- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6. Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- 11. Legal status
Use in adultsThe recommended therapeutic dose is 4 mg twice a day (b.i.d.) i.e.8 mg/day administered orally. The full therapeutic dose can be given upon starting treatment. After 3-4 weeks, this dose can be increased to 10 mg/day in case of incomplete clinical response. The maximum daily dose should not exceed 12 mg. The minimum effective dose has not yet been established.
Use in the elderlyElderly patients have been studied in clinical trials at doses of 2 mg b.i.d. However, safety and efficacy have not been evaluated in placebo-controlled conditions. Therefore, as for other antidepressants that have not been studied in placebo-controlled conditions, reboxetine cannot be recommended.
Use in children and adolescents under the age of 18 yearsReboxetine should not be used in the treatment of children and adolescents under the age of 18 years (see section 4.4).
Use in patients with renal or hepatic insufficiencyThe starting dose in patients with renal or hepatic insufficiency should be 2 mg b.i.d which can be increased based on patient tolerance.
Use in children and adolescents under 18 years of ageReboxetine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempt 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.As reboxetine has not been tested in patients with convulsive disorders in clinical studies and since rare cases of seizures have been reported in clinical studies, it should be given under close supervision to subjects with a history of convulsive disorders and it must be discontinued if the patient develops seizures.Concomitant use of MAO-inhibitors (including linezolid (an antibiotic which is a reversible non-selective MAOI) and methylene blue) and reboxetine should be avoided in view of the potential risk (tyramine-like effect) based on their mechanisms of action.Concomitant use of reboxetine with other antidepressants (tricyclics, MAO inhibitors, SSRIs and lithium) has not been evaluated during clinical trials.As with all antidepressants, switches to mania/hypomania have occurred during the clinical studies. Close supervision of bipolar patients is, therefore, recommended.
Suicide/suicidal thoughts or clinical worsening: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 ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.Clinical experience with reboxetine in patients affected by serious concomitant systemic illnesses is limited. Close supervision should be applied in patients with current evidence of urinary retention, prostatic hypertrophy, glaucoma and history of cardiac disease.At doses higher than the maximum recommended, orthostatic hypotension has been observed with greater frequency than that observed at recommended doses. Particular attention should be paid when administering reboxetine with other drugs known to lower blood pressure.Clinical experience with reboxetine in the long-term treatment of elderly patients is, at present, limited. In this population, lowering of mean potassium levels was found starting from week 14; the magnitude of this reduction did not exceed 0.8 mmol/litre and potassium levels never dropped below normal limits.Mydriasis has been reported in association with reboxetine; therefore, caution should be used when prescribing reboxetine to patients with increased intraocular pressure or those at risk of acute narrow-angle glaucoma.
PREGNANCYNo clinical trial data on exposure to reboxetine during pregnancy are available. However, postmarketing safety data on a very limited number of exposed pregnancies indicate no adverse effects of reboxetine on pregnancy or on the health of the foetus/newborn child.Animal studies in general do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development or parturition. Some impairment of growth and development has been noted in rat neonates (see section 5.3).Reboxetine should only be used in pregnancy if the potential benefits of treatment to the mother outweigh the possible risks to the developing foetus.
LACTATIONReboxetine is known to be excreted in breast milk. The level of active substance transferred in breast milk is anticipated to be very low, however there is insufficient information to exclude a risk to the nursing infant. The use of reboxetine during breastfeeding can be considered if the potential benefits outweigh the risk for the child.
Table 1: Adverse Events
|Very Common (≥1/10)||Common (≥1/100 to <1/10)||Uncommon (≥1/1000 to <1/100)||Rare (≥1/10000 to <1/1000)||Frequency not Known|
|Metabolism and nutrition disorders|
|Insomnia||Agitation*, Anxiety*||Aggressive behaviour, Hallucination, Suicidal Ideation/behaviour**|
|Nervous system disorders|
|Headache, Dizziness, Paraesthesia*, Akathisia, Dysguesia|
|Accommodation disorder||Mydriasis*||Glaucoma*||Intraocular pressure increased|
|Ear and labyrinth disorders|
|Vasodilatation, Hypotension, Hypertension*||Peripheral coldness, Raynaud`s phenomenon|
|Dry mouth, Constipation, Nausea*||Vomiting*|
|Skin and subcutaneous tissue disorders|
|Renal and urinary disorders|
|Sensation of incomplete bladder emptying, Urinary tract infection, Dysuria, Urinary retention|
|Reproductive system and breast disorders|
|Erectile dysfunction, Ejaculatory pain, Ejaculatory delay||Testicular pain|
|General disorders and administration site conditions|
* these adverse events also occurred in postmarketing experience** Cases of suicidal ideation and suicidal behaviours have been reported during reboxetine therapy or early after treatment discontinuation (see section 4.4).In placebo-controlled studies of 8 weeks duration or less, adverse events were reported in approximately 80% of reboxetine-treated patients and in approximately 70% of placebo-treated patients. Discontinuation rates for adverse events were approximately 9% and 5% for reboxetine-and placebo-treated patients, respectively.As for long-term tolerability, 143 reboxetine-treated and 140 placebo-treated adult patients participated in a long term placebo controlled study. Adverse events newly emerged on long term treatment in 28% of the reboxetine treated patients and 23% of the placebo-treated patients and caused discontinuation in 4% and 1% of the cases respectively. There was a similar risk of the development of individual events with reboxetine and placebo. In the long term studies, no individual events were seen which have not been seen on short term treatment.In short-term controlled studies of patients with depression, no clinically significant between-gender differences were noted in the frequency of treatment emergent symptoms, with the exception of urologic events (such as the sensation of incomplete bladder emptying, dysuria and urinary frequency), which were reported in a higher percentage of reboxetine-treated male patients (31.4% [143/456]) than reboxetine-treated female patients (7.0% [59/847]). In contrast, the frequency of urologic-related events was similar among male (5.0% [15/302]) and female (8.4% [37/440]) placebo-treated patients. In the elderly population, frequency of total adverse events, as well as of individual events, was no higher than that reported above.In pre-marketing clinical studies, signs and symptoms newly reported following discontinuation occurred in approximately (5%) of the reboxetine treated patients and approximately (4%) of placebo-treated patients. In post-marketing experience, there have been a few spontaneous reports of withdrawal symptoms including headache, dizziness, nervousness and nausea; however, no consistent pattern of events on cessation of treatment with reboxetine was evident in these reports.In those short-term studies in depression where heart rate was assessed with ECG, reboxetine was associated with mean increases in heart rate, compared to placebo, of 6 to 12 beats per minute.In all short-term controlled studies in depression, the mean change in pulse (in beats per minute) for reboxetine-treated patients was 3.0, 6.4 and 2.9 in the standing, sitting and supine positions respectively, compared with 0, 0, and 0.5 for placebo-treated patients in the corresponding positions. In these same studies, 0.8% of reboxetine-treated patients discontinued the drug because of tachycardia compared with 0.1% of placebo-treated patients.
|Each pack contains:||10, 20, 50, 60, 100, 120, and 180 tablets in blisters; and 60 tablets in glass bottles.|
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