ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
ARICLAIM 30 mg hard gastro-resistant capsules
2.
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.
Hard gastro-resistant capsule.
Opaque white body, imprinted with ‘30 mg’ and an opaque blue cap, imprinted with ‘9543’.
4.
Treatment of diabetic peripheral neuropathic pain.
ARICLAIM is indicated in adults.
For further information see section 5.1.
Posology
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 (see section 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
ARICLAIM must not be used in patients with liver disease resulting in hepatic impairment (see
sections 4.3 and 5.2).
2
Renal impairment
No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine
clearance 30 to 80 ml/min). ARICLAIM 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 ARICLAIM 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.
Hypersensitivity to the active substance or to any of the excipients.
Concomitant use of ARICLAIM with nonselective, irreversible monoamine oxidase inhibitors
(MAOIs) is contraindicated (see section 4.5).
Liver disease resulting in hepatic impairment (see section 5.2).
ARICLAIM 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 ARICLAIM 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).
Mania and seizures
ARICLAIM 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 ARICLAIM 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).
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 ARICLAIM 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 ARICLAIM and herbal
preparations containing St John’s wort (Hypericum perforatum).
Depression, suicidal ideation and behaviour
Although ARICLAIM is not indicated for the treatment of depression, its active ingredient
(duloxetine) also exists as an antidepressant medicinal product. Depression is associated with an
increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists
until significant remission occurs. As improvement may not occur during the first few weeks or more
of treatment, patients should be closely monitored until such improvement occurs. It is general clinical
experience that the risk of suicide may increase in the early stages of recovery. Patients with a history
of suicide-related events or those exhibiting a significant degree of suicidal thoughts prior to
commencement of treatment are known to be at greater risk of suicidal thoughts or suicidal behaviour,
and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical
trials of antidepressant medicinal products in psychiatric disorders showed an increased risk of suicidal
behaviour with antidepressants compared to placebo in patients less than 25 years old.
Cases of suicidal thoughts and suicidal behaviours have been reported during duloxetine therapy or
early after treatment discontinuation (see section 4.8). Physicians should encourage patients to report
any distressing thoughts or feelings or depressive symptoms at any time. If while on ARICLAIM
therapy, the patient develops agitation or depressive symptoms, specialised medical advice should be
sought, as depression is a serious medical condition. If a decision to initiate antidepressant
pharmacological therapy is taken, the gradual discontinuation of ARICLAIM is recommended (see
section 4.2).
Use in children and adolescents under 18 years of age
No clinical trials have been conducted with duloxetine in paediatric populations. ARICLAIM 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 ARICLAIM, 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
4
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 ARICLAIM and 23% of patients taking
placebo. The risk of withdrawal symptoms seen with SSRI’s and SNRI’s may be dependent on several
factors including the duration and dose of therapy and the rate of dose reduction. The most commonly
reported reactions are listed in section 4.8. Generally these symptoms are mild to moderate, however,
in some patients they may be severe in intensity. They usually occur within the first few days of
discontinuing treatment, but there have been very rare reports of such symptoms in patients who have
inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2
weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore
advised that duloxetine should be gradually tapered when discontinuing treatment over a period of no
less than 2 weeks, according to the patient’s needs (see section 4.2).
Akathisia/psychomotor restlessness
The use of duloxetine has been associated with the development of akathisia, characterised by a
subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability
to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who
develop these symptoms, increasing the dose may be detrimental.
Medicinal products containing duloxetine
Duloxetine is used under different trademarks in several indications (treatment of diabetic neuropathic
pain, major depressive 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
ARICLAIM 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.
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 ARICLAIM 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 ARICLAIM 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 ARICLAIM should not
be administered in combination with potent inhibitors of CYP1A2 like fluvoxamine (see section 4.3).
5
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 ARICLAIM 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
ARICLAIM 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 ARICLAIM 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.
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
6
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.
ARICLAIM 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 ARICLAIM while breast-feeding is not recommended.
