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Xeristar

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Summary for the public


What is Xeristar?

Xeristar is a medicine that contains the active substance duloxetine. It is available as gastroresistant capsules (white and blue: 30 mg; green and blue: 60 mg). ‘Gastroresistant’ means that the capsules’ contents pass through the stomach without being broken down until they reach the intestine. This prevents the active substance from being destroyed by the acid in the stomach.


What is Xeristar used for?

Xeristar is used to treat adults (aged 18 years or over) with the following diseases:

  • major depression;
  • pain due to diabetic peripheral neuropathy (damage to the nerves in the extremities that can occur in patients with diabetes);
  • generalised anxiety disorder (long-term anxiety or nervousness about everyday matters).

The medicine can only be obtained with a prescription.


How is Xeristar used?

For major depression, the recommended dose of Xeristar is 60 mg once a day. A response is usually seen in two to four weeks. In patients who respond to Xeristar, treatment should continue for several months to prevent the disease coming back, or for longer in patients who have had repeated periods of depression in the past.

For diabetic neuropathic pain, the recommended dose is 60 mg per day but some patients may need a higher dose of 120 mg per day. The response to treatment should be assessed regularly.

For generalised anxiety disorder, the recommended starting dose is 30 mg once a day, but the dose can be increased to 60, 90 or 120 mg depending on the patient’s response. Most patients will need to take 60 mg per day. Patients who also have major depression should start with 60 mg once a day. In patients who respond to Xeristar, treatment should continue for several months, to prevent the disorder coming back.

The dose of Xeristar should be reduced gradually when stopping treatment.


How does Xeristar work?

The active substance in Xeristar, duloxetine, is a serotonin-noradrenaline re-uptake inhibitor. It works by preventing the neurotransmitters 5-hydroxytryptamine (also called serotonin) and noradrenaline from being taken back up into nerve cells in the brain and spinal cord. Neurotransmitters are chemicals that allow nerve cells to communicate with one another. By blocking their re-uptake, duloxetine increases the amount of these neurotransmitters in the spaces between these nerve cells, increasing the level of communication between the cells. Since these neurotransmitters are involved in maintaining high mood and reducing the sensation of pain, blocking their re-uptake into nerve cells can improve the symptoms of depression, anxiety and neuropathic pain.


How has Xeristar been studied?

For major depression, Xeristar has been compared with placebo (a dummy treatment) in eight main studies involving a total of 2,544 patients. Six of the studies looked at the treatment of depression and measured the change in symptoms over up to six months. The other two studies looked at how long it took for symptoms to return in patients who had initially responded to Xeristar, including 288 patients with a history of repeated episodes of depression for up to five years.

For neuropathic pain, Xeristar has been compared with placebo in two 12-week studies in 809 diabetic adults. The main measure of effectiveness was the change in the severity of pain each week.

For generalised anxiety disorder, Xeristar has been compared with placebo in five studies involving a total of 2,337 patients. Four studies looked at the treatment of the disorder by measuring the reduction in symptoms after nine to 10 weeks. The fifth study looked at how long it took for symptoms to return in 429 patients who had initially responded to Xeristar.

For neuropathic pain, Xeristar has been compared with placebo in two 12-week studies in 809 diabetic adults. The main measure of effectiveness was the change in the severity of pain each week.

For generalised anxiety disorder, Xeristar has been compared with placebo in five studies involving a total of 2,337 patients. Four studies looked at the treatment of the disorder by measuring the reduction in  symptoms after nine to 10 weeks. The fifth study looked at how long it took for symptoms to return in 429 patients who had initially responded to Xeristar.


What benefit has Xeristar shown during the studies?

Although the results of the depression studies varied, Xeristar was more effective than placebo in four of the studies. In the two studies where the approved dose of Xeristar was compared with placebo, Xeristar was more effective. It also took longer for symptoms to return in patients taking Xeristar than in those taking placebo.

For the treatment of diabetic neuropathic pain, Xeristar was more effective at reducing pain than placebo. In both studies, pain reduction was seen from the first week of treatment for up to 12 weeks.

For generalised anxiety disorder, Xeristar was also more effective than placebo at treating the disorder and preventing symptoms returning.


What is the risk associated with Xeristar?

The most common side effects with Xeristar (seen in more than 1 patient in 10) are nausea (feeling sick), headache, dry mouth, somnolence (sleepiness) and dizziness. Most of these were mild or moderate, starting early in treatment and getting milder as treatment continued. For the full list of all side effects reported with Xeristar, see the Package Leaflet.

