoid potentially 
hazardous tasks such as driving or operating machinery. 
 
4.8 Undesirable effects 
 
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled 
clinical trials (comprising a total of 6828 patients, 4199 on duloxetine and 2629 on placebo).  
The most commonly observed adverse reactions in patients with diabetic neuropathic pain treated with 
DULOXETINE BOEHRINGER INGELHEIM were: nausea; headache, dry mouth and somnolence 
and dizziness. 
 
Table 1: Adverse reactions 
Frequency estimate: Very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1,000 and 
<1/100), rare (≥ 1/10,000 and <1/1,000), very rare (<1/10,000), not known (cannot be estimated from 
the available data). 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 
Very common Common Uncommon Rare Very Rare Frequency not 

known 
Investigations 
 Weight decrease  Weight increase 

Creatine 
phosphokinase 
increased 

Blood 
cholesterol 
increased 

  

Cardiac Disorders 
 Palpitations Tachycardia 

Supra-
ventricular 
arrhythmia, 
mainly atrial 
fibrillation 

   

Nervous System Disorders 
Headache 
(14.3%) 
Somnolence 

Tremor 
Paraesthesia 
 

Myoclonus 
Nervousness 
Disturbance in 

 
Convulsion1 
 

 Serotonin 
syndrome 
Extra-pyramidal 



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Very common Common Uncommon Rare Very Rare Frequency not 
known 

(10.7%) 
Dizziness 
(10.2%) 

attention 
Lethargy 
Dysgeusia 
Dyskinesia 
Restless legs 
syndrome 
Poor quality 
sleep 
 

symptoms 
Akathisia 
Psychomotor 
restlessness 
 

Eye Disorders 
 Blurred vision Mydriasis 

Visual 
disturbance 
 

Glaucoma   

Ear and Labyrinth Disorders 
 Tinnitus1  Vertigo 

Ear pain 
   

Respiratory, thoracic and mediastinal disorders 
 Yawning Throat tightness 

Epistaxis 
   

Gastrointestinal Disorders  
Nausea (24.3%) 
Dry mouth 
(12.8%) 
 

Constipation 
Diarrhoea 
Vomiting  
Dyspepsia 
Flatulence 

Gastroenteritis 
Eructation 
Gastritis 
 

Stomatitis 
Breath odour 
Haematochezia 
 

 Gastrointestinal 
haemorrhage 
 

Renal and Urinary Disorders 
  Urinary 

Retention 
Dysuria 
Urinary 
hesitation 
Nocturia 
Polyuria 
Urine flow 
decreased 

Urine odour 
abnormal 

  

Skin and Subcutaneous Tissue Disorders 
 Sweating 

increased 
Rash 
 

Night sweats 
Urticaria 
Dermatitis 
contact 
Cold sweat 
Photo-
sensitivity 
reactions 
Increased 
tendency to 
bruise 
 
 

  Angio-neurotic 
oedema 
Stevens-
Johnson 
Syndrome 
 

Musculoskeletal and connective tissue disorders 
 Musculo-

skeletal pain 
Muscle 

Muscle 
twitching 
 

Trismus   



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Very common Common Uncommon Rare Very Rare Frequency not 
known 

tightness 
Muscle spasm 

Endocrine disorders 
   Hypo-

thyroidism 
  

Metabolism and Nutrition Disorders 
 Decreased 

Appetite  
Hyperglycemia 
(reported 
especially in 
diabetic 
patients) 

Dehydration 
Hyponatremia 
 

 SIADH 
 

Infections and infestations 
  Laryngitis    
Vascular Disorders 
 Flushing Blood pressure 

increase 
Peripheral 
coldness 
Orthostatic 
hypotension2 
Syncope2 
 

  Hypertension 
Hypertensive 
crisis 
 

General Disorders and Administration Site Conditions 
 Fatigue 

Abdominal pain 
 

Feeling 
abnormal 
Feeling cold 
Thirst 
Chills 
Malaise 
Feeling hot 
Gait disturbance 
 
 

  Chest pain  
 

Immune system disorders 
   Hyper-

sensitivity 
disorder 
Anaphylactic 
reaction 

  

Hepato-biliary disorders 
  Elevated liver 

enzymes (ALT, 
AST, alkaline 
phosphatase) 
Hepatitis3 
Acute liver 
injury 
 

  Jaundice 
Hepatic failure 

Reproductive System and Breast Disorders 
 Erectile 

dysfunction 
Ejaculation 
disorder  
Ejaculation 
delayed 
Sexual 

Menopausal 
symptoms 
 

  



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Very common Common Uncommon Rare Very Rare Frequency not 
known 

dysfunction  
Gynaecological 
haemorrhage 

Psychiatric Disorders 
 Insomnia 

Agitation 
Libido 
decreased 
Anxiety 
Orgasm 
abnormal 
Abnormal 
dreams 
 

Sleep disorder 
Bruxism 
Disorientation 
Apathy 
 

Mania 
Hallucinations 
Aggression and 
anger4 

 Suicidal 
ideation 5 
Suicidal5 
behaviour 
 

1 Cases of convulsion and cases of tinnitus have also been reported after treatment discontinuation. 
2Cases of orthostatic hypotension and syncope have been reported especially at the initiation of 
treatment. 
3See section 4.4 
4Cases of aggression and anger have been reported particularly early in treatment of after treatment 
discontinuation. 
5Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or 
early after treatment discontinuation (see section 4.4) 
 
Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms. 
Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and 
intense dreams), agitation or anxiety, nausea and/or vomiting, tremor ,headache, irritability, diarrhoea, 
hyperhydrosis and vertigo are the most commonly reported reactions. 
Generally, for SSRIs and SNRIs, these events are mild to moderate and self-limiting, however, in 
some patients they may be severe and/or prolonged. It is therefore advised that when duloxetine 
treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see 
sections 4.2 and 4.4). 
 
In the 12 week acute phase of three clinical trials of duloxetine in patients with diabetic neuropathic 
pain, small but statistically significant increases in fasting blood glucose were observed in duloxetine-
treated patients. HbA1c was stable in both duloxetine-treated and placebo-treated patients. In the 
extension phase of these studies, which lasted up to 52 weeks, there was an increase in HbA1c in both 
the duloxetine and routine care groups, but the mean increase was 0.3% greater in the duloxetine-
treated group. There was also a small increase in fasting blood glucose and in total cholesterol in 
duloxetine-treated patients while those laboratory tests showed a slight decrease in the routine care 
group.  
 
Electrocardiograms were obtained from 528 duloxetine-treated and 205 placebo-treated patients with 
diabetic neuropathic pain in clinical trials lasting up to 13-weeks. The heart rate-corrected QT interval 
in duloxetine-treated patients did not differ from that seen in placebo-treated patients. No clinically 
significant differences were observed for QT, PR, QRS, or QTcB measurements between duloxetine-
treated and placebo-treated patients. 
 
4.9 Overdose 
 
Cases of overdoses, alone or in combination with other medicinal products, with duloxetine doses of 
5400mg were reported. Some fatalities have occurred, primarily with mixed overdoses, but also with 
duloxetine alone at a dose of approximately 1000 mg. Signs and symptoms of overdose (duloxetine 
alone or in combination with other medicinal products) included somnolence, coma, serotonin 
syndrome, seizures, vomiting and tachycardia.   
 



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No specific antidote is known for duloxetine but if serotonin syndrome ensues, specific treatment 
(such as with cyproheptadine and/or temperature control) may be considered. A free airway should be 
established. Monitoring of cardiac and vital signs is recommended, along with appropriate 
symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after 
ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption. 
Duloxetine has a large volume of distribution and forced diuresis, haemoperfusion, and exchange 
perfusion are unlikely to be beneficial. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other antidepressants. ATC code: N06AX21. 
 
Duloxetine is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weakly 
inhibits dopamine reuptake with no significant affinity for histaminergic, dopaminergic, cholinergic 
and adrenergic receptors. Duloxetine dose-dependently increases extracellular levels of serotonin and 
noradrenaline in various brain areas of animals. 
 
Duloxetine normalised pain thresholds in several preclinical models of neuropathic and inflammatory 
pain and attenuated pain behaviour in a model of persistent pain. The pain inhibitory action of 
duloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within the 
central nervous system. 
 
The efficacy of duloxetine as a treatment for diabetic neuropathic pain was established in 2 
randomised, 12-week, double-blind, placebo-controlled, fixed dose studies in adults (22 to 88 years) 
having diabetic neuropathic pain for at least 6 months.  Patients meeting diagnostic criteria for major 
depressive disorder were excluded from these trials.  The primary outcome measure was the weekly 
mean of 24-hour average pain, which was collected in a daily diary by patients on an 11-point Likert 
scale. 
 
