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4. CLINICAL PARTICULARS
4.1 Therapeutic Indications
Moderate to severe mMajor depressive disorder
Initiation of treatment with venlafaxine should be restricted to specialist care and treatment should be managed under specialist supervision or shared care arrangements.
Efexor is indicated for the treatment of moderate to severe major depressive disorder including depression accompanied by anxiety. All patients should be evaluated for the risk of suicidality and monitored for clinical worsening (see sections 4.2 and 4.4).
Moderate to severe Generalised Anxiety Disorder
Initiation of treatment with venlafaxine should be restricted to specialist care and treatment should be managed under specialist supervision or shared care arrangements.
4.2 Posology and Method of Administration
Efexor XL should be taken with food. Each capsule should be swallowed whole with fluid. Do not divide, crush, chew, or place the capsule in water. Efexor XL should be taken once daily, at approximately the same time, either in the morning or in the evening.
Depression:
In more severely depressed or hospitalised patients, and under close supervision of a physician, the daily dose may then be increased to the maximum recommended dose of Efexor XL capsules, 225mg given once daily. In those more severely depressed or hospitalised patients who require daily venlafaxine doses of 300 mg or more, treatment with Efexor tablets should be initiated under specialist supervision including shared care arrangements.
The dose should then be gradually reduced, to the minimum effective dose consistent with patient response and tolerance. A limited amount number of venlafaxine capsules should be provided to reduce the risk from overdose (see section 4.4).
Generalised Anxiety Disorder (GAD):
Efexor XL should be taken with food. Each capsule should be swallowed whole with fluid. Do not divide, crush, chew, or place the capsule in water. Efexor XL should be taken once daily, at approximately the same time, either in the morning or in the evening.
It is recommended that Efexor be taken with food.
Patients at increased risk for suicide (see also sections 4.4 and 4.9):
Patients with increased risk factors for suicide should be carefully evaluated for the presence or worsening of suicide-related behaviour (see sections 4.4 and 4.9) and a limited number of capsules should be provided to reduce the risk from overdose. A maximum of two weeks supply should be considered in these patients at initiation of treatment, during any dosage adjustment and until improvement occurs.
4.3 Contra-indications
3. Venlafaxine should not be used in patients with an identified very high risk of a serious cardiac ventricular arrhythmia (e.g. those with a significant left ventricular dysfunction, NYHA Class III/IV) or uncontrolled hypertension (see section 4.4).
4. 3. Efexor XL should not be used in children and adolescents under the age of 18 years with Major Depressive Disorder (see section 4.8 Undesirable Effects).
5 Venlafaxine should not be used in patients with heart disease, e.g. cardiac failure, coronary artery disease, ECG abnormalities including pre-existing QT interval prolongation, patients with electrolyte imbalance or in patients who are hypertensive (see section 4.4).
4.4 Special Warnings and Special Precautions for Use
- Suicide/suicidal thoughts. 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 self harm is highest shortly after presentation and the risk of suicide may increase again in the early stages of recovery. Furthermore, there is evidence that in children and adolescents
a small group of people, antidepressants may increase the risk of suicidal thoughts and self-harm.
There have been reports of cardiotoxicity associated with therapeutic doses of venlafaxine. Before starting treatment with venlafaxine, a baseline ECG and blood pressure measurement should be performed and blood pressure should be monitored at regular intervals. Patients with cardiac disease. Venlafaxine should be used with caution in patients with established cardiac disease that may increase the risk of ventricular arrhythmias (e.g. recent myocardial infarction) (see also sections 4.3 and 4.8). People with a recent history of myocardial infarction or unstable heart disease were excluded from all clinical trials. However, patients with other pre-existing heart disease were not excluded, although they were neither separately analysed nor systematically evaluated.
- Dose-related increases in blood pressure have been reported commonly from clinical trials, particularly in patients receiving daily doses greater than 200mg (see section 4.8). Sustained increases of blood pressure could have adverse consequences. Measurement of blood pressure is therefore recommended for patients receiving venlafaxine. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. Pre-existing hypertension should be controlled before treatment with venlafaxine (see section 4.3). Cases of elevated blood pressure requiring immediate treatment have been reported in post-marketing experience.
8. Seizures are a potential risk with antidepressant drugs, especially in overdose. Efexor XL should be introduced with caution in patients with a history of seizure and should be discontinued in any patient developing a seizure or if there is an increase in seizure frequency Efexor XL should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored (see section 4.8).