Xeristar should not be used in people who may be hypersensitive (allergic) to duloxetine or any of the other ingredients. Xeristar must not be used together with monoamine oxidase inhibitors (another group of antidepressants), fluvoxamine (another antidepressant), or ciprofloxacin or enoxacin (types of antibiotic). Xeristar must also not be used in patients with certain types of liver disease or patients with severe kidney disease. Treatment must not be started in patients with uncontrolled hypertension (high blood pressure), because of a risk of hypertensive crisis (sudden, dangerously high blood pressure). As with other antidepressants, isolated cases of suicidal thoughts and behaviour have been seen in patients taking Xeristar, particularly in the first few weeks of treatment for depression. Any patients taking Xeristar who have distressing thoughts or experiences at any time should tell their doctor immediately.


Why has Xeristar been approved?

The CHMP decided that Xeristar’s benefits are greater than its risks and recommended that it be given marketing authorisation.


Other information about Xeristar

The European Commission granted a marketing authorisation valid throughout the European Union for Xeristar on 17 December 2004. The marketing authorisation holder is Eli Lilly Netherlands B.V. The marketing authorisation is valid for an unlimited period.

For more information about treatment with Xeristar, read the Package Leaflet (also part of the EPAR) or contact your doctor or pharmacist.

Authorisation details
Name: Xeristar
EMEA Product number: EMEA/H/C/000573
Active substance: duloxetine
INN or common name: duloxetine
Therapeutic area: Depressive Disorder, MajorDiabetic NeuropathiesAnxiety Disorders
ATC Code: N06AX21
Marketing Authorisation Holder: Eli Lilly Nederland B.V.
Revision: 14
Date of issue of Market Authorisation valid throughout the European Union: 17/12/2004
Contact address:
Eli Lilly Nederland B.V.
Grootslag 1-5
NL-3991 RA Houten
The Netherlands