In both studies, duloxetine 60 mg once daily and 60 mg twice daily significantly reduced pain 
compared with placebo. The effect in some patients was apparent in the first week of treatment. The 
difference in mean improvement between the two active treatment arms was not significant.  At least 
30% reported pain reduction was recorded in approximately 65% of duloxetine treated patients versus 
40% for placebo. The corresponding figures for at least 50% pain reduction were 50% and 26% 
respectively. Clinical response rates (50% or greater improvement in pain) were analysed according to 
whether or not the patient experienced somnolence during treatment. For patients not experiencing 
somnolence, clinical response was observed in 47% of patients receiving duloxetine and 27% patients 
on placebo.  Clinical response rates in patients experiencing somnolence were 60% on duloxetine and 
30% on placebo. Patients not demonstrating a pain reduction of 30% within 60 days of treatment were 
unlikely to reach this level during further treatment. 
 
In an open label long-term uncontrolled study, the pain reduction in patients responding to 8-weeks of 
acute treatment of DULOXETINE BOEHRINGER INGELHEIM 60 mg once daily was maintained 
for a further 6-months as measured by change on the Brief Pain Inventory(BPI) 24-hour average pain 
item. 
 
5.2 Pharmacokinetic properties 
 
Duloxetine is administered as a single enantiomer. Duloxetine is extensively metabolised by oxidative 
enzymes (CYP1A2 and the polymorphic CYP2D6), followed by conjugation. The pharmacokinetics 
of duloxetine demonstrate large intersubject variability (generally 50-60%), partly due to gender, age, 
smoking status and CYP2D6 metaboliser status.  
Duloxetine is well absorbed after oral administration with a Cmax occurring 6 hours post dose. The 
absolute oral bioavailability of duloxetine ranged from 32% to 80% (mean of 50%). Food delays the 



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time to reach the peak concentration from 6 to 10 hours and it marginally decreases the extent of 
absorption (approximately 11 %). These changes do not have any clinical significance. Duloxetine is 
approximately 96% bound to human plasma proteins. Duloxetine binds to both albumin and alpha-l 
acid glycoprotein. Protein binding is not affected by renal or hepatic impairment. 
 
Duloxetine is extensively metabolised and the metabolites are excreted principally in urine. Both 
cytochromes P450-2D6 and 1A2 catalyse the formation of the two major metabolites glucuronide 
conjugate of 4-hydroxy duloxetine and sulphate conjugate of 5hydroxy,6-methoxy duloxetine. Based 
upon in vitro studies, the circulating metabolites of duloxetine are considered pharmacologically 
inactive. The pharmacokinetics of duloxetine in patients who are poor metabolisers with respect to 
CYP2D6 has not been specifically investigated. Limited data suggest that the plasma levels of 
duloxetine are higher in these patients. 
 
The elimination half-life of duloxetine ranges from 8 to 17 hours (mean of 12 hours). After an 
intravenous dose the plasma clearance of duloxetine ranges from 22 l/hr to 46 l/hr (mean of 36 l/hr).  
After an oral dose the apparent plasma clearance of duloxetine ranges from 33 to 261 l/hr (mean 101 
l/hr). 
 
Special populations: 
Gender: pharmacokinetic differences have been identified between males and females (apparent 
plasma clearance is approximatively 50% lower in females). Based upon the overlap in the range of 
clearance, gender-based pharmacokinetic differences do not justify the recommendation for using a 
lower dose for female patients.  
 
Age: pharmacokinetic differences have been identified between younger and elderly females (≥65 
years) (AUC increases by about 25% and half-life is about 25% longer in the elderly), although the 
magnitude of these changes is not sufficient to justify adjustments to the dose. As a general 
recommendation, caution should be exercised when treating the elderly (see sections 4.2 and 4.4). 
 
Renal impairment: end stage renal disease (ESRD) patients receiving dialysis had 2-fold higher 
duloxetine Cmax and AUC values compared with healthy subjects. Pharmacokinetic data on 
duloxetine is limited in patients with mild or moderate renal impairment. 
 
Hepatic impairment: moderate liver disease (Child Pugh Class B) affected the pharmacokinetics of 
duloxetine. Compared with healthy subjects, the apparent plasma clearance of duloxetine was 79% 
lower, the apparent terminal half-life was 2.3 times longer, and the AUC was 3.7 times higher in 
patients with moderate liver disease. The pharmacokinetics of duloxetine and its metabolites have not 
been studied in patients with mild or severe hepatic insufficiency. 
 
Nursing mothers: The disposition of duloxetine was studied in 6 lactating women who were at least 
12-weeks postpartum. Duloxetine is detected in breast milk, and steady-state concentrations in breast 
milk are about one-fourth those in plasma. The amount of duloxetine in breast milk is approximately 
7 µg/day while on 40 mg twice daily dosing. Lactation did not influence duloxetine pharmacokinetics.  
 
5.3 Preclinical safety data 
 
Duloxetine was not genotoxic in a standard battery of tests and was not carcinogenic in rats.  
Multinucleated cells were seen in the liver in the absence of other histopathological changes in the rat 
carcinogenicity study. The underlying mechanism and the clinical relevance are unknown. Female 
mice receiving duloxetine for 2 years had an increased incidence of hepatocellular adenomas and 
carcinomas at the high dose only (144 mg/kg/day), but these were considered to be secondary to 
hepatic microsomal enzyme induction. The relevance of this mouse data to humans is unknown. 
Female rats receiving duloxetine (45 mg/kg/day) before and during mating and early pregnancy had a 
decrease in maternal food consumption and body weight, oestrous cycle disruption, decreased live 
birth indices and progeny survival, and progeny growth retardation at systemic exposure levels 
estimated to be at the most at maximum clinical exposure (AUC). In an embryotoxicity study in the 
rabbit, a higher incidence of cardiovascular and skeletal malformations was observed at systemic 



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exposure levels below the maximum clinical exposure (AUC). No malformations were observed in 
another study testing a higher dose of a different salt of duloxetine. In prenatal/postnatal toxicity 
studies in the rat, duloxetine induced adverse behavioural effects in the offspring at exposures below 
maximum clinical exposure (AUC). 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule content: 
Hypromellose. 
Hypromellose Acetate Succinate 
Sucrose 
Sugar spheres 
Talc 
Titanium dioxide (E171) 
Triethyl citrate. 
 
Capsule shell: 
30 mg: 
Gelatin 
Sodium Lauryl Sulfate 
Titanium Dioxide (E171) 
Indigo Carmine (E132) 
Edible Green Ink  
 
Edible Green Ink contains: 
Black Iron Oxide-Synthetic (E172) 
Yellow Iron Oxide- Synthetic (E172) 
Propylene glycol 
Shellac. 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Store in the original package in order to protect from moisture. Do not store above 30 C. 
 
6.5 Nature and contents of container 
 
Polyvinylchloride (PVC), Polyethylene (PE), and Polychlorotrifluoroethylene (PCTFE) blister sealed 
with an aluminum foil. 
 
DULOXETINE BOEHRINGER INGELHEIM 30 mg is available in packs of 7, 28 and 98 capsules.  
 
Not all pack sizes may be marketed. 
 
6.6  Special precautions for disposal  
 
No special requirements. 



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7. MARKETING AUTHORISATION HOLDER 
 
Boehringer Ingelheim International GmbH, Binger Str. 173 D-55216 Ingelheim am Rhein, Germany. 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/471/003-005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
8th October 2008 
 
 
10. DATE OF REVISION OF THE TEXT 

 



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1. NAME OF THE MEDICINAL PRODUCT 
 
DULOXETINE BOEHRINGER INGELHEIM 60 mg hard gastro-resistant capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each capsule contains 60 mg of duloxetine (as hydrochloride). 
 
Excipients: sucrose 17.2 mg. 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard gastro-resistant capsule. 
 
Opaque green body, imprinted with ‘60 mg’ and an opaque blue cap, imprinted with ‘9542’. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of diabetic peripheral neuropathic pain in adults. 
 
4.2 Posology and method of administration 
 
For oral use. 
 
Adults 
The starting and recommended maintenance dose is 60 mg daily with or without food. Dosages above 
60 mg once daily, up to a maximum dose of 120 mg per day administered in evenly divided doses, 
have been evaluated from a safety perspective in clinical trials.  The plasma concentration of 
duloxetine displays large inter-individual variability (see 5.2). Hence, some patients that respond 
insufficiently to 60 mg may benefit from a higher dose. 
 
Response to treatment should be evaluated after 2 months. In patients with inadequate initial response, 
additional response after this time is unlikely. 
 
The therapeutic benefit should be reassessed regularly (at least every three months) (see Section 5.1). 
 
Elderly 
Diabetic Peripheral Neuropathic Pain: No dosage adjustment is recommended for elderly patients 
solely on the basis of age. However, caution should be exercised when treating the elderly (see section 
5.2). 
 
Children and adolescents 
There is no experience in children and adolescents (see section 4.4). 
 
Hepatic impairment 
DULOXETINE BOEHRINGER INGELHEIM should not be used in patients with liver disease 
resulting in hepatic impairment (see sections 4.3 and 5.2). 
 



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Renal insufficiency 
No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine 
clearance 30 to 80 ml/min). DULOXETINE BOEHRINGER INGELHEIM should not be used in 
patients with severe renal impairment (creatinine clearance <30 ml/min; see section 4.3).  
 
