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DULOXETINE DISTRIQUIMICA 30 MG GASTRO-RESISTANT CAPSULES HARD

Active substance(s): DULOXETINE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Duloxetine Distriquimica 30 mg gastro-resistant capsules, hard

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 30 mg of duloxetine (as hydrochloride).
Excipient(s) with known effect:
Each capsule contains approximately 59.6 – 67.8 mg sucrose.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Gastro-resistant capsule, hard.
Opaque blue cap and opaque white body capsules size 3, filled with off-white to
beige/salmon spherical pellets.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment of major depressive disorder.
Treatment of diabetic peripheral neuropathic pain.
Treatment of generalised anxiety disorder.
Duloxetine is indicated in adults.
For further information see section 5.1.

4.2

Posology and method of administration
Posology
Major depressive disorder
The starting and recommended maintenance dose is 60 mg once daily with or without
food. Dosages above 60 mg once daily, up to a maximum dose of 120 mg per day
have been evaluated from a safety perspective in clinical trials. However, there is no
clinical evidence suggesting that patients not responding to the initial recommended
dose may benefit from dose up-titrations.
Therapeutic response is usually seen after 2-4 weeks of treatment.
After consolidation of the antidepressive response, it is recommended to continue
treatment for several months, in order to avoid relapse. In patients responding to
duloxetine, and with a history of repeated episodes of major depression, further longterm treatment at a dose of 60 to 120 mg/day could be considered.

Generalised anxiety disorder
The recommended starting dose in patients with generalised anxiety disorder is 30 mg
once daily with or without food. In patients with insufficient response the dose should
be increased to 60 mg, which is the usual maintenance dose in most patients.
In patients with co-morbid major depressive disorder, the starting and maintenance
dose is 60 mg once daily (please see also dosing recommendation above).
Doses up to 120 mg per day have been shown to be efficacious and have been
evaluated from a safety perspective in clinical trials. In patients with insufficient
response to 60 mg, escalation up to 90 mg or
120 mg may therefore be considered. Dose escalation should be based upon clinical
response and tolerability.
After consolidation of the response, it is recommended to continue treatment for
several months, in order to avoid relapse.
Diabetic peripheral neuropathic pain
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 interindividual variability (see section 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).
Special populations
Elderly
No dosage adjustment is recommended for elderly patients solely on the basis of age.
However, as with any medicine, caution should be exercised when treating the
elderly, especially with Duloxetine 120 mg per day for major depressive disorder or
generalised anxiety disorder, for which data are limited (see sections 4.4 and 5.2).
Hepatic impairment
Duloxetine must not be used in patients with liver disease resulting in hepatic
impairment (see sections 4.3 and 5.2).
Renal impairment
No dosage adjustment is necessary for patients with mild or moderate renal
dysfunction (creatinine clearance 30 to 80 ml/min). Duloxetine must not be used in
patients with severe renal impairment (creatinine clearance <30 ml/min; see section
4.3).
Paediatric population
Duloxetine should not be used in children and adolescents under the age of 18 years
for the treatment of major depressive disorder because of safety and efficacy concerns
(see sections 4.4, 4.8 and 5.1).

The safety and efficacy of duloxetine for the treatment of generalised anxiety disorder
in paediatric patients aged 7-17 years have not been established. Current available
data are described in sections 4.8, 5.1 and 5.2.
The safety and efficacy of duloxetine for the treatment of diabetic peripheral
neuropathic pain or generalized anxiety disorder have not been studied. No data are
available.
Discontinuation of treatment
Abrupt discontinuation should be avoided. When stopping treatment with Duloxetine
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.
Method of administration
For oral use.