No studies on the effects on the ability to drive and use machines have been performed. ARICLAIM
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.
a. Summary of the safety profile
The most commonly reported adverse reactions in patients treated with ARICLAIM 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
7
Very common
Common
Uncommon
Rare
Very Rare
Metabolism and Nutrition Disorders
Decreased
Appetite
Hyperglycaemia
(reported
especially in
diabetic patients)
Dehydration
Hyponatraemia
SIADH
6
Psychiatric Disorders
Insomnia
Agitation
Libido decreased
Anxiety
Orgasm abnormal
Abnormal dreams
Suicidal
ideation
5,7
Sleep disorder
Bruxism
Disorientation
Apathy
Suicidal
behaviour
5,7
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
8
Very common
Common
Uncommon
Rare
Very Rare
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
Rash
Night sweats
Urticaria
Dermatitis contact
Cold sweat
Photo-sensitivity
reactions
Increased
tendency to bruise
Stevens-Johnson
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.
9
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.
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.
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.
10
5.
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
duloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within the
central nervous system.
Clinical efficacy and safety
The efficacy of duloxetine as a treatment for diabetic neuropathic pain was established in 2
randomised, 12-week, double-blind, placebo-controlled, fixed dose studies in adults (22 to 88 years)
having diabetic neuropathic pain for at least 6 months. Patients meeting diagnostic criteria for major
depressive disorder were excluded from these trials. The primary outcome measure was the weekly
mean of 24-hour average pain, which was collected in a daily diary by patients on an 11-point Likert
scale.
In both studies, duloxetine 60 mg once daily and 60 mg twice daily significantly reduced pain
compared with placebo. The effect in some patients was apparent in the first week of treatment. The
difference in mean improvement between the two active treatment arms was not significant. At least
30% reported pain reduction was recorded in approximately 65% of duloxetine treated patients versus
40% for placebo. The corresponding figures for at least 50% pain reduction were 50% and 26%
respectively. Clinical response rates (50% or greater improvement in pain) were analysed according to
whether or not the patient experienced somnolence during treatment. For patients not experiencing
somnolence, clinical response was observed in 47% of patients receiving duloxetine and 27% of
patients on placebo. Clinical response rates in patients experiencing somnolence were 60% on
duloxetine and 30% on placebo. Patients not demonstrating a pain reduction of 30% within 60 days of
treatment were unlikely to reach this level during further treatment.
In an open label long-term uncontrolled study, the pain reduction in patients responding to 8-weeks of
acute treatment of ARICLAIM 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
ARICLAIM in all subsets of the paediatric population in the treatment of diabetic neuropathic pain.
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
11
extent of absorption (approximately 11 %). These changes do not have any clinical significance.
Distribution:
Duloxetine is approximately 96% bound to human plasma proteins. Duloxetine binds to
both albumin and alpha-l acid glycoprotein. Protein binding is not affected by renal or hepatic
impairment.
Biotransformation:
Duloxetine is extensively metabolised and the metabolites are excreted principally
in urine. Both cytochromes P450-2D6 and 1A2 catalyse the formation of the two major metabolites
glucuronide conjugate of 4-hydroxy duloxetine and sulphate conjugate of 5-hydroxy 6-methoxy
duloxetine. Based upon
in vitro
studies, the circulating metabolites of duloxetine are considered
pharmacologically inactive. The pharmacokinetics of duloxetine in patients who are poor metabolisers
with respect to CYP2D6 has not been specifically investigated. Limited data suggest that the plasma
levels of duloxetine are higher in these patients.
Elimination:
The elimination half-life of duloxetine ranges from 8 to 17 hours (mean of 12 hours).
After an intravenous dose the plasma clearance of duloxetine ranges from 22 l/hr to 46 l/hr (mean of
36 l/hr). After an oral dose the apparent plasma clearance of duloxetine ranges from 33 to 261 l/hr
(mean 101 l/hr).
Special populations
Gender:
Pharmacokinetic differences have been identified between males and females (apparent
plasma clearance is approximately 50% lower in females). Based upon the overlap in the range of
clearance, gender-based pharmacokinetic differences do not justify the recommendation for using a
lower dose for female patients.