Discontinuation of treatment 
Abrupt discontinuation should be avoided. When stopping treatment with DULOXETINE 
BOEHRINGER INGELHEIM the dose should be gradually reduced over a period of at least one to 
two weeks in order to reduce the risk of withdrawal reactions (see sections 4.4 and 4.8). If intolerable 
symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming 
the previously prescribed dose may be considered. Subsequently, the physician may continue 
decreasing the dose, but at a more gradual rate. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients. 
 
Concomitant use of DULOXETINE BOEHRINGER INGELHEIM with nonselective, irreversible 
Monoamine Oxidase Inhibitors (MAOIs) is contraindicated (see section 4.5). 
 
Liver disease resulting in hepatic impairment (see section 5.2). 
 
DULOXETINE BOEHRINGER INGELHEIM should not be used in combination with fluvoxamine, 
ciprofloxacin or enoxacine (i.e. potent CYP1A2 inhibitors) since the combination results in elevated 
plasma concentrations of duloxetine (see section 4.5). 
 
Severe renal impairment (creatinine clearance <30 ml/min) (see section 4.4). 
 
The initiation of treatment with DULOXETINE BOEHRINGER INGELHEIM is contraindicated in 
patients with uncontrolled hypertension that could expose patients to a potential risk of hypertensive 
crisis (see sections 4.4 and 4.8). 
 
4.4 Special warnings and precautions for use 
 
Mania and seizures 
DULOXETINE BOEHRINGER INGELHEIM should be used with caution in patients with a history 
of mania or a diagnosis of bipolar disorder, and/or seizures. 
 
Mydriasis 
Mydriasis has been reported in association with duloxetine, therefore, caution should be used when 
prescribing DULOXETINE BOEHRINGER INGELHEIM to patients with increased intraocular 
pressure, or those at risk of acute narrow-angle glaucoma. 
 
Blood pressure and heart rate 
Duloxetine has been associated with an increase in blood pressure and clinically significant 
hypertension in some patients. This may be due to the noradrenergic effect of duloxetine. Cases of 
hypertensive crisis have been reported with duloxetine, especially in patients with pre-existing 
hypertension. Therefore,in patients with known hypertension and/or other cardiac disease, blood 
pressure monitoring is recommended, especially during the first month of treatment. Duloxetine 
should be used with caution in patients whose conditions could be compromised by an increased heart 
rate or by an increase in blood pressure. Caution should also be exercised when duloxetine is used 
with medicinal products that may impair its metabolism (see section 4.5). For patients who experience 
a sustained increase in blood pressure while receiving duloxetine either dose reduction or gradual 
discontinuation should be considered (see section 4.8). In patients with uncontrolled hypertension 
duloxetine should not be initiated (see section 4.3). 
 



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Renal impairment 
Increased plasma concentrations of duloxetine occur in patients with severe renal impairment on 
haemodialysis (creatinine clearance <30 ml/min).  For patients with severe renal impairment, see 
section 4.3. See section 4.2 for information on patients with mild or moderate renal dysfunction. 
 
Use with antidepressants 
Caution should be exercised when using DULOXETINE BOEHRINGER INGELHEIM in 
combination with antidepressants. In particular the combination with selective reversible MAOIs is not 
recommended. 
 
St John’s wort 
Undesirable effects may be more common during concomitant use of DULOXETINE BOEHRINGER 
INGELHEIM and herbal preparations containing St John’s wort (Hypericum perforatum). 
 
Depression, suicidal ideation and behaviour 
Although DULOXETINE BOEHRINGER INGELHEIM is not indicated for the treatment of 
depression, its active ingredient (duloxetine) also exists as an antidepressant medication. Depression is 
associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). 
This risk persists until significant remission occurs. As improvement may not occur during the first 
few weeks or more of treatment, patients should be closely monitored until such improvement occurs. 
It is general clinical experience that the risk of suicide may increase in the early stages of recovery. 
Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal 
thoughts prior to commencement of treatment are known to be at a greater risk of suicidal thoughts or 
suicidal behaviour, and should receive careful monitoring during treatment. A meta-analysis of 
placebo-controlled clinical trials of antidepressant medicinal products in psychiatric disorders showed 
an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 
25 years old. 
Cases of suicidal thoughts and suicidal behaviours have been reported during duloxetine therapy or 
early after treatment discontinuation (see section 4.8). Physicians should encourage patients to report 
any distressing thoughts or feelings or depressive symptoms at any time. If while on DULOXETINE 
BOEHRINGER INGELHEIM therapy, the patient develops agitation or depressive symptoms, 
specialised medical advice should be sought, as depression is a serious medical condition. If a decision 
to initiate antidepressant pharmacological therapy is taken, the gradual discontinuation of 
DULOXETINE BOEHRINGER INGELHEIM is recommended (see Section 4.2). 
 
Use in children and adolescents under 18 years of age 
No clinical trials have been conducted with duloxetine in paediatric populations. DULOXETINE 
BOEHRINGER INGELHEIM should not be used in the treatment of children and adolescents under 
the age of 18 years. Suicide-related behaviours (suicide attempts and suicidal thoughts), and hostility 
(predominantly aggression, oppositional behaviour and anger), were more frequently observed in 
clinical trials among children and adolescents treated with antidepressants compared to those treated 
with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be 
carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in 
children and adolescents concerning growth, maturation and cognitive and behavioural development 
are lacking. 
 
Haemorrhage  
There have been reports of bleeding abnormalities, such as ecchymoses, purpura and gastrointestinal 
haemorrhage with selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline 
reuptake inhibitors (SNRIs). Caution is advised in patients taking anticoagulants and/or medicinal 
products known to affect platelet function, and in patients with known bleeding tendencies. 
 



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Hyponatremia 
Hyponatremia has been reported rarely, predominantly in the elderly, when administering 
DULOXETINE BOEHRINGER INGELHEIM. Caution is required in patients at increased risk for 
hyponatremia; such as elderly, cirrhotic, or dehydrated patients or patients treated with diuretics. 
Hyponatremia may be due to a syndrome of inappropriate anti-diuretic hormone secretion (SIADH). 
 
Discontinuation of treatment 
Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is 
abrupt (see section 4.8). In clinical trials adverse events seen on abrupt treatment discontinuation 
occurred in approximately 45% of patients treated with DULOXETINE BOEHRINGER INGELHEIM 
and 23% of patients taking placebo.  
The risk of withdrawal symptoms seen with SSRI’s and SNRI’s may be dependent on several factors 
including the duration and dose of therapy and the rate of dose reduction. The most commonly 
reported reactions are listed in section 4.8. Generally these symptoms are mild to moderate, however, 
in some patients they may be severe in intensity.  They usually occur within the first few days of 
discontinuing treatment, but there have been very rare reports of such symptoms in patients who have 
inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 
weeks, though in some individuals they may be prolonged (2-3 months or more).  It is therefore 
advised that duloxetine should be gradually tapered when discontinuing treatment over a period of no 
less than 2 weeks, according to the patient’s needs (see section 4.2). 
 
Akathisia/psychomotor restlessness 
The use of duloxetine has been associated with the development of akathisia, characterised by a 
subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability 
to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who 
develop these symptoms, increasing the dose may be detrimental. 
 
Medicinal products containing duloxetine 
Duloxetine is used under different trademarks in several indications (treatment of diabetic neuropathic 
pain, major depressive episodes as well as stress urinary incontinence). The use of more than one of 
these products concomitantly should be avoided. 
 
Hepatitis/increased liver enzymes 
Cases of liver injury, including severe elevations of liver enzymes (>10 times upper limit of normal), 
hepatitis and jaundice have been reported with duloxetine (see section 4.8). Most of them occurred 
during the first months of treatment. The pattern of liver damage was predominantly hepatocellular. 
Duloxetine should be used with caution in patients treated with other medicinal products associated 
with hepatic injury. 
 
Sucrose 
DULOXETINE BOEHRINGER INGELHEIM gastro-resistant capsules contain sucrose. Patients with 
rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-
isomaltase insufficiency should not take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
CNS medicinal products: the risk of using duloxetine in combination with other CNS-active medicinal 
products has not been systematically evaluated, except in the cases described in this section. 
Consequently, caution is advised when DULOXETINE BOEHRINGER INGELHEIM is taken in 
combination with other centrally acting medicinal products and substances including alcohol and 
sedative medicinal products (e.g. benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, 
sedative antihistamines). 
 
Monoamine Oxidase Inhibitors (MAOIs): due to the risk of serotonin syndrome, DULOXETINE 
BOEHRINGER INGELHEIM should not be used in combination with nonselective irreversible 
monoamine oxidase inhibitors (MAOIs), or within at least 14 days of discontinuing treatment with an 



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MAOI. Based on the half-life of duloxetine, at least 5 days should be allowed after stopping 
DULOXETINE BOEHRINGER INGELHEIM before starting an MAOI (see section 4.3). 
 