4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section
6.1.
Concomitant use of Duloxetine with nonselective, irreversible monoamine oxidase
inhibitors (MAOIs) is contraindicated (see section 4.5).
Liver disease resulting in hepatic impairment (see section 5.2).
Duloxetine should not be used in combination with fluvoxamine, ciprofloxacin or
enoxacin (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 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 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 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).
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.
Serotonin syndrome
As with other serotonergic agents, serotonin syndrome, a potentially life-threatening
condition, may
occur with duloxetine treatment, particularly with concomitant use of other
serotonergic agents
(including SSRIs, SNRIs tricyclic antidepressants or triptans), with agents that impair
metabolism of
serotonin such as MAOIs, or with antipsychotics or other dopamine antagonists that
may affect the
serotonergic neurotransmitter systems (see sections 4.3 and 4.5).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation,
hallucinations,
coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia),
neuromuscular
aberrations (e.g. hyperreflexia, incoordination) and/or gastrointestinal symptoms
(e.g., nausea,
vomiting, diarrhoea).
If concomitant treatment with duloxetine and other serotonergic agents that may
affect the
serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted,
careful observation of the patient is advised, particularly during treatment initiation
and dose increases.
St John’s wort
Adverse reactions may be more common during concomitant use of Duloxetine and
herbal preparations containing St John’s wort (Hypericum perforatum).
Suicide
Major Depressive Disorder and Generalised Anxiety Disorder: Depression is
associated with an increased risk of suicidal thoughts, self harm and suicide (suiciderelated 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.

Other psychiatric conditions for which Duloxetine is prescribed can also be
associated with an increased risk of suicide-related events. In addition, these
conditions may be co-morbid with major depressive disorder. The same precautions
observed when treating patients with major depressive disorder should therefore be
observed when treating patients with other psychiatric disorders.
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
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).
Close supervision of patients and in particular those at high risk should accompany
medicinal product therapy especially in early treatment and following dose changes.
Patients (and caregivers of patients) should be alerted about the need to monitor for
any clinical worsening, suicidal behaviour or thoughts and unusual changes in
behaviour and to seek medical advice immediately if these symptoms present.
Diabetic Peripheral Neuropathic Pain: As with other medicinal products with similar
pharmacological action (antidepressants), isolated cases of suicidal ideation and
suicidal behaviours have been reported during duloxetine therapy or early after
treatment discontinuation. Concerning risk factors for suicidality in depression, see
above. Physicians should encourage patients to report any distressing thoughts or
feelings at any time.
Use in children and adolescents under 18 years of age
Duloxetine 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 (see section 5.1). In addition,
long-term safety data in children and adolescents concerning growth, maturation and
cognitive and behavioural development are lacking (see section 4.8).
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), including duloxetine. Caution is
advised in patients taking anticoagulants and/or medicinal products known to affect
platelet function (e.g. NSAIDs or acetylsalicylic acid (ASA)), and in patients with
known bleeding tendencies.
Hyponatraemia
Hyponatraemia has been reported when administering duloxetine, including cases
with serum sodium lower than110 mmol/l. Hyponatraemia may be due to a syndrome
of inappropriate anti-diuretic hormone secretion (SIADH). The majority of cases of
hyponatraemia were reported in the elderly, especially when coupled with a recent
history of, or condition pre-disposing to, altered fluid balance. Caution is required in

patients at increased risk for hyponatraemia, such as elderly, cirrhotic, or dehydrated
patients or patients treated with diuretics.
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 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).
Elderly
Data on the use of duloxetine 120mg in elderly patients with major depressive
disorder and
generalised anxiety disorder are limited. Therefore, caution should be exercised when
treating the elderly with the maximum dosage (see sections 4.2 and 5.2).
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 disorder, generalised anxiety disorder and
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 gastro-resistant capsules, hard 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
Monoamine oxidase inhibitors (MAOIs): Due to the risk of serotonin syndrome,
duloxetine should not be used in combination with nonselective irreversible
monoamine oxidase inhibitors (MAOIs), or within at least 14 days of discontinuing
treatment with an MAOI. Based on the half-life of duloxetine, at least 5 days should
be allowed after stopping Duloxetine before starting an MAOI (see section 4.3).
The concomitant use of Duloxetine with selective, reversible MAOIs, like
moclobemide, is not recommended (see section 4.4). The antibiotic linezolid is a
reversible non-selective MAOI and should not be given to patients treated with
Duloxetine (see section 4.4).
Inhibitors of CYP1A2: 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 should not be administered in combination with potent
inhibitors of CYP1A2 like fluvoxamine (see section 4.3).
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 is
taken in combination with other centrally acting medicinal products or substances,
including alcohol and sedative medicinal products (e.g. benzodiazepines,
morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).
Serotonergic agents: In rare cases, serotonin syndrome has been reported in patients
using SSRIs/SNRIs concomitantly with serotonergic agents. Caution is advisable if
Duloxetine is used concomitantly with serotonergic agents like SSRIs, SNRIs,
tricyclic antidepressants like clomipramine or amitriptyline, MAOIs like
moclobemide or linezolid, St John’s wort (Hypericum perforatum) or triptans,
tramadol, pethidine and tryptophan (see section 4.4).
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 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.
Inducers of CYP1A2: Population pharmacokinetic analyses have shown that smokers
have almost 50% lower plasma concentrations of duloxetine compared with nonsmokers.