Product Characteristics

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS


1.
NAME OF THE MEDICINAL PRODUCT
Xeristar 30 mg hard gastro-resistant capsules
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 30 mg of duloxetine (as hydrochloride).
Excipients:
Each capsule contains 8.6 mg sucrose.
For the 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 major depressive disorder.
Treatment of diabetic peripheral neuropathic pain.
Treatment of generalised anxiety disorder.
Xeristar 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 long-term 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
2
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 inter-individual 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).
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 Xeristar 120
mg per day for major depressive disorder, for which data are limited (see sections 4.4 and 5.2).
Children and adolescents
Duloxetine is not recommended for use in children and adolescents due to insufficient data on safety
and efficacy (see section 4.4).
Hepatic impairment
Xeristar 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). Xeristar must 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 Xeristar 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.
Concomitant use of Xeristar with nonselective, irreversible monoamine oxidase inhibitors (MAOIs) is
contraindicated (see section 4.5).
Liver disease resulting in hepatic impairment (see section 5.2).
3
Xeristar 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 Xeristar 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
Xeristar 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 Xeristar 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.
Use with antidepressants
Caution should be exercised when using Xeristar in combination with antidepressants. In particular the
combination with selective reversible MAOIs is not recommended.
St John’s wort
Adverse reactions may be more common during concomitant use of Xeristar 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 (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.
Other psychiatric conditions for which Xeristar 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.
4
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
No clinical trials have been conducted with duloxetine in paediatric populations. Xeristar 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.
Hyponatraemia
Hyponatraemia has been reported when administering Xeristar, including cases with serum sodium
lower than 110 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 Xeristar 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
5
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 Xeristar 120mg in elderly patients with major depressive disorders are limited.
Therefore, caution should be exercised when treating the elderly with the maximum dosage (see
sections 4.2 and 5.2). Data on the use of Xeristar in elderly patients with generalised anxiety disorder
are limited.
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 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
Xeristar hard 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
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 Xeristar 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 Xeristar with selective, reversible MAOIs is not recommended (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 AUC o-t 6-fold. Therefore Xeristar 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 Xeristar 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).
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
6
Xeristar 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 Xeristar 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 non-smokers.
4.6 Pregnancy and lactation
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.
7
Xeristar 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 Xeristar 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. Xeristar 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 Xeristar 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 6828 patients, 4199 on duloxetine and 2629 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
Uncommon
Rare
Very Rare
Infections and Infestations
Laryngitis
Immune System Disorders
Anaphylactic
reaction
Hyper-sensitivity
disorder
Endocrine Disorders
Hypo-thyroidism
Metabolism and Nutrition Disorders
Decreased
Appetite
Hyperglycaemia
(reported
especially in
diabetic patients)
Dehydration
Hyponatraemia
SIADH 6
Psychiatric Disorders
Insomnia
Agitation
Libido decreased
Suicidal
ideation 5,7
Sleep disorder
Suicidal
behaviour 5,7
Mania
8
Very common
Common
Uncommon
Rare
Very Rare
Anxiety
Orgasm abnormal
Abnormal dreams
Bruxism
Disorientation
Apathy
Hallucinations
Aggression and
anger 4
Nervous System Disorders
Headache (14.3%)
Somnolence
(10.7%)
Dizziness (10.2%)
Tremor
Paraesthesia
Myoclonus
Akathisia 7
Nervousness
Disturbance in
attention
Lethargy
Dysgeusia
Dyskinesia
Restless legs
syndrome
Poor quality sleep
Serotonin
syndrome 6
Convulsion 1
Psychomotor
restlessness 6
Extra-pyramidal
symptoms 6
Eye Disorders
Blurred vision
Mydriasis Visual
disturbance
Glaucoma
Ear and Labyrinth Disorders
Tinnitus 1
Vertigo
Ear pain
Cardiac Disorders
Palpitations
Tachycardia
Supra-ventricular
arrhythmia,
mainly atrial
fibrillation
Vascular Disorders
Flushing
Hypertension 3,7
Blood pressure
increase 3
Peripheral
coldness
Orthostatic
hypotension 2
Syncope 2
Hypertensive
crisis 3,6
Respiratory, Thoracic and Mediastinal Disorders
Yawning
Throat tightness
Epistaxis
Gastrointestinal Disorders
Nausea (24.3%)
Dry mouth
(12.8%)
Constipation
Diarrhoea
Vomiting
Dyspepsia
Flatulence
Gastrointestinal
haemorrhage 7
Gastroenteritis
Eructation
Gastritis
Stomatitis
Breath odour
Haematochezia
Hepato-biliary Disorders
Elevated liver
enzymes (ALT,
AST, alkaline
phosphatase)
Hepatitis 3
Acute liver injury
Hepatic failure 6
Jaundice 6
Skin and Subcutaneous Tissue Disorders
Sweating
increased
Night sweats
Urticaria
Stevens-Johnson
Syndrome 6
9
Very common
Common
Uncommon
Rare
Very Rare
Rash
Dermatitis contact
Cold sweat
Photo-sensitivity
reactions
Increased
tendency to bruise
Angio-neurotic
oedema 6
Musculoskeletal and Connective Tissue Disorders
Musculo-skeletal
pain
Muscle tightness
Muscle spasm
Muscle twitching
Trismus
Renal and Urinary Disorders
Urinary Retention
Dysuria
Urinary hesitation
Nocturia
Polyuria
Urine flow
decreased
Urine odour
abnormal
Reproductive System and Breast Disorders
Erectile
dysfunction
Ejaculation
disorder
Ejaculation
delayed
Sexual
dysfunction
Gynaecological
haemorrhage
Menopausal
symptoms
Galactorrhoea
Hyperprolactinae
mia
General Disorders and Administration Site Conditions
Fatigue
Abdominal pain
Chest pain 7
Feeling abnormal
Feeling cold
Thirst
Chills
Malaise
Feeling hot
Gait disturbance
Investigations
Weight decrease Weight increase
Creatine
phosphokinase
increased
Blood cholesterol
increased
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.
10
c. Description of selected adverse reactions
Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms.
Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and
intense dreams), fatigue, 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.
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
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 dose-dependently 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
11
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: Xeristar 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