For selective, reversible MAOIs, like moclobemide, the risk of serotonin syndrome is lower. However, 
the concomitant use of DULOXETINE BOEHRINGER INGELHEIM with selective, reversible 
MAOIs is not recommended (see section 4.4). 
 
Serotonin syndrome: in rare cases, serotonin syndrome has been reported in patients using SSRIs (e.g. 
paroxetine, fluoxetine) concomitantly with serotonergic medicinal products. Caution is advisable if 
DULOXETINE BOEHRINGER INGELHEIM is used concomitantly with serotonergic 
antidepressants like SSRIs, tricyclics like clomipramine or amitriptyline, St John’s wort (Hypericum 
perforatum), venlafaxine or triptans, tramadol, pethidine and tryptophan. 
 
Effect of duloxetine on other medicinal products 
Medicinal products metabolised by CYP1A2: The pharmacokinetics of theophylline, a CYP1A2 
substrate, were not significantly affected by co-administration with duloxetine (60 mg twice daily).  
Medicinal products metabolised by CYP2D6: Duloxetine is a moderate inhibitor of CYP2D6. When 
duloxetine was administered at a dose of 60 mg twice daily with a single dose of desipramine, a 
CYP2D6 substrate, the AUC of desipramine increased 3-fold. The co-administration of duloxetine (40 
mg twice daily) increases steady state AUC of tolterodine (2 mg twice daily) by 71 %, but does not 
affect the pharmacokinetics of its active 5-hydroxyl metabolite and no dosage adjustment is 
recommended. Caution is advised if DULOXETINE BOEHRINGER INGELHEIM is co-administered 
with medicinal products that are predominantly metabolised by CYP2D6 (risperidone, tricyclic 
antidepressants [TCAs] such as nortriptyline, amitriptyline, and imipramine) particularly if they have a 
narrow therapeutic index (such as flecainide, propafenone and metoprolol). 
 
Oral contraceptives and other steroidal agents: results of in vitro studies demonstrate that duloxetine 
does not induce the catalytic activity of CYP3A. Specific in vivo drug interaction studies have not 
been performed. 
 
Anticoagulants and antiplatelet agents: Caution should be exercised when duloxetine is combined 
with oral anticoagulants or antiplatelet agents due to a potential increased risk of bleeding attributable 
to a pharmacodynamic interaction. Furthermore, increases in INR values have been reported when 
duloxetine was co-administered to patients treated with warfarin. However, concomitant 
administration of duloxetine with warfarin under steady state conditions, in healthy volunteers, as part 
of a clinical pharmacology study, did not result in a clinically significant change in INR from baseline 
or in the pharmacokinetics of R- or S-warfarin. 
 
Effects of other medicinal products on duloxetine 
Antacids and H2 antagonists: co-administration of duloxetine with aluminium- and magnesium-
containing antacids or duloxetine with famotidine had no significant effect on the rate or extent of 
duloxetine absorption after administration of a 40 mg oral dose. 
 
Inhibitors of CYP 1A2: because CYP1A2 is involved in duloxetine metabolism, concomitant use of 
duloxetine with potent inhibitors of CYP1A2 is likely to result in higher concentrations of duloxetine. 
Fluvoxamine (100 mg once daily), a potent inhibitor of CYP1A2, decreased the apparent plasma 
clearance of duloxetine by about 77% and increased AUCo-t 6-fold. Therefore DULOXETINE 
BOEHRINGER INGELHEIM should not be administered in combination with potent inhibitors of 
CYP1A2 like fluvoxamine (see section 4.3). 
 
Inducers of CYP1A2: Population pharmacokinetic analyses have shown that smokers have almost 50% 
lower plasma concentrations of duloxetine compared with non-smokers. 
 



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4.6 Pregnancy and lactation 
 
Pregnancy  
There are no data on the use of duloxetine in pregnant women. Studies in animals have shown 
reproductive toxicity at systemic exposure levels (AUC) of duloxetine lower than the maximum 
clinical exposure (see section 5.3).  
The potential risk for humans is unknown. As with other serotonergic medicinal products, 
discontinuation symptoms may occur in the neonate after maternal duloxetine use near term. 
DULOXETINE BOEHRINGER INGELHEIM should be used in pregnancy only if the potential 
benefit justifies the potential risk to the foetus. Women should be advised to notify their physician if 
they become pregnant, or intend to become pregnant, during therapy.  
 
Breast feeding 
Duloxetine is very weakly excreted into human milk based on a study of 6 lactating patients, who did  
not breast feed their children . The estimated daily infant dose on a mg/kg basis is approximately 
0.14% of the maternal dose (see section 5.2). As the safety of duloxetine in infants is not known, the 
use of DULOXETINE BOEHRINGER INGELHEIM while breast-feeding is not recommended. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed. 
DULOXETINE BOEHRINGER INGELHEIM may be associated with sedation and dizziness. 
Patients should be instructed that if they experience sedation or dizziness they should avoid potentially 
hazardous tasks such as driving or operating machinery. 
 
4.8 Undesirable effects 
 
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled 
clinical trials (comprising a total of 6828 patients, 4199 on duloxetine and 2629 on placebo).  
The most commonly observed adverse reactions in patients with diabetic neuropathic pain treated with 
DULOXETINE BOEHRINGER INGELHEIM were: nausea; headache, dry mouth and somnolence 
and dizziness. 
 
Table 1: Adverse reactions 
Frequency estimate: Very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1,000 and 
<1/100), rare (≥ 1/10,000 and <1/1,000), very rare (<1/10,000), not known (cannot be estimated from 
the available data). 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 
Very common Common Uncommon Rare Very Rare Frequency not 

known 
Investigations 
 Weight decrease  Weight increase 

Creatine 
phosphokinase 
increased 

Blood 
cholesterol 
increased 

  

Cardiac Disorders 
 Palpitations Tachycardia 

Supra-
ventricular 
arrhythmia, 
mainly atrial 
fibrillation 

   

Nervous System Disorders 
Headache 
(14.3%) 
Somnolence 

Tremor 
Paraesthesia 
 

Myoclonus 
Nervousness 
Disturbance in 

 
Convulsion1 
 

 Serotonin 
syndrome 
Extra-pyramidal 



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Very common Common Uncommon Rare Very Rare Frequency not 
known 

(10.7%) 
Dizziness 
(10.2%) 

attention 
Lethargy 
Dysgeusia 
Dyskinesia 
Restless legs 
syndrome 
Poor quality 
sleep 
 

symptoms 
Akathisia 
Psychomotor 
restlessness 
 

Eye Disorders 
 Blurred vision Mydriasis 

Visual 
disturbance 
 

Glaucoma   

Ear and Labyrinth Disorders 
 Tinnitus1  Vertigo 

Ear pain 
   

Respiratory, thoracic and mediastinal disorders 
 Yawning Throat tightness 

Epistaxis 
   

Gastrointestinal Disorders  
Nausea (24.3%) 
Dry mouth 
(12.8%) 
 

Constipation 
Diarrhoea 
Vomiting  
Dyspepsia 
Flatulence 

Gastroenteritis 
Eructation 
Gastritis 
 

Stomatitis 
Breath odour 
Haematochezia 
 

 Gastrointestina-l 
haemorrhage 
 

Renal and Urinary Disorders 
  Urinary 

Retention 
Dysuria 
Urinary 
hesitation 
Nocturia 
Polyuria 
Urine flow 
decreased 

Urine odour 
abnormal 

  

Skin and Subcutaneous Tissue Disorders 
 Sweating 

increased 
Rash 
 

Night sweats 
Urticaria 
Dermatitis 
contact 
Cold sweat 
Photo-
sensitivity 
reactions 
Increased 
tendency to 
bruise 
 
 

  Angio-neurotic 
oedema 
Stevens-
Johnson 
Syndrome 
 

Musculoskeletal and connective tissue disorders 
 Musculo-

skeletal pain 
Muscle 

Muscle 
twitching 
 

Trismus   



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Very common Common Uncommon Rare Very Rare Frequency not 
known 

tightness 
Muscle spasm 

Endocrine disorders 
   Hypo-

thyroidism 
  

Metabolism and Nutrition Disorders 
 Decreased 

Appetite  
Hyperglycemia 
(reported 
especially in 
diabetic 
patients) 

Dehydration 
Hyponatremia 
 

 SIADH 
 

Infections and infestations 
  Laryngitis    
Vascular Disorders 
 Flushing Blood pressure 

increase 
Peripheral 
coldness 
Orthostatic 
hypotension2 
Syncope2 
 

  Hypertension 
Hypertensive 
crisis 
 

General Disorders and Administration Site Conditions 
 Fatigue 

Abdominal pain 
 

Feeling 
abnormal 
Feeling cold 
Thirst 
Chills 
Malaise 
Feeling hot 
Gait disturbance 
 
 

  Chest pain  
 

Immune system disorders 
   Hyper-

sensitivity 
disorder 
Anaphylactic 
reaction 

  

