Ariclaim - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

ARICLAIM 30 mg hard gastro-resistant capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 30 mg of duloxetine (as hydrochloride).

Excipient(s) with known effect:

Each capsule may contain up to 56 mg sucrose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard gastro-resistant capsule.

Opaque white body, imprinted with ‘30 mg’ and an opaque blue cap, imprinted with ‘9543’.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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).

The safety and efficacy of duloxetine for the treatment of diabetic peripheral neuropathic pain has not been studied. No data are available.

Special populations

Elderly

No dosage adjustment is recommended for elderly patients solely on the basis of age. However, as with any medicine, caution should be exercised when treating the elderly (see section 5.2).

Hepatic impairment

ARICLAIM must not be used in patients with liver disease resulting in hepatic impairment (see sections 4.3 and 5.2).

Renal impairment

No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine clearance 30 to 80 ml/min). 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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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).

4.4 Special warnings and precautions for use

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).

Renal impairment

Increased plasma concentrations of duloxetine occur in patients with severe renal impairment on haemodialysis (creatinine clearance <30 ml/min). For patients with severe renal impairment, see section 4.3. See section 4.2 for information on patients with mild or moderate renal dysfunction.

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with duloxetine treatment, particularly with concomitant use of other serotonergic agents (including SSRIs, SNRIs tricyclic antidepressants or triptans), with agents that impair metabolism of serotonin such as MAOIs, or with antipsychotics or other dopamine antagonists that may affect the serotonergic neurotransmitter systems (see sections 4.3 and 4.5).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular

aberrations (e.g. hyperreflexia, incoordination) and/or gastrointesti vomiting, diarrhoea).

If concomitant treatment with duloxetine and other serotonergic agents that may affect the serotonergic and/or dopaminergic neurotransmitter systems in clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

St John’s wort

Adverse reactions may be more common during concomitant use of ARICLAIM and herbal preparations containing St John’s wort (Hypericum perforatum).

viour

or 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

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), including duloxetine. Caution is advised in patients taking anticoagulants and/or medicinal products known to affect platelet function (e.g. NSAIDs or acetylsalicylic acid (ASA)), and in patients with known bleeding tendencies.

Hyponatraemia

Hyponatraemia has been reported when administering ARICLAIM, including cases wit sodium lower than 110 mmol/l. Hyponatraemia may be due to a syndrome of inappropri

diuretic hormone secretion (SIADH). The majority of cases of hyponatraemia w elderly, especially when coupled with a recent history of, or condition pre-disp balance. Caution is required in patients at increased risk for hyponatraemia, 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 and stress urinary incontinence). The use of more than one of these products concomitantly should be avoided.

Hepatitis/incre­ased liver enzymes

Cases of liver injury, including severe elevations of liver enzymes (>10 times upper limit of normal), hepatitis and jaundice have been reported with duloxetine (see section 4.8). Most of them occurred during the first months of treatment. The pattern of liver damage was predominantly hepatocellular. Duloxetine should be used with caution in patients treated with other medicinal products associated with hepatic injury.

Sucrose

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.

4.5 Interaction with other medicinal products and other forms of interaction

Monoamine oxidase inhibitors (MAOIs): Due to the risk of serotonin syndrome, duloxetine should not be used in combination with non-selective 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).

The concomitant use of ARICLAIM with selective, reversible MAOIs, like moclobemide, is not recommended (see section 4.4). The antibiotic linezolid is a reversible non-selective MAOI and should not be given to patients treated with ARICLAIM (see section 4.4).

Inhibitors of CYP1A2: Because CYP1A2 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP1A2 is likely to result in higher concentrations of duloxetine. Fluvoxamine (100 mg once daily), a potent inhibitor of CYP1A2, decreased the apparent plasma clearance of duloxetine by about 77% and increased AUCo-t 6-fold. Therefore 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 or substances, including alcohol and sedative medicinal products (e.g. benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).

Serotonergic agents: In rare cases, serotonin syndrome has been reported in patients using SSRIs/SNRIs concomitantly with serotonergic agents. Caution is advisable if ARICLAIM is used concomitantly with serotonergic agents like SSRIs, SNRIs, tricyclic antidepressants like clomipramine or amitriptyline, MAOIs like moclobemide or linezolid, St John’s wort (Hypericum perforatum) or triptans, tramadol, pethidine and tryptophan (see section 4.4).

Effect of duloxetine on other medicinal products

Medicinal products metabolised by CYP1A2: The pharmacokinetics of theophylline, a CYP1A2 substrate, were not significantly affected by co-administration with duloxetine (60 mg twice daily).

Medicinal products metabolised by CYP2D6: Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered at a dose of 60 mg twice daily with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. The co-administration of duloxetine (40 mg twice daily) increases steady state AUC of tolterodine (2 mg twice daily) by 71 %, but does not affect the pharmacokinetics of its active 5-hydroxyl metabolite and no dosage adjustment is recommended. Caution is advised if 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.

4.6 Fertility, pregnancy and lactation

♦ CnT

Fertility

Duloxetine had no effect on male fertility, and effects in females were only evident at doses that caused maternal toxicity.

Pregnancy

There are no adequate data on the use of duloxetine in pregnant women. Studies in animals have shown reproductive toxicity at systemic exposure levels (AUC) of duloxetine lower than the maximum clinical exposure (see section 5.3).

The potential risk for humans is unknown.

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated the association of PPHN to SNRI treatment, this potential risk cannot be ruled out with duloxetine taking into account the related mechanism of action (inhibition of the re-uptake of serotonin).

As with other serotonergic medicinal products, discontinuation symptoms may occur in the neonate after maternal duloxetine use near term. Discontinuation symptoms seen with duloxetine may include hypotonia, tremor, jitteriness, feeding difficulty, respiratory distress and seizures. The majority of cases have occurred either at birth or within a few days of birth.

. <y

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.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. 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.

4.8 Undesirable effects

• 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.

• 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 Hyp er- sensitivity disorder
Endocrine disorders
			Hypo-thyroidism
Metabolism and nutrition disorders
	Decreased Appetite	Hyperglycaemia (reported especially in diabetic patients)	Dehydration Hyponatraemia SIADH6
Psychiatric disorders
	Insomnia Agitation Libido decreased Anxiety Orgasm abnormal Abnormal dreams	Suicidal ideation5,7 Sleep disorder Bruxism Disorientation Apathy	Suicidal behaviour5,7 Mania Hallucinations Aggression and _ 4 anger
Nervous system disord ers
Headache Somnolence	Dizziness Lethargy Tremor Paraesthesia	Myoclonus Akathisia7 Nervousness Disturbance in attention Dysgeusia Dyskinesia Restless legs syndrome Poor quality sleep	Serotonin syndrome6 Convulsion1 Psychomotor restlessness6 Extra-pyramidal symptoms6
Eye disorders
	Blurred vision	Mydriasis Visual impairment	Glaucoma
Ear and labyrinth disorders
	Tinnitus1	Vertigo Ear pain

Very common	Common	Uncommon	Rare	Very Rare
Cardiac disorders
	Palpitations	Tachycardia Supra-ventricular arrhythmia, mainly atrial fibrillation
Vascular disorders
	Blood pressure increase3 Flushing	Syncope2 Hypertension3,7 Or­thostatic hypotension2 Peripheral coldness	Hypertensive crisis3,6
Respiratory, thoracic and mediastinal disorders
	Yawning	Throat tightness Epistaxis		-p-
Gastrointestinal disorders
Nausea Dry mouth	Constipation Diarrhoea Abdominal pain Vomiting Dyspepsia Flatulence	Gastrointestinal haemorrhage7 Gastroenteritis Eructation Gastritis Dysphagia	Stomatitis Haematoch ezia : Breath odour Microscopic colitis9
Hepato-biliary disorders
		Hepatitis3 Elevated liver enzymes (ALT, AST, alkaline phosphatase) Acute liver injury	Hepatic failure6 Jaundice6
Skin and subcutaneous tissue disorders
♦ < ♦ ■	Sweating increased Rash	Night sweats Urticaria Dermatitis contact Cold sweat Photo-sensitivity reactions Increased tendency to bruise	Stevens-Johnson Syndrome6 Angio-neurotic oedema6	Cutaneous vasculitis
Musculoskeletal and connective tissue disorders
	Musculo-skeletal pain Muscle spasm	Muscle tightness Muscle twitching	Trismus
Renal and urinary disorders
	Dysuria Pollakiuria	Urinary retention Urinary hesitation Nocturia Polyuria Urine flow decreased	Urine odour abnormal
Reproductive system and breast disorders
	Erectile dysfunction Ejaculation	Gynaecological haemorrhage Menstrual	Menopausal symptoms Galactorrhoea

Very common	Common	Uncommon	Rare	Very Rare
	disorder Ejaculation delayed	disorder Sexual dysfunction Testicular pain	Hyperprolactinae mia
General disorders and administration site conditions
	Falls8 Fatigue	Chest pain7 Feeling abnormal Feeling cold Thirst Chills Malaise Feeling hot Gait disturbance
Investigations
	Weight decrease	Weight increase Blood creatine phosphokinase increased Blood potassium 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.

• 8 Falls were more common in the elderly ( >  65 years old).

• 9 Estimated frequency based on all clinical trial data.

c. Description of selected adverse reactions

Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia or electric shock-like sensations, particularly in the head), sleep disturbances (including insomnia and intense dreams), fatigue, somnolence, agitation or anxiety, nausea and/or vomiting, tremor, headache, myalgia, irritability, diarrhoea, hyperhydrosis and vertigo are the most commonly reported reactions.

Generally, for SSRIs and SNRIs, these events are mild to moderate and self-limiting, however, in some patients they may be severe and/or prolonged. It is therefore advised that when duloxetine treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4).