Xeristar at the recommended dose of 60 mg once a day was demonstrated in three out of three
randomised, double-blind, placebo-controlled, fixed dose acute studies in adult outpatients with major
depressive disorder. Overall, Xeristar’s efficacy has been demonstrated at daily doses between 60 and
120 mg in a total of five out of seven randomised, double-blind, placebo-controlled, fixed dose acute
studies in adult outpatients with major depressive disorder.
Xeristar 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 Xeristar 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
Xeristar 60 mg once daily were randomised to either Xeristar 60 mg once daily or placebo for a further
6-months. Xeristar 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
placebo-treated patients experience a return of their depressive symptoms (p<0.001).
The effect of Xeristar 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 Xeristar 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 : Xeristar demonstrated statistically significant superiority over placebo
in five out of five studies including four randomised, double-blind, placebo-controlled acute studies
and a relapse prevention study in adult patients with generalised anxiety disorder.
Xeristar 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 Xeristar compared to
placebo. Xeristar 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
Xeristar were randomised to either Xeristar or placebo for a further 6-months. Xeristar 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 follow-up period was 14% for Xeristar and 42% for placebo.
Diabetic Peripheral Neuropathic Pain: The efficacy of Xeristar as a treatment for diabetic neuropathic
pain was established in 2 randomised, 12-week, double-blind, placebo-controlled, fixed dose studies in
12
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, Xeristar 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 Xeristar 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
The European Medicines Agency has waived the obligation to submit the results of studies with
Xeristar 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 C max 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).
13
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 2-fold higher
duloxetine C max 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.
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).
6.
PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Capsule content:
Hypromellose
Hypromellose acetate succinate
Sucrose
Sugar spheres
Talc
Titanium dioxide (E171)
14
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 30º C.
6.5 Nature and contents of container
Polyvinylchloride (PVC), polyethylene (PE), and polychlorotrifluoroethylene (PCTFE) blister sealed
with an aluminium foil.
Xeristar 30 mg is available in packs of 7 and 28 capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
MARKETING AUTHORISATION HOLDER
Eli Lilly Nederland BV, Grootslag 1-5, NL-3991 RA Houten, The Netherlands.
8.
MARKETING AUTHORISATION NUMBER(S)
EU/1/04/297/001
EU/1/04/297/006
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 17 December 2004
15
Date of latest renewal: 24 June 2009
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu
16
1.
NAME OF THE MEDICINAL PRODUCT
Xeristar 60 mg hard gastro-resistant capsules
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 60 mg of duloxetine (as hydrochloride).
Excipients:
Each capsule contains 17.2 mg sucrose.
For the 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 major depressive disorder.
Treatment of diabetic peripheral neuropathic pain.
Treatment of generalised anxiety disorder.
Xeristar 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 long-term 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
17
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 inter-individual 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).
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 Xeristar 120
mg per day for major depressive disorder, for which data are limited (see sections 4.4 and 5.2).
Children and adolescents
Duloxetine is not recommended for use in children and adolescents due to insufficient data on safety
and efficacy (see section 4.4).
Hepatic impairment
Xeristar 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). Xeristar must 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 Xeristar 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.
Concomitant use of Xeristar with nonselective, irreversible monoamine oxidase inhibitors (MAOIs) is
contraindicated (see section 4.5).
Liver disease resulting in hepatic impairment (see section 5.2).
18
Xeristar 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 Xeristar 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
Xeristar 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 Xeristar 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.
Use with antidepressants
Caution should be exercised when using Xeristar in combination with antidepressants. In particular the
combination with selective reversible MAOIs is not recommended.
St John’s wort
Adverse reactions may be more common during concomitant use of Xeristar 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 (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.
Other psychiatric conditions for which Xeristar 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.
19
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
No clinical trials have been conducted with duloxetine in paediatric populations. Xeristar 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.
Hyponatraemia
Hyponatraemia has been reported when administering Xeristar, including cases with serum sodium
lower than 110 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 Xeristar 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
20
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 Xeristar 120mg in elderly patients with major depressive disorders are limited.
Therefore, caution should be exercised when treating the elderly with the maximum dosage (see
sections 4.2 and 5.2). Data on the use of Xeristar in elderly patients with generalised anxiety disorder
are limited.
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 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 s evere 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
Xeristar hard 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
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 Xeristar 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 Xeristar with selective, reversible MAOIs is not recommended (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 AUC o-t 6-fold. Therefore Xeristar 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 Xeristar 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).
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
21
Xeristar 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 Xeristar 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 non-smokers.
4.6 Pregnancy and lactation
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.
22
Xeristar 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 Xeristar 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. Xeristar 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 Xeristar 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 6828 patients, 4199 on duloxetine and 2629 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
Uncommon
Rare
Very Rare
Infections and Infestations
Laryngitis
Immune System Disorders
Anaphylactic
reaction
Hyper-sensitivity
disorder
Endocrine Disorders