Hepato-biliary disorders 
  Elevated liver 

enzymes (ALT, 
AST, alkaline 
phosphatase) 
Hepatitis3 
Acute liver 
injury 
 

  Jaundice 
Hepatic failure 

Reproductive System and Breast Disorders 
 Erectile 

dysfunction 
Ejaculation 
disorder  
Ejaculation 
delayed 
Sexual 

Menopausal 
symptoms 
 

  



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Very common Common Uncommon Rare Very Rare Frequency not 
known 

dysfunction  
Gynaecological 
haemorrhage 

Psychiatric Disorders 
 Insomnia 

Agitation 
Libido 
decreased 
Anxiety 
Orgasm 
abnormal 
Abnormal 
dreams 
 

Sleep disorder 
Bruxism 
Disorientation 
Apathy 
 

Mania 
Hallucinations 
Aggression and 
anger4 

 Suicidal 
ideation 5 
Suicidal5 
behaviour 
 

1 Cases of convulsion and cases of tinnitus have also been reported after treatment discontinuation. 
2Cases of orthostatic hypotension and syncope have been reported especially at the initiation of 
treatment. 
3See section 4.4 
4Cases of aggression and anger have been reported particularly early in treatment of after treatment 
discontinuation. 
5Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or 
early after treatment discontinuation (see section 4.4) 
 
Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms. 
Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and 
intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, headache, irritability, diarrhoea, 
hyperhydrosis and vertigo are the most commonly reported reactions. 
Generally, for SSRIs and SNRIs, these events are mild to moderate and self-limiting, however, in 
some patients they may be severe and/or prolonged. It is therefore advised that when duloxetine 
treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see 
sections 4.2 and 4.4). 
 
In the 12 week acute phase of three clinical trials of duloxetine in patients with diabetic neuropathic 
pain, small but statistically significant increases in fasting blood glucose were observed in duloxetine-
treated patients HbA1c was stable in both duloxetine-treated and placebo-treated patients. In the 
extension phase of these studies, which lasted up to 52 weeks, there was an increase in HbA1c in both 
the duloxetine and routine care groups, but the mean increase was 0.3% greater in the duloxetine-
treated group. There was also a small increase in fasting blood glucose and in total cholesterol in 
duloxetine-treated patients while those laboratory tests showed a slight decrease in the routine care 
group.  
 
Electrocardiograms were obtained from 528 duloxetine-treated and 205 placebo-treated patients with 
diabetic neuropathic pain in clinical trials lasting up to 13-weeks. The heart rate-corrected QT interval 
in duloxetine-treated patients did not differ from that seen in placebo-treated patients. No clinically 
significant differences were observed for QT, PR, QRS, or QTcB measurements between duloxetine-
treated and placebo-treated patients. 
 
4.9 Overdose 
 
Cases of overdoses, alone or in combination with other medicinal products, with duloxetine doses of 
5400mg were reported. Some fatalities have occurred, primarily with mixed overdoses, but also with 
duloxetine alone at a dose of approximately 1000 mg. Signs and symptoms of overdose (duloxetine 
alone or in combination with other medicinal products) included somnolence, coma, serotonin 
syndrome, seizures, vomiting and tachycardia.   
 



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No specific antidote is known for duloxetine but if serotonin syndrome ensues, specific treatment 
(such as with cyproheptadine and/or temperature control) may be considered. A free airway should be 
established. Monitoring of cardiac and vital signs is recommended, along with appropriate 
symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after 
ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption. 
Duloxetine has a large volume of distribution and forced diuresis, haemoperfusion, and exchange 
perfusion are unlikely to be beneficial. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other antidepressants. ATC code: N06AX21. 
 
Duloxetine is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weakly 
inhibits dopamine reuptake with no significant affinity for histaminergic, dopaminergic, cholinergic 
and adrenergic receptors. Duloxetine dose-dependently increases extracellular levels of serotonin and 
noradrenaline in various brain areas of animals. 
 
Duloxetine normalised pain thresholds in several preclinical models of neuropathic and inflammatory 
pain and attenuated pain behaviour in a model of persistent pain. The pain inhibitory action of 
duloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within the 
central nervous system. 
 
The efficacy of duloxetine as a treatment for diabetic neuropathic pain was established in 2 
randomised, 12-week, double-blind, placebo-controlled, fixed dose studies in adults (22 to 88 years) 
having diabetic neuropathic pain for at least 6 months.  Patients meeting diagnostic criteria for major 
depressive disorder were excluded from these trials.  The primary outcome measure was the weekly 
mean of 24-hour average pain, which was collected in a daily diary by patients on an 11-point Likert 
scale. 
 
In both studies, duloxetine 60 mg once daily and 60 mg twice daily significantly reduced pain 
compared with placebo. The effect in some patients was apparent in the first week of treatment. The 
difference in mean improvement between the two active treatment arms was not significant.  At least 
30% reported pain reduction was recorded in approximately 65% of duloxetine treated patients versus 
40% for placebo. The corresponding figures for at least 50% pain reduction were 50% and 26% 
respectively. Clinical response rates (50% or greater improvement in pain) were analysed according to 
whether or not the patient experienced somnolence during treatment. For patients not experiencing 
somnolence, clinical response was observed in 47% of patients receiving duloxetine and 27% patients 
on placebo.  Clinical response rates in patients experiencing somnolence were 60% on duloxetine and 
30% on placebo. Patients not demonstrating a pain reduction of 30% within 60 days of treatment were 
unlikely to reach this level during further treatment. 
 
In an open label long-term uncontrolled study, the pain reduction in patients responding to 8-weeks of 
acute treatment of DULOXETINE BOEHRINGER INGELHEIM 60 mg once daily was maintained 
for a further 6-months as measured by change on the Brief Pain Inventory (BPI) 24-hour average pain 
item. 
 
5.2 Pharmacokinetic properties 
 
Duloxetine is administered as a single enantiomer. Duloxetine is extensively metabolised by oxidative 
enzymes (CYP1A2 and the polymorphic CYP2D6), followed by conjugation. The pharmacokinetics 
of duloxetine demonstrate large intersubject variability (generally 50-60%), partly due to gender, age, 
smoking status and CYP2D6 metaboliser status.  
Duloxetine is well absorbed after oral administration with a Cmax occurring 6 hours post dose. The 
absolute oral bioavailability of duloxetine ranged from 32% to 80% (mean of 50%). Food delays the 



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time to reach the peak concentration from 6 to 10 hours and it marginally decreases the extent of 
absorption (approximately 11 %). These changes do not have any clinical significance. Duloxetine is 
approximately 96% bound to human plasma proteins. Duloxetine binds to both albumin and alpha-l 
acid glycoprotein. Protein binding is not affected by renal or hepatic impairment. 
 
Duloxetine is extensively metabolised and the metabolites are excreted principally in urine. Both 
cytochromes P450-2D6 and 1A2 catalyse the formation of the two major metabolites glucuronide 
conjugate of 4-hydroxy duloxetine and sulphate conjugate of 5hydroxy,6-methoxy duloxetine. Based 
upon in vitro studies, the circulating metabolites of duloxetine are considered pharmacologically 
inactive. The pharmacokinetics of duloxetine in patients who are poor metabolisers with respect to 
CYP2D6 has not been specifically investigated. Limited data suggest that the plasma levels of 
duloxetine are higher in these patients. 
 
The elimination half-life of duloxetine ranges from 8 to 17 hours (mean of 12 hours). After an 
intravenous dose the plasma clearance of duloxetine ranges from 22 l/hr to 46 l/hr (mean of 36 l/hr).  
After an oral dose the apparent plasma clearance of duloxetine ranges from 33 to 261 l/hr (mean 101 
l/hr). 
 
Special populations: 
Gender: pharmacokinetic differences have been identified between males and females (apparent 
plasma clearance is approximatively 50% lower in females). Based upon the overlap in the range of 
clearance, gender-based pharmacokinetic differences do not justify the recommendation for using a 
lower dose for female patients.  
 
Age: pharmacokinetic differences have been identified between younger and elderly females (≥65 
years) (AUC increases by about 25% and half-life is about 25% longer in the elderly), although the 
magnitude of these changes is not sufficient to justify adjustments to the dose. As a general 
recommendation, caution should be exercised when treating the elderly (see sections 4.2 and 4.4). 
 
Renal impairment: end stage renal disease (ESRD) patients receiving dialysis had 2-fold higher 
duloxetine Cmax and AUC values compared with healthy subjects. Pharmacokinetic data on 
duloxetine is limited in patients with mild or moderate renal impairment. 
 
Hepatic impairment: moderate liver disease (Child Pugh Class B) affected the pharmacokinetics of 
duloxetine. Compared with healthy subjects, the apparent plasma clearance of duloxetine was 79% 
lower, the apparent terminal half-life was 2.3 times longer, and the AUC was 3.7 times higher in 
patients with moderate liver disease. The pharmacokinetics of duloxetine and its metabolites have not 
been studied in patients with mild or severe hepatic insufficiency. 
 