4.6

Fertility, pregnancy and lactation
Fertility
Duloxetine had no effect on male fertility, and effects in females were only evident at
doses that caused maternal toxicity.
Pregnancy
There are no adequate 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.
Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly
in late pregnancy, may increase the risk of persistent pulmonary hypertension in the
newborn (PPHN). Although no studies have investigated the association of PPHN to
SNRI treatment, this potential risk cannot be ruled out with duloxetine taking into
account the related mechanism of action (inhibition of the re-uptake of serotonin).
As with other serotonergic medicinal products, discontinuation symptoms may occur
in the neonate after maternal duloxetine use near term. Discontinuation symptoms
seen with duloxetine may include hypotonia, tremor, jitteriness, feeding difficulty,
respiratory distress and seizures. The majority of cases have occurred either at birth or
within a few days of birth.
Duloxetine 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 while breastfeeding 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 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
a. Summary of the safety profile
The most commonly reported adverse reactions in patients treated with duloxetine
were nausea, headache, dry mouth, somnolence, and dizziness. However, the majority
of common adverse reactions were mild to moderate, they usually started early in
therapy, and most tended to subside even as therapy was continued.
b. Tabulated summary of adverse reactions
Table 1 gives the adverse reactions observed from spontaneous reporting and in
placebo-controlled clinical trials (comprising a total of 9454 patients, 5703 on
duloxetine and 3751 on placebo) in depression, generalised anxiety disorder and
diabetic neuropathic pain.
Table 1: Adverse reactions
Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10), uncommon
(≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).
Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.

Very common
Common
Infections and infestations

Uncommon

Rare

Laryngitis
Immune system disorders
Anaphylactic
reaction
Hyper-sensitivity
disorder
Endocrine disorders
Hypo-thyroidism
Metabolism and nutrition disorders
Decreased
appetite

Psychiatric disorders

Hyperglycaemia
(reported
especially in
diabetic patients)

Dehydration
Hyponatraemia
SIADH6

Very Rare

Very common

Common
Insomnia
Agitation
Libido decreased
Anxiety
Orgasm abnormal
Abnormal dreams
Nervous system disorders
Headache
Dizziness
Somnolence
Lethargy
Tremor
Paraesthesia

Uncommon
Suicidal
ideation5,7
Sleep disorder
Bruxism
Disorientation
Apathy

Rare
Suicidal
behaviour5,7
Mania
Hallucinations
Aggression and
anger4

Myoclonus
Akathisia7
Nervousness
Disturbance in
attention
Dysgeusia
Dyskinesia
Restless legs
syndrome
Poor quality sleep

Serotonin
syndrome6
Convulsion1
Psychomotor
restlessness6
Extra-pyramidal
symptoms6

Mydriasis
Visual impairment

Glaucoma

Eye disorders
Blurred vision

Ear and labyrinth disorders
Tinnitus1

Vertigo
Ear pain

Cardiac disorders
Palpitations

Tachycardia
Supra-ventricular
arrhythmia,
mainly atrial
fibrillation

Vascular disorders
Syncope2
Hypertension3,7
Orthostatic
hypotension2
Peripheral
coldness
Respiratory, thoracic and mediastinal disorders
Yawning
Throat tightness
Epistaxis
Gastrointestinal disorders
Nausea
Constipation
Gastrointestinal
Dry mouth
Diarrhoea
haemorrhage7
Gastroenteritis
Abdominal pain
Eructation
Vomiting
Gastritis
Dyspepsia
Dysphagia
Flatulence
Hepato-biliary disorders
Blood pressure
increase3
Flushing