Hypo-thyroidism
Metabolism and Nutrition Disorders
Decreased
Appetite
Hyperglycaemia
(reported
especially in
diabetic patients)
Dehydration
Hyponatraemia
SIADH 6
Psychiatric Disorders
Insomnia
Agitation
Suicidal
ideation 5,7
Suicidal
behaviour 5,7
23
Very common
Common
Uncommon
Rare
Very Rare
Libido decreased
Anxiety
Orgasm abnormal
Abnormal dreams
Sleep disorder
Bruxism
Disorientation
Apathy
Mania
Hallucinations
Aggression and
anger 4
Nervous System Disorders
Headache (14.3%)
Somnolence
(10.7%)
Dizziness (10.2%)
Tremor
Paraesthesia
Myoclonus
Akathisia 7
Nervousness
Disturbance in
attention
Lethargy
Dysgeusia
Dyskinesia
Restless legs
syndrome
Poor quality sleep
Serotonin
syndrome 6
Convulsion 1
Psychomotor
restlessness 6
Extra-pyramidal
symptoms 6
Eye Disorders
Blurred vision
Mydriasis Visual
disturbance
Glaucoma
Ear and Labyrinth Disorders
Tinnitus 1
Vertigo
Ear pain
Cardiac Disorders
Palpitations
Tachycardia
Supra-ventricular
arrhythmia,
mainly atrial
fibrillation
Vascular Disorders
Flushing
Hypertension 3,7
Blood pressure
increase 3
Peripheral
coldness
Orthostatic
hypotension 2
Syncope 2
Hypertensive
crisis 3,6
Respiratory, Thoracic and Mediastinal Disorders
Yawning
Throat tightness
Epistaxis
Gastrointestinal Disorders
Nausea (24.3%)
Dry mouth
(12.8%)
Constipation
Diarrhoea
Vomiting
Dyspepsia
Flatulence
Gastrointestinal
haemorrhage 7
Gastroenteritis
Eructation
Gastritis
Stomatitis
Breath odour
Haematochezia
Hepato-biliary Disorders
Elevated liver
enzymes (ALT,
AST, alkaline
phosphatase)
Hepatitis 3
Acute liver injury
Hepatic failure 6
Jaundice 6
Skin and Subcutaneous Tissue Disorders
Sweating
Night sweats
Stevens-Johnson
24
Very common
Common
Uncommon
Rare
Very Rare
increased
Rash
Urticaria
Dermatitis contact
Cold sweat
Photo-sensitivity
reactions
Increased
tendency to bruise
Syndrome 6
Angio-neurotic
oedema 6
Musculoskeletal and Connective Tissue Disorders
Musculo-skeletal
pain
Muscle tightness
Muscle spasm
Muscle twitching
Trismus
Renal and Urinary Disorders
Urinary Retention
Dysuria
Urinary hesitation
Nocturia
Polyuria
Urine flow
decreased
Urine odour
abnormal
Reproductive System and Breast Disorders
Erectile
dysfunction
Ejaculation
disorder
Ejaculation
delayed
Sexual
dysfunction
Gynaecological
haemorrhage
Menopausal
symptoms
Galactorrhoea
Hyperprolactinae
mia
General Disorders and Administration Site Conditions
Fatigue
Abdominal pain
Chest pain 7
Feeling abnormal
Feeling cold
Thirst
Chills
Malaise
Feeling hot
Gait disturbance
Investigations
Weight decrease Weight increase
Creatine
phosphokinase
increased
Blood cholesterol
increased
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.
25
c. Description of selected adverse reactions
Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms.
Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and
intense dreams), fatigue, 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.
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
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 dose-dependently 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
26
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: Xeristar 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
Xeristar at the recommended dose of 60 mg once a day was demonstrated in three out of three
randomised, double-blind, placebo-controlled, fixed dose acute studies in adult outpatients with major
depressive disorder. Overall, Xeristar’s efficacy has been demonstrated at daily doses between 60 and
120 mg in a total of five out of seven randomised, double-blind, placebo-controlled, fixed dose acute
studies in adult outpatients with major depressive disorder.
Xeristar 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 Xeristar 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
Xeristar 60 mg once daily were randomised to either Xeristar 60 mg once daily or placebo for a further
6-months. Xeristar 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
placebo-treated patients experience a return of their depressive symptoms (p<0.001).
The effect of Xeristar 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 Xeristar 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: Xeristar demonstrated statistically significant superiority over placebo
in five out of five studies including four randomised, double-blind, placebo-controlled acute studies
and a relapse prevention study in adult patients with generalised anxiety disorder.
Xeristar 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 Xeristar compared to
placebo. Xeristar 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
Xeristar were randomised to either Xeristar or placebo for a further 6-months. Xeristar 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 follow-up period was 14% for Xeristar and 42% for placebo.
Diabetic Peripheral Neuropathic Pain: The efficacy of Xeristar as a treatment for diabetic neuropathic
pain was established in 2 randomised, 12-week, double-blind, placebo-controlled, fixed dose studies in
27
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, Xeristar 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 Xeristar 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
The European Medicines Agency has waived the obligation to submit the results of studies with
Xeristar 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 C max 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).
28
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 2-fold higher
duloxetine C max 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.
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).
6.
PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Capsule content:
Hypromellose
Hypromellose acetate succinate
Sucrose
Sugar spheres
Talc
Titanium dioxide (E171)
29
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 30º C.
6.5 Nature and contents of container
Polyvinylchloride (PVC), polyethylene (PE), and polychlorotrifluoroethylene (PCTFE) blister sealed
with an aluminium foil.
Xeristar 60 mg is available in packs of 28, 56, 84, 98, 100 (Each pack contains 5 cartons of 20
capsules) and 500 capsules (Each pack contains 25 cartons of 20 capsules).
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
MARKETING AUTHORISATION HOLDER
Eli Lilly Nederland BV, Grootslag 1-5, NL-3991 RA Houten, The Netherlands.
8.
MARKETING AUTHORISATION NUMBER(S)
EU/1/04/297/002
EU/1/04/297/003
EU/1/04/297/004
EU/1/04/297/005
EU/1/04/297/007
EU/1/04/297/008
30
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 17 December 2004
Date of latest renewal: 24 June 2009
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu
31
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
32
A
MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) 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, 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 version 05 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, any
updated RMP should be submitted at the same time as the following 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 European Medicines Agency
PSURs
PSURs will have to be submitted with a 1-year frequency, until otherwise specified by the CHMP.
33
ANNEX III
LABELLING AND PACKAGE LEAFLET
34
A. LABELLING
35
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTONS FOR 30 MG HARD GASTRO-RESISTANT CAPSULES
1.
NAME OF THE MEDICINAL PRODUCT
Xeristar 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
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 in order to protect from moisture. Do not store above 30°C
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
36
 
APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Eli Lilly Nederland BV, Grootslag 1-5, NL-3991 RA, Houten, The Netherlands.
12. MARKETING AUTHORISATION NUMBER(S)
EU/1/04/297/001
EU/1/04/297/006
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Xeristar 30 mg
37
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
30 mg hard gastro-resistant capsules
1.
NAME OF THE MEDICINAL PRODUCT
Xeristar 30 mg hard gastro-resistant capsules
Duloxetine
2.
NAME OF THE MARKETING AUTHORISATION HOLDER
Lilly
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
38
 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTONS FOR 60 MG HARD GASTRO-RESISTANT CAPSULES
1.
NAME OF THE MEDICINAL PRODUCT
Xeristar 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
84, hard gastro-resistant capsules
98, hard gastro-resistant capsules
56, hard gastro-resistant capsules
500, hard gastro-resistant capsules (25 cartons of 20 capsules)
100, hard gastro-resistant capsules (5 cartons of 20 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 in order to protect from moisture. Do not store above 30°C
39
 
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
Eli Lilly Nederland BV, Grootslag 1-5, NL-3991 RA, Houten, The Netherlands.
12. MARKETING AUTHORISATION NUMBER(S)
EU/1/04/297/002 (28 capsules)
EU/1/04/297/003 (84 capsules)
EU/1/04/297/004 (98 capsules)
EU/1/04/297/ 005 (56 capsules)
EU/1/04/297/007 (500 capsules)
EU/1/04/297/008 (100 capsules)
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Xeristar 60 mg
40
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
60 mg hard gastro-resistant capsules
1.
NAME OF THE MEDICINAL PRODUCT
Xeristar 60 mg hard gastro-resistant capsules
Duloxetine
2.
NAME OF THE MARKETING AUTHORISATION HOLDER
Lilly
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
41
 