10. 9. Due to the possibility of drug abuse with CNS-active drugs, physicians should evaluate patients for a history of drug abuse, and follow such patients closely. Clinical studies have shown no evidence of drug-seeking behaviour, development of tolerance, or dose escalation over time among patients taking venlafaxine.
10. Increases in heart rate can occur, particularly at high doses. In clinical trials the mean heart rate was increased by approximately 4 beats/minute in patients treated with venlafaxine. Caution should be exercised in patients whose underlying conditions might be compromised by increases in heart rate.
11. Dosage should be reduced in patients with moderate-severe renal impairment or hepatic cirrhosis (see sections 4.2 and 4.5).
12. Postural hypotension has been observed occasionally during venlafaxine treatment. Patients, especially the elderly, should be alerted to the possibility of dizziness or unsteadiness.
13. Hyponatraemia (usually in the elderly and possibly due to inappropriate secretion of antidiuretic hormone) has been associated with all types of antidepressants and should be considered in all patients who develop drowsiness, confusion or convulsions while taking an antidepressant.
14. Mydriasis has been reported in association with venlafaxine; therefore patients with raised intra-ocular pressure or at a risk of narrow angle glaucoma should be monitored closely.
15. There have been reports of cutaneous bleeding abnormalities, such as ecchymosis and purpura, with serotonin-reuptake inhibitors (SSRIs). Other bleeding manifestations (e.g. gastrointestinal bleeding and mucous membrane bleeding) have been reported. Caution is advised in patients predisposed to bleeding due to factors such as age, underlying medical conditions or concomitant medications.
16. Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials. Measurement of serum cholesterol levels should be considered during long-term treatment.
17. The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of venlafaxine and weight loss agents is not recommended. Venlafaxine is not indicated for weight loss alone or in combination with other products.
18. As with SSRIs, venlafaxine should be used with caution in patients already receiving neuroleptics, since symptoms suggestive of Neuroleptic Malignant Syndrome cases have been reported with this combination.
- Serotonin syndrome has been rarely reported in association with concomitant use with SSRIs. Therefore venlafaxine should not be used in combination with SSRIs unless clinically indicated and on the advice of a specialist.
Drugs metabolised by Cytochrome P450 isoenzymes: The major elimination pathways for venlafaxine are through CYP2D6 and CYP3A4. Venlafaxine is primarily metabolised to its active metabolite, ODV, by the cytochrome P450 enzyme CYP2D6. Co-administration of ketoconazole suggests that inhibition of CYP3A4 may Although CYP3A4 is a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, there is potential for a clinically significant drug interaction between inhibitors of CYP3A4 mediated metabolism and venlafaxine as this could result in increased venlafaxine plasma levels in poor CYP2D6 metabolisers. Caution should be used with concomitant intake of drugs which inhibit either CYP2D6 or CYP3A4. Therefore, potent CYP3A4 inhibitors (e.g. ketoconazole, erythromycin) or drug combinations that inhibit both CYP3A4 and CYP2D6 should only be co-administered with venlafaxine if strictly indicated.
4.9 Overdose
There have been some reports of fatalities in patients taking overdoses of Efexor XL, predominantly in combination with alcohol and/or other CNS drugs.
Management of Overdosage - Ensure an adequate airway, oxygenation and ventilation. Monitoring of cardiac rhythm and vital signs is recommended, as are general supportive and symptomatic measures. Use of activated charcoal or gastric lavage should be considered. Induction of emesis is not recommended. No specific antidotes for venlafaxine are known. In managing overdose, consider the possibility of multiple drug involvement (e.g. concomitant intake with SSRIs or other psychotropic drugs).
Retrospective analyses from the United Kingdom (UK) report the rate of antidepressant overdose deaths per million prescriptions. In these analyses, the rate for venlafaxine is higher than that for SSRIs, but lower than that for tricyclic antidepressants. These analyses did not adjust for suicide risk factors. An epidemiological study in patients prescribed antidepressants in the UK showed that venlafaxine is prescribed to patients with a higher pre-existing burden of suicide risk factors than patients prescribed SSRIs. As such these patients should be carefully evaluated for the presence or worsening of suicide-related behaviour (see sections 4.2 and 4.4).
10. DATE OF (PARTIAL) REVISION OF TEXT
6 December 2004 26 May 2006
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