Hypertensive
crisis3,6

Stomatitis
Haematochezia
Breath odour

Very Rare

Very common

Common

Skin and subcutaneous tissue disorders
Sweating
increased
Rash

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

Night sweats
Urticaria
Dermatitis contact
Cold sweat
Photo-sensitivity
reactions
Increased
tendency to bruise
Musculoskeletal and connective tissue disorders
Musculo-skeletal
Muscle tightness
pain
Muscle twitching
Muscle spasm
Renal and urinary disorders
Dysuria
Urinary retention
Pollakiuria
Urinary hesitation
Nocturia
Polyuria
Urine flow
decreased
Reproductive system and breast disorders
Erectile
Gynaecological
dysfunction
haemorrhage
Ejaculation
Menstrual
disorder
disorder
Ejaculation
Sexual
delayed
dysfunction
Testicular pain
General disorders and administration site conditions
Falls8
Chest pain7
Fatigue
Feeling abnormal
Feeling cold
Thirst
Chills
Malaise
Feeling hot
Gait disturbance
Investigations
Weight decrease
Weight increase
Blood creatine
phosphokinase
increased
Blood potassium
increased

Rare
Hepatic failure6
Jaundice6

Stevens-Johnson
Syndrome6
Angio-neurotic
oedema6

Trismus

Urine odour
abnormal

Menopausal
symptoms
Galactorrhoea
Hyperprolactinae
mia

Blood cholesterol
increased

Very Rare

1

Cases of convulsion and cases of tinnitus have also been reported after
treatment discontinuation.
2
Cases of orthostatic hypotension and syncope have been reported especially
at the initiation of treatment.
3
See section 4.4.
4
Cases of aggression and anger have been reported particularly early in
treatment or after treatment discontinuation.
5
Cases of suicidal ideation and suicidal behaviours have been reported during
duloxetine therapy or early after treatment discontinuation (see section 4.4).
6
Estimated frequency of post-marketing surveillance reported adverse
reactions; not observed in placebo-controlled clinical trials.
7
Not statistically significantly different from placebo.
8
Falls were more common in the elderly (≥65 years old)
c. Description of selected adverse reactions
Discontinuation of duloxetine (particularly when abrupt) commonly leads to
withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia or
electric shock-like sensations, particularly in the head), sleep disturbances (including
insomnia and intense dreams), fatigue, somnolence, agitation or anxiety, nausea
and/or vomiting, tremor, headache, myalgia, 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.
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.
d. Paediatric population
A total of 509 paediatric patients aged 7 to 17 years with major depressive disorder
and 241 paediatric patients aged 7 to 17 years with generalised anxiety disorderwere
treated with duloxetine in clinical trials. In general, the adverse reaction profile of
duloxetine in children and adolescents was similar to that seen for adults.
A total of 467 paediatric patients initially randomized to duloxetine in clinical trials,
experienced a 0.1 kg mean decrease in weight at 10-weeks compared with a sixmonth extension period, patients on average trended toward recovery to their
expected baseline weight percentile based on population data from age- and gendermatched peers.

In studies of up to 9 months an overall mean decrease of 1% in height percentile
(decrease of 2% in children (7-11 years) and increase of 0.3% in adolescents (12-17
years)) was observed in duloxetine-treated paediatric patients (see section 4.4)”.
Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard.
4.9

Overdose
Cases of overdoses, alone or in combination with other medicinal products, with
duloxetine doses of 5400 mg 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.
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.
Mechanism of action
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 dosedependently increases extracellular levels of serotonin and noradrenaline in various
brain areas of animals.
Pharmacodynamic effects
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.
Clinical efficacy and safety
Major Depressive Disorder: Duloxetine was studied in a clinical programme
involving 3,158 patients (1,285 patient-years of exposure) meeting DSM-IV criteria

for major depression. The efficacy of duloxetine at the recommended dose of 60 mg
once a day was demonstrated in three out of three randomised, double-blind, placebocontrolled, fixed dose acute studies in adult outpatients with major depressive
disorder. Overall, duloxetine’s efficacy has been demonstrated at daily doses between
60 and 120 mg in a total of five out of seven randomised, double-blind, placebocontrolled, fixed dose acute studies in adult outpatients with major depressive
disorder.
Duloxetine demonstrated statistical superiority over placebo as measured by
improvement in the 17-item Hamilton Depression Rating Scale (HAM-D) total score
(including both the emotional and somatic symptoms of depression). Response and
remission rates were also statistically significantly higher with duloxetine compared
with placebo. Only a small proportion of patients included in pivotal clinical trials
had severe depression (baseline HAM-D>25).