Nursing mothers: The disposition of duloxetine was studied in 6 lactating women who were at least 
12-weeks postpartum. Duloxetine is detected in breast milk, and steady-state concentrations in breast 
milk are about one-fourth those in plasma. The amount of duloxetine in breast milk is approximately 
7 µg/day while on 40 mg twice daily dosing. Lactation did not influence duloxetine pharmacokinetics 
 
5.3 Preclinical safety data 
 
Duloxetine was not genotoxic in a standard battery of tests and was not carcinogenic in rats.  
Multinucleated cells were seen in the liver in the absence of other histopathological changes in the rat 
carcinogenicity study. The underlying mechanism and the clinical relevance are unknown. Female 
mice receiving duloxetine for 2 years had an increased incidence of hepatocellular adenomas and 
carcinomas at the high dose only (144 mg/kg/day), but these were considered to be secondary to 
hepatic microsomal enzyme induction. The relevance of this mouse data to humans is unknown. 
Female rats receiving duloxetine (45 mg/kg/day) before and during mating and early pregnancy had a 
decrease in maternal food consumption and body weight, oestrous cycle disruption, decreased live 
birth indices and progeny survival, and progeny growth retardation at systemic exposure levels 
estimated to be at the most at maximum clinical exposure (AUC). In an embryotoxicity study in the 
rabbit, a higher incidence of cardiovascular and skeletal malformations was observed at systemic 



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exposure levels below the maximum clinical exposure (AUC). No malformations were observed in 
another study testing a higher dose of a different salt of duloxetine. In prenatal/postnatal toxicity 
studies in the rat, duloxetine induced adverse behavioural effects in the offspring at exposures below 
maximum clinical exposure (AUC). 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule content: 
Hypromellose. 
Hypromellose Acetate Succinate 
Sucrose 
Sugar spheres 
Talc 
Titanium dioxide (E171) 
Triethyl citrate. 
 
Capsule shell: 
60 mg: 
Gelatin 
Sodium Lauryl Sulfate 
Titanium Dioxide (E171) 
Indigo Carmine (E132) 
Yellow Iron Oxide (E172) 
Edible White Ink  
 
Edible White Ink contains: 
Titanium Dioxide (E171) 
Propylene glycol 
Shellac 
Povidone. 
  
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Store in the original package in order to protect from moisture. Do not store above 30 C. 
 
6.5 Nature and contents of container 
 
Polyvinylchloride (PVC), Polyethylene (PE), and Polychlorotrifluoroethylene (PCTFE) blister sealed 
with an aluminum foil. 
 
DULOXETINE BOEHRINGER INGELHEIM 60 mg is available in packs of 28 and 98 capsules. 
 
Not all pack sizes may be marketed. 
 



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6.6 Special precautions for disposal  
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Boehringer Ingelheim International GmbH, Binger Str. 173 D-55216 Ingelheim am Rhein, Germany. 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/471/011-012 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
8th October 2008 
 
10. DATE OF REVISION OF THE TEXT 
 



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ANNEX II 
 
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE 

FOR BATCH RELEASE 
 
B. CONDITIONS OF THE MARKETING AUTHORISATION 
 



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A MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
Name and address of the manufacturer responsible for batch release 
 
Lilly S.A.  
Avda. de la Industria Nº 30,  
28108 Alcobendas  
Madrid 
Spain 
 
 
B CONDITIONS OF THE MARKETING AUTHORISATION 
 
• CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON 

THE MARKETING AUTHORISATION HOLDER 
 
Medicinal product subject to medical prescription 
 
• CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
Not applicable. 
 
• OTHER CONDITIONS 
 
Pharmacovigilance system 
The MAH must ensure that the system of pharmacovigilance, as described in Edition 5.2 
dated April 2009 presented in Module 1.8.1. of the Marketing Authorisation Application, is in 
place and functioning before and whilst the product is on the market. 
 
Risk Management Plan 
The MAH commits to performing the studies and additional pharmacovigilance activities 
detailed in the Pharmacovigilance Plan, as agreed in Revision 0 of 24 April 2008 of the Risk 
Management Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation 
Application and any subsequent updates of the RMP agreed by the CHMP. 
 
As per the CHMP Guideline on Risk Management Systems for medicinal products for human 
use, the updated RMP should be submitted at the same time as the next Periodic Safety 
Update Report (PSUR). 
 
In addition, an updated RMP should be submitted 

• When new information is received that may impact on the current Safety Specification, 
Pharmacovigilance Plan or risk minimisation activities 

• Within 60 days of an important (pharmacovigilance or risk minimisation) milestone 
being reached 

• At the request of the EMEA  
 
PSURs 
 
The PSUR cycle of Duloxetine Boehringer Ingelheim will correspond to the one attributed to 
the cross-referred product, Ariclaim, until otherwise specified.  



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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



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A. LABELLING 



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PARTICULARS TO APPEAR ON THE  OUTER PACKAGING 
 
CARTONS FOR 30 MG HARD GASTRO-RESISTANT CAPSULES 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
DULOXETINE BOEHRINGER INGELHEIM 30 mg, hard gastro-resistant capsules. 
Duloxetine  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 30 mg of duloxetine (as hydrochloride) 
 
 
3. LIST OF EXCIPIENTS 
 
Contains sucrose 
See leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
7 hard gastro-resistant capsules, 
28 hard gastro-resistant capsules 
98 hard gastro-resistant capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS
 
Store in the original package. Do not store above 30°C 
 
 



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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Boehringer Ingelheim International GmbH, Binger Str. 173 D-55216 Ingelheim am Rhein, Germany. 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/08/471/003 
EU/1/08/471/004 
EU/1/08/471/005 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
DULOXETINE BOEHRINGER INGELHEIM 30 mg  



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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
30 mg hard gastro-resistant capsules 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
DULOXETINE BOEHRINGER INGELHEIM  30 mg hard gastro-resistant capsules 
Duloxetine 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Boehringer Ingelheim 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTONS FOR 60 MG HARD GASTRO-RESISTANT CAPSULES 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
DULOXETINE BOEHRINGER INGELHEIM 60 mg, hard gastro-resistant capsules. 
Duloxetine  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 60 mg of duloxetine (as hydrochloride) 
 
 
3. LIST OF EXCIPIENTS 
 
Contains sucrose 
See leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28, hard gastro-resistant capsules 
98, hard gastro-resistant capsules. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS
 
Store in the original package. Do not store above 30°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 



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APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Boehringer Ingelheim International GmbH, Binger Str. 173 D-55216 Ingelheim am Rhein, Germany. 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/08/471/011 
EU/1/08/471/012 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
DULOXETINE BOEHRINGER INGELHEIM 60 mg 



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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
60 mg hard gastro-resistant capsules 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
DULOXETINE BOEHRINGER INGELHEIM  60 mg  hard gastro-resistant capsules 
Duloxetine 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Boehringer Ingelheim 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 



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B. PACKAGE LEAFLET 
 



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PACKAGE LEAFLET: INFORMATION FOR THE USER 

 
DULOXETINE BOEHRINGER INGELHEIM 30 mg hard gastro-resistant capsules 
DULOXETINE BOEHRINGER INGELHEIM 60 mg hard gastro-resistant capsules 

Duloxetine (as hydrochloride) 
 
 

Read all of this leaflet carefully before you start taking this medicine. 
- 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. Do not pass it on to others. It may harm them, even 

if their symptoms are the same as yours 
- If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 

please tell your doctor or pharmacist 
 
In this leaflet:  
1. What DULOXETINE BOEHRINGER INGELHEIM is and what it is used for 
2. Before you take DULOXETINE BOEHRINGER INGELHEIM 
3. How to take DULOXETINE BOEHRINGER INGELHEIM 
4. Possible side effects 
5 How to store DULOXETINE BOEHRINGER INGELHEIM 
6. Further information 
 
 
1. WHAT DULOXETINE BOEHRINGER INGELHEIM IS AND WHAT IT IS USED FOR 
 
DULOXETINE BOEHRINGER INGELHEIM increases the levels of serotonin and noradrenaline in 
the nervous system. 
 
DULOXETINE BOEHRINGER INGELHEIM is used in adults to treat a condition called diabetic 
neuropathic pain (often described as burning, stabbing, stinging, shooting or aching or like an electric 
shock. There may be loss of feeling in the affected area, or sensations such as touch, heat, cold or 
pressure may cause pain). 
 
The effect of DULOXETINE BOEHRINGER INGELHEIM may be noticeable in many patients with 
diabetic neuropathic pain within 1 week of treatment. 
 
 
2. BEFORE YOU TAKE DULOXETINE BOEHRINGER INGELHEIM 
 
DO NOT take DULOXETINE BOEHRINGER INGELHEIM if you: 
− are allergic (hypersensitive) to duloxetine or any of the other ingredients of DULOXETINE 

BOEHRINGER INGELHEIM 
− have liver disease 
− have severe kidney disease are taking or have recently taken within the last 14 days, another 

antidepressant medicine called a monoamine oxidase inhibitor (MAOI) (see also below in 
section: ‘Taking other medicines’) 

−  
− are taking fluvoxamine which is usually used to treat depression, ciprofloxacin or enoxacine 

which are used to treat some infections 
 
Talk to your doctor if you have high blood pressure. Your doctor will tell you if you should be taking 
DULOXETINE BOEHRINGER INGELHEIM. 
 