B. PACKAGE LEAFLET
42
PACKAGE LEAFLET: INFORMATION FOR THE USER
Xeristar 30 mg hard gastro-resistant capsules
Xeristar 60 mg hard gastro-resistant capsules
Duloxetine (as hydrochloride)
Read all of this leaflet carefully before you start taking this medicine.
-
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 Xeristar is and what it is used for
3.
How to take Xeristar
4.
Possible side effects
5.
How to store Xeristar
6.
Further information
1.
WHAT XERISTAR IS AND WHAT IT IS USED FOR
Xeristar increases the levels of serotonin and noradrenaline in the nervous system.
Xeristar is used to treat:
depression
generalised anxiety disorder (chronic feeling of anxiety or nervousness)
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)
Your doctor may continue to give you Xeristar when you are feeling better to prevent your depression
or anxiety from returning.
2.
BEFORE YOU TAKE XERISTAR
DO NOT take Xeristar if you:
are allergic (hypersensitive) to duloxetine or any of the other ingredients of Xeristar (see ‘Further
Information’)
have liver disease
have severe kidney disease
are taking or have taken within the last 14 days, another medicine known as a monoamine
oxidase inhibitor (MAOI) (see ‘Taking other medicines’)
are taking fluvoxamine which is usually used to treat depression, ciprofloxacin or enoxacin
which are used to treat some infections
are taking other medicines containing duloxetine (see ‘Taking other medicines’)
Talk to your doctor if you have high blood pressure or heart disease. Your doctor will tell you if you
should be taking Xeristar.
43
-
Keep this leaflet. You may need to read it again.
2.
Before you take Xeristar
Take special care with Xeristar
The following are reasons why Xeristar 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 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 (for example if you are taking diuretics, especially if you are
elderly)
-
are currently being treated with another medicine which may cause liver damage
Xeristar 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
Xeristar 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 Xeristar for patients under 18 because
he/she decides that this is in their best interests. If your doctor has prescribed Xeristar 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 Xeristar.
Also, the long-term safety effects concerning growth, maturation, and cognitive and behavioural
development of Xeristar 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 Xeristar, duloxetine, is used in other medicines for other conditions:
diabetic neuropathic pain, 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.
Your doctor should decide whether you can take Xeristar 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.
44
-
have kidney disease
-
are taking other medicines containing duloxetine (see ‘Taking other medicines’)
You should also tell your doctor if you are taking any of the following:
Monoamine oxidase inhibitors (MAOIs): You should not take Xeristar 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 Xeristar, 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 Xeristar. Also, you need to wait at least 5 days after you
stop taking Xeristar before you take a MAOI.
Medicines that cause sleepiness: These include medicines prescribed by your doctor including
benzodiazepines, strong painkillers, antipsychotics, phenobarbital and 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 Xeristar, you should see your doctor.
Oral anticoagulants : Medicines which thin the blood. These medicines might increase the risk of
bleeding.
Taking Xeristar with food and drink
Xeristar may be taken with or without food. Care should be taken if you drink alcohol while you are
being treated with Xeristar.
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 Xeristar. You should use Xeristar only after discussing the potential benefits and any
potential risks to your unborn child with your doctor.
Make sure your midwife and/or doctor knows you are on Xeristar. When taken during
pregnancy, similar drugs (SSRIs) may increase the risk of a serious condition in babies, called
persistent pulmonary hypertension of the newborn (PPHN), making the baby breathe faster and
appear bluish. These symptoms usually begin during the first 24 hours after the baby is born. If
this happens to your baby you should contact your midwife and/or doctor immediately.
If you take Xeristar near the end of your pregnancy, your baby might have some symptoms
when it is born. These usually begin at birth or within a few days of your baby being born.
These symptoms may include floppy muscles, trembling, jitteriness, not feeding properly,
trouble with breathing and fits. If your baby has any of these symptoms when it is born, or you
are concerned about your baby’s health, contact your doctor or midwife who will be able to
advise you.
Tell your doctor if you are breast-feeding. The use of Xeristar while breastfeeding is not
recommended. You should ask your doctor or pharmacist for advice.
Driving and using machines
Xeristar may make you feel sleepy or dizzy. Do not drive or use any tools or machines until you know
how Xeristar affects you.
Important information about some of the ingredients of Xeristar
Xeristar 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.
45
3.
HOW TO TAKE XERISTAR
Always take Xeristar exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
Xeristar starts to work in most people with depression or anxiety within two weeks of starting
treatment.
Xeristar starts to work in most people with diabetic neuropathic pain within 1 week of starting
treatment.
For depression and diabetic neuropathic pain:
The usual dose of Xeristar is one capsule (60 mg duloxetine) once a day, but your doctor will
prescribe the dose that is right for you.
For generalised anxiety disorder:
The usual starting dose of Xeristar is 30 mg once a day after which most patients will receive 60 mg
once a day, but your doctor will prescribe the dose that is right for you. The dose may be adjusted up
to 120 mg a day based on your response to Xeristar.
Xeristar is for oral use. You should swallow your capsule whole with a drink of water.
To help you remember to take Xeristar, 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 Xeristar. Do not stop taking Xeristar
without talking to your doctor.
If you take more Xeristar than you should
Call your doctor or pharmacist immediately if you take more than the amount of Xeristar prescribed