Age:
Pharmacokinetic differences have been identified between younger and elderly females (≥65
years) (AUC increases by about 25% and half-life is about 25% longer in the elderly), although the
magnitude of these changes is not sufficient to justify adjustments to the dose. As a general
recommendation, caution should be exercised when treating the elderly (see sections 4.2 and 4.4).
Renal impairment:
End stage renal disease (ESRD) patients receiving dialysis had 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
12
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.
6.1 List of excipients
Capsule content:
Hypromellose
Hypromellose acetate succinate
Sucrose
Sugar spheres
Talc
Titanium dioxide (E171)
Triethyl citrate
Capsule shell:
30 mg:
Gelatin
Sodium lauryl sulfate
Titanium dioxide (E171)
Indigo carmine (E132)
Edible green ink
Edible green ink contains:
Black iron oxide - synthetic (E172)
Yellow iron oxide - synthetic (E172)
Propylene glycol
Shellac
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in the original package in order to protect from moisture. Do not store above 30º C.
6.5 Nature and contents of container
Polyvinylchloride (PVC), polyethylene (PE), and polychlorotrifluoroethylene (PCTFE) blister sealed
with an aluminium foil.
ARICLAIM 30 mg is available in packs of 7, 28 and 98 capsules.
Not all pack sizes may be marketed.
13
6.6 Special precautions for disposal
No special requirements.
7.
Eli Lilly Nederland BV, Grootslag 1-5, NL-3991 RA Houten, The Netherlands.
8.
EU/1/04/283/008
EU/1/04/283/009
EU/1/04/283/010
9.
Date of first authorisation: 11 August 2004
Date of latest renewal: 24 June 2009
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu
14
1.
ARICLAIM 60 mg hard gastro-resistant capsules
2.
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.
Hard gastro-resistant capsule.
Opaque green body, imprinted with ‘60 mg’ and an opaque blue cap, imprinted with ‘9542’.
4.
Treatment of diabetic peripheral neuropathic pain.
ARICLAIM is indicated in adults.
For further information see section 5.1.
Posology
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 (see section 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
ARICLAIM must not be used in patients with liver disease resulting in hepatic impairment (see
sections 4.3 and 5.2).
15
Renal impairment
No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine
clearance 30 to 80 ml/min). ARICLAIM 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 ARICLAIM 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.
Hypersensitivity to the active substance or to any of the excipients.
Concomitant use of ARICLAIM with nonselective, irreversible monoamine oxidase inhibitors
(MAOIs) is contraindicated (see section 4.5).
Liver disease resulting in hepatic impairment (see section 5.2).
ARICLAIM 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 ARICLAIM 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).
Mania and seizures
ARICLAIM 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 ARICLAIM 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).
16
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 ARICLAIM 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 ARICLAIM and herbal
preparations containing St John’s wort (Hypericum perforatum).
Depression, suicidal ideation and behaviour
Although ARICLAIM is not indicated for the treatment of depression, its active ingredient
(duloxetine) also exists as an antidepressant medicinal product. Depression is associated with an
increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists
until significant remission occurs. As improvement may not occur during the first few weeks or more
of treatment, patients should be closely monitored until such improvement occurs. It is general clinical
experience that the risk of suicide may increase in the early stages of recovery. Patients with a history
of suicide-related events or those exhibiting a significant degree of suicidal thoughts prior to
commencement of treatment are known to be at greater risk of suicidal thoughts or suicidal behaviour,
and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical
trials of antidepressant medicinal products in psychiatric disorders showed an increased risk of suicidal
behaviour with antidepressants compared to placebo in patients less than 25 years old.
Cases of suicidal thoughts and suicidal behaviours have been reported during duloxetine therapy or
early after treatment discontinuation (see section 4.8). Physicians should encourage patients to report
any distressing thoughts or feelings or depressive symptoms at any time. If while on ARICLAIM
therapy, the patient develops agitation or depressive symptoms, specialised medical advice should be
sought, as depression is a serious medical condition. If a decision to initiate antidepressant
pharmacological therapy is taken, the gradual discontinuation of ARICLAIM is recommended (see
section 4.2).
Use in children and adolescents under 18 years of age
No clinical trials have been conducted with duloxetine in paediatric populations. ARICLAIM 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 ARICLAIM, 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
17
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 ARICLAIM and 23% of patients taking
placebo. The risk of withdrawal symptoms seen with SSRI’s and SNRI’s may be dependent on several
factors including the duration and dose of therapy and the rate of dose reduction. The most commonly
reported reactions are listed in section 4.8. Generally these symptoms are mild to moderate, however,
in some patients they may be severe in intensity. They usually occur within the first few days of
discontinuing treatment, but there have been very rare reports of such symptoms in patients who have
inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2
weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore
advised that duloxetine should be gradually tapered when discontinuing treatment over a period of no
less than 2 weeks, according to the patient’s needs (see section 4.2).
Akathisia/psychomotor restlessness
The use of duloxetine has been associated with the development of akathisia, characterised by a
subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability
to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who
develop these symptoms, increasing the dose may be detrimental.
Medicinal products containing duloxetine
Duloxetine is used under different trademarks in several indications (treatment of diabetic neuropathic
pain, major depressive 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
ARICLAIM 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.
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 ARICLAIM 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 ARICLAIM with selective, reversible MAOIs is not recommended (see section
4.4).
18
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 ARICLAIM 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 ARICLAIM 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
ARICLAIM 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 ARICLAIM 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.
19
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.
ARICLAIM 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 ARICLAIM while breast-feeding is not recommended.
No studies on the effects on the ability to drive and use machines have been performed. ARICLAIM
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.
a. Summary of the safety profile
The most commonly reported adverse reactions in patients treated with ARICLAIM 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.
20
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
Anxiety
Orgasm abnormal
Abnormal dreams
Suicidal
ideation
5,7
Sleep disorder
Bruxism
Disorientation
Apathy
Suicidal
behaviour
5,7
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
21
Very common
Common
Uncommon
Rare
Very Rare
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
Rash
Night sweats
Urticaria
Dermatitis contact
Cold sweat
Photo-sensitivity
reactions
Increased
tendency to bruise
Stevens-Johnson
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
22
Very common
Common
Uncommon
Rare
Very Rare
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.
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.
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
23
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.
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
duloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within the
central nervous system.
Clinical efficacy and safety
The efficacy of duloxetine as a treatment for diabetic neuropathic pain was established in 2
randomised, 12-week, double-blind, placebo-controlled, fixed dose studies in adults (22 to 88 years)
having diabetic neuropathic pain for at least 6 months. Patients meeting diagnostic criteria for major
depressive disorder were excluded from these trials. The primary outcome measure was the weekly
mean of 24-hour average pain, which was collected in a daily diary by patients on an 11-point Likert
scale.
In both studies, duloxetine 60 mg once daily and 60 mg twice daily significantly reduced pain
compared with placebo. The effect in some patients was apparent in the first week of treatment. The
difference in mean improvement between the two active treatment arms was not significant. At least
30% reported pain reduction was recorded in approximately 65% of duloxetine treated patients versus
40% for placebo. The corresponding figures for at least 50% pain reduction were 50% and 26%
respectively. Clinical response rates (50% or greater improvement in pain) were analysed according to
whether or not the patient experienced somnolence during treatment. For patients not experiencing
somnolence, clinical response was observed in 47% of patients receiving duloxetine and 27% of
patients on placebo. Clinical response rates in patients experiencing somnolence were 60% on
duloxetine and 30% on placebo. Patients not demonstrating a pain reduction of 30% within 60 days of
treatment were unlikely to reach this level during further treatment.
In an open label long-term uncontrolled study, the pain reduction in patients responding to 8-weeks of
acute treatment of ARICLAIM 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
ARICLAIM in all subsets of the paediatric population in the treatment of diabetic neuropathic pain.
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,
24
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).