In the 12 week acute phase of three clinical trials of duloxetine in patients with diabetic neuropathic pain, small but statistically significant increases in fasting blood glucose were observed in duloxetine-treated patients. HbA1c was stable in both duloxetine-treated and placebo-treated patients. In the extension phase of these studies, which lasted up to 52 weeks, there was an increase in HbA1c in both the duloxetine and routine care groups, but the mean increase was 0.3% greater in the duloxetine-treated group. There was also a small increase in fasting blood glucose and in total cholesterol in duloxetine-treated patients while those laboratory tests showed a slight decrease in the routine care group.

The heart rate-corrected QT interval in duloxetine-treated patients did not differ from that seen in placebo-treated patients. No clinically significant differences were observed for QT, PR, QRS, or QTcB measurements between duloxetine-treated and placebo-treated patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

er 4.9 Overdose

Cases of overdoses, alone or in combination with other medicinal products, with duloxetine doses of 5400 mg were reported. Some fatalities have occurred, primarily with mixed overdoses, but also with duloxetine alone at a dose of approximately 1000 mg. Signs and symptoms of overdose (duloxetine alone or in combination with other medicinal products) included somnolence, coma, serotonin syndrome, seizures, vomiting and tachycardia.

No specific antidote is known for duloxetine but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. A free airway should be established. Monitoring of cardiac and vital signs is recommended, along with appropriate symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption. Duloxetine has a large volume of distribution and forced diuresis, haemoperfusion, and exchange perfusion are unlikely to be beneficial.

5. PHARMACOLOGICAL PROPERTIES5.1 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 i enzymes (CYP1A2 and the polymorphic CYP2D6), followed b of duloxetine demonstrate large intersubject variability (general smoking status and CYP2D6 metaboliser status.

Absorption: Duloxetine is well absorbed after oral administration with a Cmax occurring 6 hours post dose. The absolute oral bioavailability of duloxetine ranged from 32% to 80% (mean of 50%). Food delays the time to reach the peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (approximately 11 %). These changes do not have any clinical significance.

Distribution: Duloxetine is approximately 96% bound to human plasma proteins. Duloxetine binds to both albumin and alpha-l acid glycoprotein. Protein binding is not affected by renal or hepatic impairment.

Biotransforma­tion: Duloxetine is extensively metabolised and the metabolites are excreted principally in urine. Both cytochromes P450–2D6 and 1A2 catalyse the formation of the two major metabolites glucuronide conjugate of 4-hydroxy duloxetine and sulfate 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 Cmax and AUC values compared with healthy subjects. Pharmacokinetic data on duloxetine is limited in patients with mild or moderate renal impairment.

Hepatic impairment: Moderate liver disease (Child Pugh Class B) affected the pharmacokinetics of duloxetine. Compared with healthy subjects, the apparent plasma clearance of duloxetine was 79% lower, the apparent terminal half-life was 2.3 times longer, and the AUC was 3.7 times higher in patients with moderate liver disease. The pharmacokinetics of duloxetine and its metabolites have not been studied in patients with mild or severe hepatic insufficiency.

Breast-feeding mothers: The disposition of duloxetine was studied in 6 lactating women who were at least 12-weeks postpartum. Duloxetine is detected in breast milk, and steady-state concentrations in breast milk are about one-fourth those in plasma. The amount of duloxetine in breast milk is approximately 7 ^g/day while on 40 mg twice daily dosing. Lactation did not influence duloxetine pharmacokinetics.

5.3 Preclinical safety data

Duloxetine was not genotoxic in a standard battery of tests and was not carcinogenic in rats. Multinucleated cells were seen in the liver in the absence of other histopathological changes in the rat carcinogenicity study. The underlying mechanism and the clinical relevance are unknown. Female mice receiving duloxetine for 2 years had an increased incidence of hepatocellular adenomas and carcinomas at the high dose only (144 mg/kg/day), but these were considered to be secondary to hepatic microsomal enzyme induction. The relevance of this mouse data to humans is unknown. Female rats receiving duloxetine (45 mg/kg/day) before and during mating and early pregnancy had a decrease in maternal food consumption and body weight, oestrous cycle disruption, decreased live birth indices and progeny survival, and progeny growth retardation at systemic exposure levels estimated to be at the most at maximum clinical exposure (AUC). In an embryotoxicity study in the rabbit, a higher incidence of cardiovascular and skeletal malformations was observed at systemic exposure levels below the maximum clinical exposure (AUC). No malformations were observed in another study testing a higher dose of a different salt of duloxetine. In prenatal/postnatal toxicity studies in the rat, duloxetine induced adverse behavioural effects in the offspring at exposures below maximum clinical exposure (AUC).

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

6. PHARMACEUTICAL PARTICULARS6.1 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 moistur;. Do not store above 30° C.

6.5 Nature and contents of container

Polyvinylchloride (PVC), polyethylene (PE), and polychlorotri­fluoroethylene (PCTFE) blister sealed

ARICLAIM 30 mg is available in packs of 7, 28 and 98 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

ederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands.

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/04/283/008

EU/1/04/283/009

EU/1/04/283/010

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11 August 2004

Date of latest renewal: 24 June 2009