Drug Class Description

Generic Name

Drug Description

Presentation

Indications

Adult Dosage

For oral use.

Major Depressive Episodes: The starting and recommended maintenance dose is 60 mg once daily with or without food. Dosages above 60 mg once daily, up to a maximum dose of 120 mg per day administered in evenly divided doses, have been evaluated from a safety perspective in clinical trials. However, there is no clinical evidence suggesting that patients not responding to the initial recommended dose may benefit from dose up-titrations. Therapeutic response is usually seen after 2-4 weeks of treatment. After consolidation of the antidepressive response, it is recommended to continue treatment for several months, in order to avoid relapse.

Diabetic Peripheral Neuropathic Pain: The starting and recommended maintenance dose is 60 mg daily with or without food. Dosages above 60 mg once daily, up to a maximum dose of 120 mg per day administered in evenly divided doses, have been evaluated from a safety perspective in clinical trials. The plasma concentration of duloxetine displays large inter-individual variability. Hence, some patients that respond insufficiently to 60 mg may benefit from a higher dose. The medicinal product response should be evaluated after 2 months’ of treatment. Additional response after this time is unlikely. The therapeutic benefit should regularly (at least every three months) be reassessed.

Renal insufficiency: No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine clearance 30 to 80 ml/min). See Contraindications for severe renal impairment. Discontinuation of treatment When discontinuing XERISTAR after more than 1 week of therapy, it is generally recommended that the dose be tapered over no less than 2 weeks before discontinuation in an effort to decrease the risk of discontinuation symptoms. As a general recommendation, the dose should be reduced by half or administered on alternate days during this period. The precise regimen followed should however take into account the individual circumstances of the patient, such as duration of treatment, dose at discontinuation etc.

Child Dosage

The safety and efficacy of duloxetine in these age groups have not been studied. Therefore, administration of XERISTAR to children and adolescents is not recommended (See Special Precautions).

Elderly Dosage

Diabetic Peripheral Neuropathic Pain: No dosage adjustment is recommended for elderly patients solely on the basis of age. However, caution should be exercised when treating the elderly. Hepatic impairment XERISTAR should not be used in patients with liver disease resulting in hepatic impairment (See Contraindications).

Contra Indications

Hypersensitivity to the active substance or to any of the excipients. Concomitant use of XERISTAR with nonselective, irreversible Monoamine Oxidase Inhibitors (MAOIs) is contraindicated (See Interactions). Liver disease resulting in hepatic impairment. XERISTAR should not be used in combination with fluvoxamine, ciprofloxacin or enoxacine (i.e. potent CYP1A2 inhibitors) since the combination results in elevated plasma concentrations of duloxetine (See Interactions). Severe renal impairment (creatinine clearance <30 ml/min).

Special Precautions

Mania and seizures

XERISTAR should be used with caution in patients with a history of mania or a diagnosis of bipolar disorder, and/or seizures. Mydriasis Mydriasis has been reported in association with duloxetine, therefore, caution should be used when prescribing XERISTAR to patients with increased intraocular pressure, or those at risk of acute narrow-angle glaucoma.

Blood pressure In patients with known hypertension and/or other cardiac disease, blood pressure monitoring is recommended as appropriate. 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 Contraindications.

See Adult Dosage for information on patients with mild or moderate renal dysfunction. Use with antidepressants Caution should be exercised when using XERISTAR in combination with antidepressants. In particular the combination with selective reversible MAOIs is not recommended. St John’s wort Undesirable effects may be more common during concomitant use of XERISTAR and herbal preparations containing St John’s wort (Hypericum perforatum).

Suicide Major Depressive Episodes Depression is associated with an increased risk of suicidal thoughts, self harm and suicide. 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 with all antidepressant therapies that the risk of suicide may increase in the early stages of recovery. Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation. Close supervision of high-risk patients should accompany drug therapy (See Adverse Reactions).

Patients, (and caregivers of patients) should be alerted about the need to monitor for the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. Diabetic Peripheral Neuropathic Pain As with other medicinal products with similar pharmacological action (antidepressants), isolated cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation.

Physicians should encourage patients to report any distressing thoughts or feelings at any time. Use in children and adolescents under 18 years of age No clinical trials have been conducted with duloxetine in paediatric populations. XERISTAR should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempts and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger), were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Sucrose XERISTAR hard gastro-resistant capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine. Haemorrhage There have been reports of cutaneous bleeding abnormalities, such as ecchymoses and purpura with selective serotonin reuptake inhibitors (SSRIs). Caution is advised in patients taking anticoagulants and/or medicinal products known to affect platelet function, and in patients with known bleeding tendencies.