Take special care with DULOXETINE BOEHRINGER INGELHEIM 



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The following are reasons why DULOXETINE BOEHRINGER INGELHEIM may not be suitable for 
you. Talk to your doctor before you take the medicine if you: 
 
- are taking other medicines to treat depression(see ‘Taking other medicines’) 
- are taking St. John’s Wort, a herbal treatment (Hypericum perforatum) 
- have kidney disease 
- have had seizures (fits) 
- have had mania  
- suffer from  bipolar disorder 
- have eye problems, such as certain kinds of glaucoma (increased pressure in the eye) 
- have a history of bleeding disorders (tendency to develop bruises) 
- are at risk of low sodium levels 
- are currently being treated with another medicine which may cause liver damage 
- are taking other medicines containing duloxetine 
- have intolerance to some sugars (see end of Section 2) 
- are considering stopping DULOXETINE BOEHRINGER INGELHEIM (see section 3) 
 
DULOXETINE BOEHRINGER INGELHEIM may cause a sensation of restlessness or an inability to 
sit or stand still. You should tell your doctor if this happens to you. 
 
Thoughts of suicide and worsening of your depression or anxiety disorder 
If you are depressed and/or have anxiety disorders you can sometimes have thoughts of harming or 
killing yourself. These may be increased when first starting antidepressants, since these medicines all 
take time to work, usually about two weeks but sometimes longer. 
You may be more likely to think like this if you:  
- have previously had thoughts about killing or harming yourself. 
- are a young adult. Information from clinical trials has shown an increased risk of suicidal 

behaviour in adults aged less than 25 years with psychiatric conditions who were treated with an 
antidepressant.     

If you have thoughts of harming or killing yourself at any time, contact your doctor or go to a 
hospital straight away. 
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 might ask them to tell you if they think your depression 
or anxiety is getting worse, or if they are worried about changes in your behaviour. 
 
Use in children and adolescents under 18 years of age 
DULOXETINE BOEHRINGER INGELHEIM should normally not be used for children and 
adolescents under 18 years. Also, you should know that patients under 18 have an increased risk of 
side-effects such as suicide attempt, suicidal thoughts and hostility (predominantly aggression, 
oppositional behaviour and anger) when they take this class of medicines. Despite this, your doctor 
may prescribe DULOXETINE BOEHRINGER INGELHEIM for patients under 18 because he/she 
decides that this is in their best interests. If your doctor has prescribed DULOXETINE 
BOEHRINGER INGELHEIM for a patient under 18 and you want to discuss this, please go back to 
your doctor. You should inform your doctor if any of the symptoms listed above develop or worsen 
when patients under 18 are taking DULOXETINE BOEHRINGER INGELHEIM. Also, the long-term 
safety effects concerning growth, maturation, and cognitive and behavioural development of 
DULOXETINE BOEHRINGER INGELHEIM in this age group have not yet been demonstrated. 
 
Taking other medicines 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription. The main ingredient of DULOXETINE 
BOEHRINGER INGELHEIM, duloxetine, is used in other medicines for other conditions:  
• depression, anxiety and urinary incontinence.  
Using more than one of these medicines at the same time should be avoided. Check with your doctor if 
you are already taking other medicines containing duloxetine.  



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Your doctor should decide whether you can take DULOXETINE BOEHRINGER INGELHEIM with 
other medicines. Do not start or stop taking any medicines, including those bought without a 
prescription and herbal remedies, before checking with your doctor.   
 
You should also tell your doctor if you are taking any of the following: 
 
Monoamine Oxidase Inhibitors (MAOIs): You should not take DULOXETINE BOEHRINGER 
INGELHEIM if you are taking, or have recently taken within the last 14 days, another antidepressant 
medicine called a monoamine oxidase inhibitor (MAOI).  Taking a MAOI together with many 
prescription medicines, including DULOXETINE BOEHRINGER INGELHEIM, can cause serious or 
even life-threatening side effects. You must wait at least 14 days after you have stopped taking an 
MAOI before you can take DULOXETINE BOEHRINGER INGELHEIM. Also, you need to wait at 
least 5 days after you stop taking DULOXETINE BOEHRINGER INGELHEIM before you take a 
MAOI. 
 
Medicines that cause sleepiness: These include medicines prescribed by your doctor including 
benzodiazepines, strong painkillers, antipsychotics, phenobarbital, antihistamines.  
 
Medicines that increase the level of serotonin: triptans, tramadol, tryptophan, SSRIs (such as 
paroxetine and fluoxetine), tricyclics (such as clomipramine, amitriptyline), pethidine, St John’s Wort 
and venlafaxine. These medicines increase the risk of side effects; if you get any unusual symptom 
taking any of these medicines together with DULOXETINE BOEHRINGER INGELHEIM, you 
should see your doctor. 
 
Oral anticoagulants: medicines which thin the blood. These medicines might increase the risk of 
bleeding. 
 
Taking DULOXETINE BOEHRINGER INGELHEIM with food and drink 
DULOXETINE BOEHRINGER INGELHEIM may be taken with or without food. Care should be 
taken if you drink alcohol while you are being treated with DULOXETINE BOEHRINGER 
INGELHEIM. 
 
Pregnancy and breast-feeding 
Ask your doctor or pharmacist for advice before taking any medicine. 
Tell your doctor if you  
• become pregnant, or you are trying to become pregnant, while you are taking DULOXETINE 

BOEHRINGER INGELHEIM. You should use DULOXETINE BOEHRINGER 
INGELHEIM only after discussing the potential benefits and any potential risks to your 
unborn child with your doctor. 

 
• are breast-feeding. The use of DULOXETINE BOEHRINGER INGELHEIM while 

breastfeeding is not recommended. You should ask your doctor or pharmacist for advice. 
 
Driving and using machines 
DULOXETINE BOEHRINGER INGELHEIM may make you feel sleepy of dizzy. Do not drive or 
use any tools or machines until you know how DULOXETINE BOEHRINGER INGELHEIM affects 
you. 
 
Important information about some of the ingredients of DULOXETINE BOEHRINGER 
INGELHEIM 
DULOXETINE BOEHRINGER INGELHEIM contains sucrose. If you have been told by your doctor 
that you have an intolerance to some sugars, contact your doctor before taking this medicinal product. 
 
 



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3. HOW TO TAKE DULOXETINE BOEHRINGER INGELHEIM 
 
Always take DULOXETINE BOEHRINGER INGELHEIM exactly as your doctor has told you. You 
should check with your doctor or pharmacist if you are not sure. 
 
The usual dose of DULOXETINE BOEHRINGER INGELHEIM is 1 capsule (60 mg) once a day, but 
your doctor will prescribe the dose that is right for you.  
 
DULOXETINE BOEHRINGER INGELHEIM is for oral use. You should swallow your capsule 
whole with a drink of water. 
 
To help you remember to take DULOXETINE BOEHRINGER INGELHEIM, you may find it easier 
to take it at the same times every day. 
 
Talk with your doctor about how long you should keep taking DULOXETINE BOEHRINGER 
INGELHEIM. Do not stop taking DULOXETINE BOEHRINGER INGELHEIM without talking to 
your doctor. 
 
If you take more DULOXETINE BOEHRINGER INGELHEIM than you should 
Call your doctor or pharmacist immediately if you take more than the amount of DULOXETINE 
BOEHRINGER INGELHEIM prescribed by your doctor. 
 
If you forget to take DULOXETINE BOEHRINGER INGELHEIM 
If you miss a dose, take it as soon as you remember. However, if it is time for your next dose, skip the 
missed dose and take only a single dose as usual. Do not take a double dose to make up for a forgotten 
dose. Do not take more than the daily amount of DULOXETINE BOEHRINGER INGELHEIM that 
has been prescribed for you in one day. 
 
If you stop taking DULOXETINE BOEHRINGER INGELHEIM 
DO NOT stop taking your capsules without the advice of your doctor even if you feel better. If your 
doctor thinks that you no longer need DULOXETINE BOEHRINGER INGELHEIM he or she will 
ask you to reduce your dose over at least 2 weeks before stopping treatment altogether.  
Some patients who stop taking DULOXETINE BOEHRINGER INGELHEIM suddenly have had 
symptoms such as : 
• dizziness, tingling feelings like pins and needles, sleep disturbances (vivid dreams, nightmares, 

inability to sleep), feeling restless or agitated, feeling anxious, feeling sick (nausea) or being 
sick (vomiting), tremor (shakiness), headaches, feeling irritable, diarrhoea, excessive sweating 
or vertigo.  These symptoms are usually not serious and disappear within a few days, but if 
you have symptoms that are troublesome you should ask your doctor for advice. 

 
If you have any further questions on the use of this product, ask your doctor or pharmacist. 
 
 
4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, DULOXETINE BOEHRINGER INGELHEIM can cause side effects, although not 
everybody gets them. These effects are normally mild to moderate and often disappear after a few 
weeks. 
 