In a relapse prevention study, patients responding to 12-weeks of acute
treatment with open-label duloxetine 60 mg once daily were randomised to
either duloxetine 60 mg once daily or placebo for a further 6-months.
Duloxetine 60 mg once daily demonstrated a statistically significant
superiority compared to placebo (p=0.004) on the primary outcome measure,
the prevention of depressive relapse, as measured by time to relapse. The
incidence of relapse during the 6-months double-blind follow-up period was
17% and 29% for duloxetine and placebo, respectively.
During 52 weeks of placebo-controlled double blind treatment, duloxetine-treated
patients with recurrent MDD had a significantly longer symptom free period
(p<0.001) compared with patients randomised to placebo. All patients had previously
responded to duloxetine during open-label duloxetine treatment (28 to 34 weeks) at a
dose of 60 to 120 mg/day. During the 52-week placebo-controlled double blind
treatment phase 14.4% of the duloxetine-treated patients and 33.1% of the placebotreated patients experience a return of their depressive symptoms (p<0.001).
The effect of duloxetine 60 mg once a day in elderly depressed patients (≥65 years)
was specifically examined in a study that showed a statistically significative
difference in the reduction of the HAMD17 score for duloxetine-treated patients
compared to placebo. Tolerability of duloxetine 60 mg once daily in elderly patients
was comparable to that seen in the younger adults. However, data on elderly patients
exposed to the maximum dose (120mg per day) are limited and thus, caution is
recommended when treating this population.
Generalised Anxiety Disorder: Duloxetine demonstrated statistically significant
superiority over placebo in five out of five studies including four randomised, doubleblind, placebo-controlled acute studies and a relapse prevention study in adult patients
with generalised anxiety disorder.
Duloxetine demonstrated statistically significant superiority over placebo as measured
by improvement in the Hamilton Anxiety Scale (HAM-A) total score and by the
Sheehan Disability Scale (SDS) global functional impairment score. Response and
remission rates were also higher with duloxetine compared to placebo. Duloxetine
showed comparable efficacy results to venlafaxine in terms of improvements on the
HAM-A total score.
In a relapse prevention study, patients responding to 6 months of acute treatment with
open-label duloxetine were randomised to either duloxetine or placebo for a further 6-

months. Duloxetine 60 mg to 120 mg once daily demonstrated statistically significant
superiority compared to placebo (p<0.001) on the prevention of relapse, as measured
by time to relapse. The incidence of relapse during the 6-months double-blind followup period was 14% for duloxetine and 42% for placebo.
The efficacy of duloxetine 30-120 mg (flexible dosing) once a day in elderly patients
(>65 years) with
generalised anxiety disorder was evaluated in a study that demonstrated statistically
significant
improvement in the HAM-A total score for duloxetine treated patients compared to
placebo treated
patients. The efficacy and safety of duloxetine 30-120 mg once daily in elderly
patients with
generalised anxiety disorder was similar to that seen in studies of younger adult
patients. However,
data on elderly patients exposed to the maximum dose (120 mg per day) are limited
and, thus, caution
is recommended when using this dose with the elderly population.
Diabetic Peripheral Neuropathic Pain: 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% of 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 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.
Paediatric population

Duloxetine has not been studied in patients under the age of 7.
Two randomized, double-blind, parallel clinical trials were performed in 800
paediatric patients aged 7 to 17 years with major depressive disorder (see
section 4.2). These two studies included a 10 week placebo and active
(fluoxetine) controlled acute phase followed by six months period of active
controlled extension treatment. Neither duloxetine (30-120 mg) nor the active

control arm (fluoxetine 20-40 mg) statistically separated from placebo on
change from baseline to endpoint in the Children´s Depression Rating ScaleRevised (CDRS-R) total score. Discontinuation due to adverse events was
higher in patients taking duloxetine compared with those treated with
fluoxetine, mostly due to nausea. During the 10-week acute treatment period,
suicidal behaviours were reported (duloxetine 0/333 [0%], fluoxetine 2/225
[0.9%], placebo 1/220 [0.5%]). Over the entire 36-week course of the study, 6
out of 333 patients initially randomized to duloxetine and 3 out of 225 patients
initially randomized to fluoxetine experienced suicidal behaviour (exposure
adjusted incidence 0.039 events per patient year for duloxetine, and 0.026 for
fluoxetine). In addition, one patient who transitioned from placebo to
duloxetine experienced a suicidal behaviour while taking duloxetine.
A randomised, double-blind, placebo-controlled study was performed in 272
patients aged 7-17 years with generalised anxiety disorder. The study included
a 10 week placebo-controlled acute phase, followed by an 18 week extension
treatment period. A flexible dose regimen was used in this study, to allow for
slow dose escalation from 30 mg once daily to higher doses (maximum 120
mg once daily). Treatment with duloxetine showed a statistically significantly
greater improvement in GAD symptoms, as measured by PARS severity score
for GAD (mean difference between duloxetine and placebo of 2.7 points [95%
CI 1.3-4.0]), after 10 weeks of treatment. The maintenance of the effect has
not been evaluated. There was no statistically significant difference in
discontinuation due to adverse events between duloxetine and placebo groups
during the 10 week acute treatment phase. Two patients who transitioned from
placebo to duloxetine after the acute phase experienced suicidal behaviours
while taking duloxetine during the extension phase. A conclusion on the
overall benefit/risk in this age group has not been established (see also
sections 4.2 and 4.8).
The European Medicines Agency has waived the obligation to submit the results of
studies with the reference medicinal product containing duloxetine in all subsets of
the paediatric population in the treatment of major depressive disorder, diabetic
neuropathic pain and generalised anxiety disorder. See section 4.2 for information on
paediatric use.

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.
Absorption: 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 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.

Distribution: 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.
Biotransformation: 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 5-hydroxy 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.
Elimination: 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 approximately 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 2fold 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.
Breast-feeding 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.
Paediatric population: Pharmacokinetics of duloxetine in paediatric patients aged 7
to 17 years with major depressive disorder following oral administration of 20 to 120
mg once daily dosing regimen was characterized using population modelling analyses
based on data from 3 studies. The model-predicted duloxetine steady state plasma

concentrations in paediatric patients were mostly within the concentration range
observed in adult patients.

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
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).
Studies in juvenile rats reveal transient effects on neurobehaviour, as well as
significantly decreased body weight and food consumption; hepatic enzyme
induction; and hepatocellular vacuolation at 45 mg/kg/day. The general toxicity
profile of duloxetine in juvenile rats was similar to that in adult rats. The no-adverse
effect level was determined to be 20 mg/kg/day.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Capsule content:
Hypromellose
Talc
Titanium dioxide
Methacrylic acid-ethyl acrylate copolymer dispersion 30% (sodium lauryl sulphate
and polysorbate 80)
Triethyl citrate
Sugar spheres (maize starch and sucrose)
Sucrose
Capsule shell:
30 mg:
Gelatin
Titanium dioxide (E171)
FD& C Blue 2/Indigo carmine (E132)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years.

6.4

Special precautions for storage
Blister Alu/Alu: This medicinal product does not require any special
temperature storage conditions. Store in the original package in order to protect
from light.
Blister PVD/PVDC-/Alu: Store below 30ºC. Keep the blister in the outer
carton in order to protect from light.
Bottle: This medicinal product does not require any special temperature
storage conditions. Keep the bottle tightly closed in order to protect from light.

6.5

Nature and contents of container
- Aluminium / Aluminium blister foil.
- PVC/PVDC – Aluminium blister foil.
- White opaque polyethylene (PE) bottle, containing desiccant sachets, and a
polypropylene (PP) cap with a tamper evident ring closure.
Duloxetine is available in:
- Alu/Alu blister packs of 7, 10, 14, 20, 28, 30, 50, 56, 60, 84, 98 and 504 (8x63)
(hospital pack) capsules.
- PVC/PVDC-Alu blister packs of 7, 10, 14, 20, 28, 30, 50, 56, 60, 84, 98 and 504
(4x126) (hospital pack) capsules.
- Bottle packs of 500 (hospital pack) capsules.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Distriquimica, S.A., Avda. Mare de Déu de Montserrat 221, 08041 Barcelona,
Spain.

8

MARKETING AUTHORISATION NUMBER(S)
PL 21562/0008

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
14/08/2015

10

DATE OF REVISION OF THE TEXT
14/08/2015

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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