Hyponatremia Hyponatremia has been reported rarely, predominantly in the elderly, when administering XERISTAR and other drugs of the same pharmacodynamic class. Discontinuation of treatment Some patients may experience symptoms on discontinuation of XERISTAR, particularly if treatment is stopped abruptly (See Adult Dosage and Adverse Reactions). Elderly Major Depressive Episodes: Data on the use of XERISTAR 120mg in elderly patients with major depressive disorders are limited. Therefore, caution should be exercised when treating the elderly with the maximum dosage (See Adult Dosage). Medicinal products containing duloxetine Duloxetine is used under different trademarks in several indications (treatment of diabetic neuropathic pain, major depressive episodes as well as stress urinary incontinence). The use of more than one of these products concomitantly should be avoided.

Interactions

CNS medicinal products:

The risk of using duloxetine in combination with other CNS-active medicinal products has not been systematically evaluated, except in the cases described in this section. Consequently, caution is advised when XERISTAR is taken in combination with other centrally acting medicinal products and substances including alcohol and sedative medicinal products (e.g. benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).

Monoamine Oxidase Inhibitors (MAOIs): due to the risk of serotonin syndrome, XERISTAR should not be used in combination with nonselective irreversible monoamine oxidase inhibitors (MAOIs), or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of duloxetine, at least 5 days should be allowed after stopping XERISTAR before starting an MAOI (See Contraindications).

For selective, reversible MAOIs, like moclobemide, the risk of serotonin syndrome is lower. However, the concomitant use of XERISTAR with selective, reversible MAOIs is not recommended (See Special Precautions). 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 XERISTAR is used concomitantly with serotonergic antidepressants like SSRIs, tricyclics like clomipramine or amitriptyline, St John’s wort (Hypericum perforatum), venlafaxine or triptans, tramadol, pethidine and tryptophan. Effect of duloxetine on other drugs Medicinal products metabolised by CYP1A2: in a clinical study, the pharmacokinetics of theophylline, a CYP1A2 substrate, were not significantly affected by co-administration with duloxetine (60 mg twice daily).

The study was performed in males and it can not be excluded that females having a lower CYP1A2 activity and higher plasma concentrations of duloxetine may experience an interaction with a CYP1A2 substrate. Medicinal products metabolised by CYP2D6: 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 5-hydroxyl metabolite and no dosage adjustment is recommended. Caution is advised if XERISTAR is co-administered with medicinal products that are predominantly metabolised by CYP2D6 if they have a narrow therapeutic index. 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. Effects of other drugs on duloxetine Antacids and H2 antagonists: co-administration of duloxetine with aluminium- and magnesiumcontaining antacids or duloxetine with famotidine had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose. Inhibitors of CYP 1A2: because CYP1A2 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP1A2 is likely to result in higher concentrations of duloxetine. Fluvoxamine (100 mg once daily), a potent inhibitor of CYP1A2, decreased the apparent plasma clearance of duloxetine by about 77% and increased AUCo-t 6-fold. Therefore XERISTAR should not be administered in combination with potent inhibitors of CYP1A2 like fluvoxamine (See Contraindications).

Inducers of CYP1A2: Population pharmacokinetic studies have shown that smokers have almost 50% lower plasma concentrations of duloxetine compared with non-smokers. Pregnancy There are no data on the use of duloxetine in pregnant women. Studies in animals have shown reproductive toxicity at systemic exposure levels (AUC) of duloxetine lower than the maximum clinical exposure. The potential risk for humans is unknown. As with other serotoninergic drugs, discontinuation symptoms may occur in the neonate after maternal duloxetine use near term.

XERISTAR should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus. Women should be advised to notify their physician if they become pregnant, or intend to become pregnant, during therapy. Breast feeding Duloxetine and/or its metabolites are excreted into the milk of lactating rats. Adverse behavioural effects were seen in offspring in a peri-post natal toxicity study in rats. Excretion of duloxetine and/or metabolites into human milk has not been studied. The use of XERISTAR while breast-feeding is not recommended.

Adverse Reactions

The most common side effects with Xeristar (seen in more than 1 patient in 10) are nausea (feeling sick), headache, dry mouth, somnolence (sleepiness), fatigue (tiredness), insomnia (difficulty sleeping), dizziness and constipation. Most of these were mild or moderate, starting early in treatment and getting milder as treatment continued.

Xeristar should not be used in people who may be hypersensitive (allergic) to duloxetine or any of the other ingredients. Xeristar should not be used with monoamine oxidase inhibitors (another group of antidepressants), fluvoxamine (another antidepressant), or ciprofloxacin or enoxacin (types of antibiotic). Xeristar should also not be used in patients with certain types of liver disease or patients with severe kidney disease. Treatment should not be started in patients with uncontrolled hypertension (high blood pressure), because of a risk of hypertensive crisis (sudden, dangerously high blood pressure).

As with other antidepressants, isolated cases of suicidal thoughts and behaviour have been seen in patients taking Xeristar, particularly in the first few weeks of treatment for depression. Any patients taking Xeristar who have distressing thoughts or experiences at any time should tell their doctor immediately.

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