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
25
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.
6.1 List of excipients
Capsule content:
Hypromellose
Hypromellose acetate succinate
Sucrose
Sugar spheres
Talc
Titanium dioxide (E171)
Triethyl citrate
Capsule shell:
60 mg:
Gelatin
Sodium lauryl sulfate
Titanium dioxide (E171)
Indigo carmine (E132)
Yellow iron oxide (E172)
Edible white ink
Edible white ink contains:
Titanium dioxide (E171)
Propylene glycol
Shellac
Povidone
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in the original package in order to protect from moisture. Do not store above 30º C.
26
6.5 Nature and contents of container
Polyvinylchloride (PVC), polyethylene (PE), and polychlorotrifluoroethylene (PCTFE) blister sealed
with an aluminium foil.
ARICLAIM 60 mg is available in packs of 28 and 98 capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Eli Lilly Nederland BV, Grootslag 1-5, NL-3991 RA Houten, The Netherlands.
8.
EU/1/04/283/011
EU/1/04/283/012
9.
Date of first authorisation: 11 August 2004
Date of latest renewal: 24 June 2009
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu
27
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE
FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
28
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
•
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.
29
ANNEX III
LABELLING AND PACKAGE LEAFLET
30
A. LABELLING
31
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTONS FOR 30 MG HARD GASTRO-RESISTANT CAPSULES
1.
ARICLAIM 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.
7 hard gastro-resistant capsules
28 hard gastro-resistant capsules
98 hard gastro-resistant capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from moisture. Do not store above 30°C
32
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Eli Lilly Nederland BV, Grootslag 1-5, NL-3991 RA, Houten, The Netherlands.
EU/1/04/283/008
EU/1/04/283/009
EU/1/04/283/010
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
ARICLAIM 30 mg
33
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
30 mg hard gastro-resistant capsules
1.
ARICLAIM 30 mg hard gastro-resistant capsules
Duloxetine
2.
Lilly
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
34
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTONS FOR 60 MG HARD GASTRO-RESISTANT CAPSULES
1.
ARICLAIM 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.
28, hard gastro-resistant capsules
98, hard gastro-resistant capsules.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in the original package 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
35
APPROPRIATE
Eli Lilly Nederland BV, Grootslag 1-5, NL-3991 RA, Houten, The Netherlands.
EU/1/04/283/011
EU/1/04/283/012
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
ARICLAIM 60 mg
36
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
60 mg hard gastro-resistant capsules
1.
ARICLAIM 60 mg hard gastro-resistant capsules
Duloxetine
2.
Lilly
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
37
B. PACKAGE LEAFLET
38
PACKAGE LEAFLET: INFORMATION FOR THE USER
ARICLAIM
30 mg
hard gastro-resistant capsules
ARICLAIM 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 ARICLAIM is and what it is used for
3.
How to take ARICLAIM
4.
Possible side effects
5.
How to store ARICLAIM
6.
Further information
1.
WHAT ARICLAIM IS AND WHAT IT IS USED FOR
ARICLAIM increases the levels of serotonin and noradrenaline in the nervous system.
ARICLAIM is used in adults to treat a condition called diabetic neuropathic pain (often described as
burning, stabbing, stinging, shooting or aching or like an electric shock. There may be loss of feeling
in the affected area, or sensations such as touch, heat, cold or pressure may cause pain).
2.
BEFORE YOU TAKE ARICLAIM
DO NOT take ARICLAIM if you:
−
are allergic (hypersensitive) to duloxetine or any of the other ingredients of ARICLAIM (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 ARICLAIM.
Take special care with ARICLAIM
The following are reasons why ARICLAIM may not be suitable for you. Talk to your doctor before
you take the medicine if you:
-
are taking 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
39
-
Keep this leaflet. You may need to read it again.
2.