Very common side effects (these can affect more than 10 in 100 patients treated) 
• feeling sick (nausea), somnolence, headache, dizziness and dry mouth 
 
Common side effects (these can affect from 1 to 10 users in 100 patients treated) 
• tiredness, trouble sleeping, anxiety, feeling agitated or having abnormal dreams 
• tremor or numbness, including numbness or tingling of the skin 
• diarrhoea, constipation, being sick (vomiting), heartburn, breaking wind, stomach pain 



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• tinnitus (perception of sound in the ear when there is no external sound) 
• blurred eyesight 
• feeling the heart pumping in the chest, flushing, increased sweating, night sweats 
• problems getting an erection, less sex drive 
• (itchy) rash 
• muscle pain, muscle tightness, muscle spasm 
• increased yawning 
• lack of appetite, weight loss 
 
Uncommon side effects (these can affect from 1 to 10 users in 1,000 patients treated) 
• throat inflammation 
• feeling disorientated, feeling sleepy, lack of motivation 
• tasting things differently than usual, disturbance in attention, stiffness, spasms and involuntary 

movements of the muscles, muscle twitching, abnormal manner of walking 
• poor sleep quality  
• restless legs syndrome 
• burping, indigestion, gastroenteritis 
• vertigo, ear pain 
• inflammation of the liver that may cause abdominal pain 
• large pupils (the dark centre of the eye), visual disturbance 
• fast or irregular heart beat 
• sexual problems, including changes in ejaculation and abnormal orgasm 
• abnormal periods, including heavy or prolonged periods 
• allergic reactions, increased tendency to bruise, blisters or sensitivity to sunlight 
• increase in blood pressure, feeling cold in your fingers and/or toes, feeling dizzy (particularly 

when standing up too quickly), cold sweats, shivering or fainting 
• an increased level of sugar in the blood 
• need to pass more urine than normal, need to pass urine during the night, difficulty or inability 

to pass urine or having an urine flow decreased 
• grinding of teeth, feeling hot/cold, thirst, throat tightness, nose bleeds 
• weight gain 

 
Rare side effects (these can affect from 1 to 10 users in 10,000 patients treated) 
• decreased thyroid gland activity 
• dehydration 
• mania (over activity, racing thoughts and decrease need for sleep) 
• bad breath 
• increased pressure in the eye (glaucoma) 
• menopausal symptoms 
• contraction of the jaw muscle 
• increased level of cholesterol in the blood, low levels of sodium in the blood (the symptoms are 

feeling sick and unwell with weak muscles or confused),  
• serious allergic reaction which causes difficulty in breathing or dizziness or hives 
• fits 
 
Other possible side effects  
• hallucinations, suicidal thoughts, behaviour aggression and anger 
• a sensation of restlessness or an inability to sit or stand still or “Serotonin syndrome” (a rare 

reaction which may cause feelings of great happiness, drowsiness, clumsiness, restlessness, 
feeling of being drunk, fever, sweating or rigid muscles) 

• passing bright red blood in your stools, vomiting blood, or black tarry stools (faeces) 
• having abnormal urine odour  
• syndrome of inadequate secretion of anti-diuretic hormone (SIADH) 
• chest pain 



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• yellow colouration of the skin (jaundice), hepatic failure, Stevens-Johnson syndrome, sudden 
swelling of skin or mucosa (angioedema) 

 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 
please tell your doctor. 
 
 
5. HOW TO STORE DULOXETINE BOEHRINGER INGELHEIM 
 
Keep out of the reach and sight of children 
 
Do not use DULOXETINE BOEHRINGER INGELHEIM after the expiry date which is stated on the 
carton. 
 
Store in the original package. Do not store above 30°C. 
 
 
6. FURTHER INFORMATION 
 
What DULOXETINE BOEHRINGER INGELHEIM contains 
The active substance is duloxetine.  
Each capsule contains 30 or 60 mg of duloxetine (as hydrochloride). 
 
The other ingredients are: 
Capsule content: 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 sulphate, titanium dioxide (E171), indigo carmine (E132), iron 
oxide yellow (E172) (60 mg only) and edible green ink (30 mg) or edible white ink (60 mg). 
Edible green ink: black iron oxide-synthetic (E172), yellow iron oxide- synthetic (E172), propylene 
glycol, shellac. 
Edible White Ink: titanium dioxide (E171), propylene glycol, shellac, povidone. 
 
What DULOXETINE BOEHRINGER INGELHEIM looks like and contents of the pack 
DULOXETINE BOEHRINGER INGELHEIM is a hard gastro-resistant capsule 
Each capsule of DULOXETINE BOEHRINGER INGELHEIM contains pellets of duloxetine 
hydrochloride with a covering to protect them from stomach acid.   
 
DULOXETINE BOEHRINGER INGELHEIM is available in two strengths: 30 and 60 mg. 
The 30 mg capsules has an opaque white body, imprinted with ‘30 mg’ and an opaque blue cap, 
imprinted with ‘9543’. 
The 60 mg capsules has an opaque green body, imprinted with ‘60 mg’ and an opaque blue cap, 
imprinted with ‘9542’. 
 
DULOXETINE BOEHRINGER INGELHEIM 30 mg is available in packs of 7, 28 and 98 capsules.  
DULOXETINE BOEHRINGER INGELHEIM 60 mg is available in packs of 28 and 98 capsules. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
Marketing Authorisation Holder: Boehringer Ingelheim International GmbH, Binger Str. 173 D-55216 
Ingelheim am Rhein, Germany. 
Manufacturer: Lilly S.A., Avda. De la Industria, 30,28108 Alcobendas, Madrid, Spain. 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 



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België/Belgique/Belgien 
S.C.S. Boehringer Ingelheim Comm.V. 
Tél/Tel: +32 27 73 33 11 

Luxembourg/Luxemburg 
S.C.S. Boehringer Ingelheim Comm.V. 
Tél/Tel: +32 2 773 33 11 
 

България 
ТП "Ели Лили Недерланд" Б.В. - България 
тел. + 359 2 491 41 40 

Magyarország 
Boehringer Ingelheim Pharma  
Tel.: +36 1 224 7120 
 

Česká republika 
Boehringer Ingelheim spol. s r.o.  
Tel.: + 42 02 34 65 51 11 

Malta 
Boehringer Ingelheim Ltd.  
Tel: +44 1344 424 600 
 

Danmark 
Boehringer Ingelheim Danmark A/S  
Tlf: +45 39 15 88 88 

Nederland 
Boehringer Ingelheim b.v.  
Tel: +31 30 6 02 59 14 
 

Deutschland 
Boehringer Ingelheim Pharma GmbH & Co. KG 
Tel: +49 (0) 69 50 50 83 09 

Norge 
Boehringer Ingelheim Norway KS  
Tlf: +47 66 76 13 00 
 

Eesti 
Boehringer Ingelheim Pharma GmbH  
Tel: + 37 2 60 80 940 

Österreich 
Boehringer Ingelheim Austria GmbH 
Tel: +43 1 80 105 0 
 

Ελλάδα 
Boehringer Ingelheim Ellas A.E. 
Tηλ: +30 2 10 89 06 300 

Polska 
Eli Lilly Polska Sp. z o.o. 
Tel. + 48 22 4403300 
 

España 
Boehringer Ingelheim España S.A. 
Tel: +34 93 404 58 00 

Portugal 
Boehringer Ingelheim, Lda  
Tel: +351 21 313 53 00 
 

France 
Boehringer Ingelheim France S.A.S.  
Tél: +33 3 26 50 45 33 
 

România 
Eli Lilly România S.R.L. 
Tel: + 40 21 4023000 

Ireland 
Boehringer Ingelheim Ireland Ltd.  
Tel: +353 1 295 9620 

Slovenija 
Boehringer Ingelheim Pharma  
Tel.: +386 1 586 40 00 
 

Ísland 
Vistor hf. 
Tel: +354 535 7000 

Slovenská republika 
Boehringer Ingelheim Pharma  
Tel.: +421 2  5341 8445 
 

Italia 
Boehringer Ingelheim Italia S.p.A. 
Tel: +39 02 535 51 

Suomi/Finland 
Boehringer Ingelheim Finland Ky 
Puh/Tel: +358 10 310 2800 
 

Κύπρος 
Boehringer Ingelheim Ellas A.E.  
Tηλ: +30 2 10 89 06 300 

Sverige 
Boehringer Ingelheim AB  
Tel: +46 8 721 21 00 
 

Latvija 
Boehringer Ingelheim Pharma GmbH  
Tel: +37 167 24 00 68 
 

United Kingdom 
Boehringer Ingelheim Ltd.  
Tel: +44 (0) 1256 315999 



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Lietuva 
Boehringer Ingelheim Pharma Ges mbH  
Tel.: +370 37 47 39 22 
 

 

 
This leaflet was last approved in 
 
 
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web 
site: http://www.emea.europa.eu. 
 
 

  
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCHRELEASE
	B CONDITIONS OF THE MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET