Venlaxor®

Major depressive disorder, including depression accompanied by anxiety.

Prevention of relapses of the initial episode of depression or for the prevention of the recurrence of new episodes.

4.2       Posology and method of administration

Venlaxor should be taken with food. Each tablet should be swallowed a whole with fluid.

Depression.

The usual initial dose is 75 mg per day given in 2-3 divided doses. If, after several weeks, further clinical improvement is required, the dose may be increased to 150 mg per day given in 2-3 divided doses. Depending on clinical improvement further dose may be increased to up 225 mg per day. Usually the dose may be increased by 75 mg per day at intervals 4 days.

In severe depressed or hospitalised patients a initial dose is 150 mg per day, if necessary, the dose may be gradually increased to up the maximal dose of 375 mg per day, which is given in 3 divided doses. When desired response is achieved the dose gradually to be reduced.

In patients with renal or hepatic impairment dose should be reduced. The daily dose should be reduced by half or even lower in the patients with moderate hepatic impairment; for patients with moderate renal impairment - by 25 to 50 % of daily dose.

In elderly patients usual dosage adjustment is not required, however, caution should be exercised in treating the elderly.

4.3       Contraindications

Known hypersensitivity to venlafaxine or any other component of the product.

Concomitant use of Venlaxor with monoamine oxidase inhibitors (MAOIs).

If is necessary switching from MAOI to Venlaxor, at least interval of 2 weeks is recommended between cessation of MAOI and initiation of Venlaxor therapy; controversially, at least a week should be allowed between cessation of Venlaxor therapy and the initiation of MAOI therapy.

Venlaxor 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.

Severe hepatic or renal impairment.

Pregnancy and breast-feeding.

Venlaxor should not be used in children and adolescents under the age of 18 years with Major Depressive Disorder.

4.4       Special warnings and special precautions for use

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.

Other psychiatric conditions for which Venlaxor is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

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.

It is known, an increase in suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those with placebo.

Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt. The risk of withdrawal symptoms may be dependent on several

factors including the duration and dose of therapy and the rate of dose reduction.

Dizziness, sensory disturbances (including paraesthesia and electric shock sensations), sleep disturbances (including insomnia and abnormal dreams), agitation or anxiety, nausea and/or vomiting, tremor, sweating, headache, diarrhoea, palpitations and emotional instability are the most commonly reported withdrawal reactions. 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 venlafaxine should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs.

Activation of mania or hypomania has been reported rarely in patients who have received antidepressants, including venlafaxine. As with all antidepressants, Venlaxor should be used with caution in patients with a history of mania.

Treatment with venlafaxine (especially starting and discontinuing treatment) has been associated with reports of aggression.

The use of venlafaxine has been associated with the development of psychomotor restlessness, which clinically may be very similar to akathisia. 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 Venlaxor.

Venlaxor should be used with caution in patients with established cardiac disease that may increase the risk of ventricular arrhythmias (e.g. recent myocardial infarction or unstable heart disease).

Significant changes in PR, QRS or QTc intervals were rarely observed in patients treated with venlafaxine during clinical trials.

Dose-related increases in blood pressure have been reported commonly from clinical trials, particularly in patients receiving daily doses greater than 200 mg. Measurement of blood pressure is therefore recommended for patients receiving Venlaxor. For patients who experience a sustained increase in blood pressure while receiving Venlaxor, either dose reduction or discontinuation should be considered. Pre-existing hypertension should be controlled before treatment with Venlaxor. Cases of elevated blood pressure requiring immediate treatment have been reported in post-marketing experience.

Seizures are a potential risk with antidepressant drugs. Venlaxor 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. Venlaxor should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored.

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.

Increases in heart rate can occur, particularly at high doses. Caution should be exercised in patients whose underlying conditions might be compromised by increases in heart rate.

Dosage should be reduced in patients with moderate-severe renal impairment or hepatic cirrhosis.

Postural hypotension has been observed occasionally during venlafaxine treatment. Patients, especially the elderly, should be alerted to the possibility of dizziness or unsteadiness.

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.

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.

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.

Clinically relevant increases in serum cholesterol were observed in venlafaxine-treated patients treated for at least 3 months. Measurement of serum cholesterol levels should be considered during long-term treatment.

The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of Venlaxor and weight loss agents is not recommended. Venlaxor is not indicated for weight loss alone or in combination with other products.

As with SSRIs, Venlaxor 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 Venlaxor should not be used in combination with SSRIs unless clinically indicated and on the advice of a specialist.

Venlaxor tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5                Interaction with other medicinal products and other forms of interaction

MAOIs: Adverse reactions, some serious, have been reported when venlafaxine therapy is initiated soon after discontinuation of an MAOI, and when an MAOI is initiated soon after discontinuation of venlafaxine. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, and hyperthermia with features resembling neuroleptic malignant syndrome, seizures and death. Do not use Venlaxor in combination with a MAOI, or within at least 14 days of discontinuing MAOI treatment. Allow at least 7 days after stopping Venlaxor before starting an MAOI (see also section 4.3).

Serotonergic drugs: Based on the known mechanism of action of venlafaxine and the potential for serotonergic syndrome, caution is advised when venlafaxine is co-administered with drugs that may affect the serotonergic neurotransmitter systems (such as triptans, SSRIs or lithium).

Lithium: Reports have been received of an interaction between lithium and venlafaxine leading to increased lithium levels.

Imipramine/desipramine: The metabolism of imipramine and its metabolite 2-OH-imipramine were unaffected by venlafaxine although the total renal clearance of 2‑hydroxydesipramine was reduced and desipramine AUC and C_max were increased by approximately 35 %.