by your doctor. Symptoms of overdose include sleepiness, coma, serotonin syndrome (a rare reaction
which may cause feelings of great happiness, drowsiness, clumsiness, restlessness, feeling of being
drunk, fever, sweating or rigid muscles), fits, vomiting and fast heart rate.
If you forget to take Xeristar
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 Xeristar that has been prescribed for you in one day.
If you stop taking Xeristar
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 Xeristar he or she will ask you to reduce your dose over at least
2 weeks before stopping treatment altogether.
Some patients who stop taking Xeristar suddenly have had symptoms such as:
dizziness, fatigue, 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 further questions on the use of this product, ask your doctor or pharmacist.
46
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Xeristar 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 (affects more than 1 user in 10)
feeling sick (nausea), headache, dry mouth feeling sleepy and dizziness.
Common side effects (affects 1 to 10 users in 100)
fatigue, 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
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
problems getting an erection, less sex drive and abnormal orgasm
(itchy) rash
muscle pain, muscle tightness, muscle spasm
increased yawning
lack of appetite, weight loss
Uncommon side effects (affects 1 to 10 users in 1,000)
throat inflammation
feeling disorientated, tiredness, trouble sleeping, 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
restless legs syndrome
poor sleep quality
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
abnormal periods, including heavy or prolonged periods
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), night sweats, 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
passing bright red blood in your stools, vomiting blood, or black tarry stools (faeces)
grinding of teeth, feeling hot/cold, thirst, throat tightness, nose bleeds
weight gain
suicidal thoughts
chest pain
a sensation of restlessness or an inability to sit or stand still
Rare side effects (affects 1 to 10 users in 10,000)
decreased thyroid gland activity
allergic reactions
dehydration
mania (over activity, racing thoughts and decrease need for sleep), experiencing aggression and
anger
47
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 (mostly in elderly people). The symptoms may include feeling
dizzy, weak, confused, sleepy or very tired, or feeling or being sick. More serious symptoms are
fainting, fits or falls
syndrome of inadequate secretion of anti-diuretic hormone (SIADH)
serious allergic reaction which causes difficulty in breathing or dizziness or hives
fits
abnormal production of breast milk in men and women
hallucinations
having abnormal urine odour
suicidal behaviour
“Serotonin syndrome” (a rare reaction which may cause feelings of great happiness, drowsiness,
clumsiness, restlessness, feeling of being drunk, fever, sweating or rigid muscles)
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 or pharmacist.
5.
HOW TO STORE XERISTAR
Keep out of the reach and sight of children.
Do not use Xeristar after the expiry date which is stated on the carton.
Store in the original package to protect from moisture. Do not store above 30°C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Xeristar 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), yellow
iron oxide (E172) (60 mg only) and edible green ink (30 mg) or edible white ink (60 mg).
Edible green ink: synthetic black iron oxide (E172), synthetic yellow iron oxide (E172), propylene
glycol, shellac.
Edible white ink: titanium dioxide (E171), propylene glycol, shellac, povidone.
What Xeristar looks like and contents of the pack
Xeristar is a hard gastro-resistant capsule. Each capsule of Xeristar contains pellets of duloxetine
hydrochloride with a covering to protect them from stomach acid.
Xeristar is available in 2 strengths: 30 mg and 60 mg.
48
The 30 mg capsules are blue and white and are printed with ‘30 mg’ and the code ‘9543’.
The 60 mg capsules are blue and green and are printed with ‘60 mg’ and the code ‘9542’.
Xeristar 30 mg is available in packs of 7 and 28 capsules.
Xeristar 60 mg is available in packs of 28, 56, 84, 98, 100 and 500 capsules.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder : Eli Lilly Nederland BV, Grootslag 1-5, NL-3991 RA Houten, The
Netherlands.
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:
België/Belgique/Belgien
Eli Lilly Benelux S.A./N.V.
Tél/Tel: + 32-(0)2 548 84 84
Luxembourg/Luxemburg
Eli Lilly Benelux S.A./N.V.
Tél/Tel: + 32-(0)2 548 84 84
България
ТП "Ели Лили Недерланд" Б.В. - България
тел. + 359 2 491 41 40
Magyarország
Lilly Hungária Kft.
Tel: + 36 1 328 5100
Česká republika
ELI LILLY ČR, s.r.o.
Tel: + 420 234 664 111
Malta
Charles de Giorgio Ltd.
Tel: + 356 25600 500
Danmark
Eli Lilly Danmark A/S
Tlf: +45 45 26 60 00
Nederland
Eli Lilly Nederland B.V.
Tel: + 31-(0) 30 60 25 800
Deutschland
Lilly Deutschland GmbH
Tel. + 49-(0) 6172 273 2222
Norge
Eli Lilly Norge A.S.
Tlf: + 47 22 88 18 00
Eesti
Eli Lilly Holdings Limited Eesti filiaal
Tel: + 372 6 817 280
Österreich
Eli Lilly Ges.m.b.H.
Tel: + 43-(0) 1 711 780
Ελλάδα
ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε.
Τηλ: +30 210 629 4600
Polska
Eli Lilly Polska Sp. z o.o.
Tel. +48 (0) 22 440 33 00
España
Lilly S.A.
Tel: + 34-91 663 50 00
Portugal
Lilly Portugal Produtos Farmacêuticos, Lda
Tel: + 351-21-4126600
France
Lilly France S.A.S
Tél: +33-(0) 1 55 49 34 34
România
Eli Lilly România S.R.L.
Tel: + 40 21 4023000
Ireland
Eli Lilly and Company (Ireland) Limited
Tel: + 353-(0) 1 661 4377
Slovenija
Eli Lilly farmacevtska družba, d.o.o.
Tel: +386 (0)1 580 00 10
Ísland
Slovenská republika
49
Icepharma hf.
Sími + 354 540 8000
Eli Lilly Slovakia, s.r.o.
Tel: + 421 220 663 111
Italia
Eli Lilly Italia S.p.A.
Tel: + 39- 055 42571
Suomi/Finland
Oy Eli Lilly Finland Ab
Puh/Tel: + 358-(0) 9 85 45 250
Κύπρος
Phadisco Ltd
Τηλ: +357 22 715000
Sverige
Eli Lilly Sweden AB
Tel: + 46-(0) 8 7378800
Latvija
Eli Lilly Holdings Limited pārstāvniecība Latvijā
Tel: + 371 67364000
United Kingdom
Eli Lilly and Company Limited
Tel: + 44-(0) 1256 315000
Lietuva
Eli Lilly Holdings Limited atstovybė
Tel. +370 (5) 2649600
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web
site: http://www.ema.europa.eu.
50


Source: European Medicines Agency



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