2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Added:
Excipients: Sucrose.
4. CLINICAL PARTICULARS
4.2 Posology and method of administration
Deleted:
When discontinuing Cymbalta 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.
Replaced by:
Discontinuation of Treatment
Abrupt discontinuation should be avoided. When stopping treatment with Cymbalta 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.
4.4 Special warnings and precautions for use
Added (new text in bold):
Blood Pressure and Heart Rate
Duloxetine is associated with an increase in blood pressure in some patients. This may be due to the noradrenergic effect of duloxetine. In patients with known hypertension and/or other cardiac disease, blood pressure monitoring is recommended as appropriate, especially at the beginning 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.
Deleted:
Discontinuation of Treatment
Some patients may experience symptoms on discontinuation of Cymbalta, particularly if treatment is stopped abruptly (see sections 4.2 and 4.8).
Replaced by:
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 Cymbalta and 23% of patients taking placebo.
The risk of withdrawal symptoms seen with SSRIs and SNRIs 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).
Added:
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 and it may be necessary to review the use of duloxetine.
4.5 Interactions with other medicinal products and other forms of interaction
Added (new text in bold):
Medicinal products metabolised by CYP2D6: The co-administration of duloxetine (40mg twice daily) increases steady-state AUC of tolterodine (2mg 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 Cymbalta is co-administered with medicinal products that are predominantly metabolised by CYP2D6 if they have a narrow therapeutic index (such as flecainide, propafenone, and metoprolol).
Added:
Warfarin and INR: Increases in INR have been reported when duloxetine was co-administered with warfarin.
4.6 Pregnancy and lactation
Added (new text in bold):
Breast-Feeding
Duloxetine is excreted into the milk of lactating women. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose (see section 5.2). Adverse behavioural effects were seen in offspring in a perinatal/postnatal toxicity study in rats (see section 5.3). As the safety of duloxetine in infants is not known, the use of Cymbalta while breast-feeding is not recommended.
4.8 Undesirable effects
Added (Nervous system disorders, frequency not known):
Akathisia
Psychomotor restlessness
Added (Psychiatric disorders, frequency not known):
Hallucinations
Added (Vascular disorders, frequency not known):
Hypertension
Added (General disorders and administration site conditions, frequency not known):
Chest pain
Deleted:
Discontinuation symptoms have been reported when stopping Cymbalta. Common symptoms, particularly on abrupt discontinuation, include dizziness, nausea, insomnia, headache, and anxiety (see sections 4.2 and 4.4).
Replaced by:
Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, and headache 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).
Deleted:
In 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 compared to placebo at 12 weeks and routine care at 52 weeks. The increase was similar at both time points and was not considered clinically relevant. Relative to placebo or routine care, mean HbA1c values were stable, there was no mean weight gain, mean lipid concentrations (cholesterol, LDL, HDL, triglycerides) were stable, and there were no differences in incidence of serious and non-serious diabetes-related adverse reactions.
Replaced by:
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.
4.9 Overdose
Deleted:
There is limited clinical experience with duloxetine overdose in humans. In pre-marketing clinical trials, no cases of fatal overdose of duloxetine have been reported. Cases of acute ingestions up to 1400mg, alone or in combination with other medicinal products, have been reported.
No specific antidote is known for duloxetine.
Replaced by:
There is limited clinical experience with duloxetine overdose in humans. Cases of overdoses, alone or in combination with other drugs, with duloxetine doses of almost 2000mg were reported. Fatalities have been very rarely reported, primarily with mixed overdoses, but also with duloxetine alone at a dose of approximately 1000mg. Signs and symptoms of overdose (mostly with mixed drugs) included serotonin syndrome, somnolence, vomiting, and seizures.
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.
5. PHARMACOLOGICAL PROPERTIES
5.2 Pharmacokinetic properties
Added:
Nursing 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 7µg/day while on 40mg twice daily dosing. Lactation did not influence duloxetine pharmacokinetics.
10. DATE OF REVISION OF THE TEXT
New date of revision:
31 May 2006
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