Before you take ARICLAIM
-
have kidney disease
-
suffer from bipolar disorder
-
have eye problems, such as certain kinds of glaucoma (increased pressure in the eye)
-
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
ARICLAIM 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 depression or anxiety disorder
Although ARICLAIM is not indicated for the treatment of depression, its active ingredient
(duloxetine) is used as an antidepressant medicine. If you are depressed and/or have anxiety disorders
you 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
ARICLAIM 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 ARICLAIM for patients
under 18 because he/she decides that this is in their best interests. If your doctor has prescribed
ARICLAIM 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 ARICLAIM. Also, the long-term safety effects concerning growth, maturation, and
cognitive and behavioural development of ARICLAIM 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 ARICLAIM, duloxetine, is used in other medicines for other conditions:
•
depression, anxiety and urinary incontinence
Using more than one of these medicines at the same time should be avoided. Check with your doctor if
you are already taking other medicines containing duloxetine.
Your doctor should decide whether you can take ARICLAIM with other medicines.
Do not start or
stop taking any medicines, including those bought without a prescription and herbal remedies,
before checking with your doctor.
You should also tell your doctor if you are taking any of the following:
Monoamine oxidase inhibitors (MAOIs):
You should not take ARICLAIM if you are taking, or have
recently taken (within the last 14 days) an antidepressant medicine called a monoamine oxidase
40
-
have a history of bleeding disorders (tendency to develop bruises)
-
are taking other medicines containing duloxetine (see ‘Taking other medicines’)
inhibitor (MAOI). Taking a MAOI together with many prescription medicines, including ARICLAIM,
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 ARICLAIM. Also, you need to wait at least 5 days after
you stop taking ARICLAIM 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 ARICLAIM, you should see your doctor.
Oral anticoagulants
:
Medicines which thin the blood. These medicines might increase the risk of
bleeding.
Taking ARICLAIM
with food and drink
ARICLAIM may be taken with or without food. Care should be taken if you drink alcohol while you
are being treated with ARICLAIM.
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 ARICLAIM. You should use ARICLAIM 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 ARICLAIM. 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 ARICLAIM 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 ARICLAIM while breastfeeding is not
recommended. You should ask your doctor or pharmacist for advice.
Driving and using machines
ARICLAIM may make you feel sleepy or dizzy. Do not drive or use any tools or machines until you
know how ARICLAIM affects you.
Important information about some of the ingredients of ARICLAIM
ARICLAIM 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.
3.
HOW TO TAKE ARICLAIM
Always take ARICLAIM exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
ARICLAIM starts to work in most people with diabetic neuropathic pain within 1 week of starting
treatment.
41
The usual dose of ARICLAIM is 1 capsule (60 mg) once a day, but your doctor will prescribe the dose
that is right for you.
ARICLAIM is for oral use. You should swallow your capsule whole with a drink of water.
To help you remember to take ARICLAIM, 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 ARICLAIM. Do not stop taking
ARICLAIM without talking to your doctor.
If you take more ARICLAIM
than you should
Call your doctor or pharmacist immediately if you take more than the amount of ARICLAIM
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 ARICLAIM
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 ARICLAIM that has been prescribed for you in one
day.
If you stop taking ARICLAIM
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 ARICLAIM he or she will ask you to reduce your dose over at
least 2 weeks before stopping treatment altogether.
Some patients who stop taking ARICLAIM 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.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, ARICLAIM 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
42
•
(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
•
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
43
•
“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 ARICLAIM
Keep out of the reach and sight of children
Do not use ARICLAIM 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 ARICLAIM 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 ARICLAIM looks like and contents of the pack
ARICLAIM is a hard gastro-resistant capsule. Each capsule of ARICLAIM contains pellets of
duloxetine hydrochloride with a covering to protect them from stomach acid.
ARICLAIM is available in 2 strengths: 30 mg and 60 mg.
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’.
ARICLAIM 30 mg is available in packs of 7, 28 and 98 capsules.
ARICLAIM 60 mg is available in packs of 28 and 98 capsules.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: 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:
44
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
Dista S.A..
Tel: + 34 91 623 17 32
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
Icepharma hf.
Sími + 354 540 8000
Slovenská republika
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
45
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.
46
Source: European Medicines Agency
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