Haloperidol: In a pharmacokinetic study co-administration of venlafaxine with a single 2 mg oral dose of haloperidol resulted in a 42 % decrease in renal clearance, a 70 % increase in AUC and an 88 % increase in C_max for haloperidol. The elimination half-life remained unchanged.

Diazepam: The pharmacokinetic profiles of venlafaxine and ODV were not significantly altered by the administration of diazepam. Venlafaxine has no effect on the pharmacokinetic profile of diazepam or on the psychomotor or psychometric effects induced by diazepam.

Clozapine: Increased levels of clozapine, that were temporally associated with adverse events, including seizures, have been reported following the addition of venlafaxine.

Alcohol: Venlafaxine has been shown not to increase the impairment of mental or motor skills caused by ethanol. However, as with all CNS-active drugs, patients should be advised to avoid alcohol consumption while taking Venlaxor.

ECT: There is little clinical experience of the concurrent use of venlafaxine with ECT. As prolonged seizure activity has been reported with concomitant SSRI antidepressants, caution is advised.

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. 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. 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.

Effect of venlafaxine on the metabolism of other drugs metabolised by cytochrome P450: Studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP1A2, CYP2C9 or CYP3A4. This was confirmed by in vivo studies with the following drugs: alprazolam (CYP3A4), caffeine (CYP1A2), carbamazepine (CYP3A4) and diazepam (CYP3A4 and CYP2C19).

Cimetidine: Cimetidine inhibited the first-pass metabolism of venlafaxine but had no significant effect on the formation or elimination of ODV, which is present in much greater quantities in the systemic circulation. No dosage adjustment therefore seems necessary when Venlaxor is co-administered with cimetidine. For elderly patients, or patients with hepatic dysfunction the interaction could potentially be more pronounced, and for such patients clinical monitoring is indicated when Venlaxor is administered with cimetidine.

Warfarin: Potentiation of anticoagulant effects including increases in PT or INR have been reported in patients taking warfarin following the addition of venlafaxine.

Indinavir: A pharmacokinetic study with indinavir has shown a 28 % decrease in AUC and a 36 % decrease in C_max for indinavir. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this interaction is not known.

4.6              Pregnancy and lactation

There are no adequate data from the use of venlafaxine in pregnant women. Animal studies are insufficient with respect to effects on pregnancy. The potential risk for humans is unknown. Venlaxor should not be used during pregnancy unless clearly necessary. If venlafaxine is used until or shortly before birth, discontinuation effects in the newborn should be considered.

There is evidence to suggest that venlafaxine and its metabolite, ODV, transfers into breast milk. Therefore, a decision should be made whether or not to breast-feed or to discontinue Venlaxor.

4.7       Effects on ability to drive and use machines

As with all CNS-active drugs, Venlaxor may affect ability to drive or operate machinery. Before to start driving or operating machinery patients should be convinced that their judgement or motor skills are not impaired due to therapy.

4.8       Undesirable effects

The most commonly observed adverse events associated with the use of venlafaxine in clinical trials, and which occurred more frequently than those which were associated with placebo were: nausea, insomnia, dry mouth, somnolence, dizziness, constipation, sweating, nervousness, asthenia and abnormal ejaculation/orgasm.

The occurrence of most of these adverse events was dose-related, and the majority of them decreased in intensity and frequency over time. They generally did not lead to cessation of treatment.

Adverse events observed with venlafaxine, from both spontaneous and clinical trials reports, are classified in body systems and listed below as 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):

Blood and lymphatic system disorders - Uncommon: ecchymosis, mucous membrane bleeding. Rare: prolonged bleeding time, haemorrhage, thrombocytopenia. Very rare: blood dyscrasias (including agranulocytosis, aplastic anaemia, neutropenia and pancytopenia).

Cardiovascular and vascular disorders - Common: hypertension, palpitation, vasodilatation. Uncommon: hypotension/postural hypotension, syncope, arrhythmias (including tachycardia). Very rare: Torsade de Pointes, QT prolongation, ventricular tachycardia, ventricular fibrillation.

Gastrointestinal disorders - Very common: constipation, nausea (see below). Common: anorexia, appetite decreased, diarrhoea, dyspepsia, vomiting. Uncommon: bruxism. Rare: gastrointestinal bleeding. Very rare: pancreatitis.

General disorders - Very common: asthenia, headache. Common: abdominal pain, chills, pyrexia. Rare: anaphylaxis.

Metabolic and nutritional disorders - Common: serum cholesterol increased (particularly with prolonged administration and possibly with higher doses, weight gain or loss. Uncommon: hyponatraemia including SIADH, increased liver enzymes. Rare: hepatitis. Very rare: prolactin increased.

Musculo-skeletal disorders - Common: arthralgia, myalgia. Uncommon: muscle spasm. Very rare: rhabdomyolysis.

Neurological disorders - Very common: dizziness, dry mouth, insomnia, nervousness, somnolence. Common: abnormal dreams, agitation, anxiety, confusion, hypertonia, paraesthesia, tremor. Uncommon: apathy, hallucinations, myoclonus. Rare: ataxia and disorders of balance and co-ordination, speech disorders including dysarthria, mania or hypomania, neuroleptic malignant syndrome-like effects, seizures, serotonergic syndrome. Very rare: delirium, extrapyramidal disorders including dyskinesia and dystonia, tardive dyskinesia, psychomotor restlessness/akathisia.

Frequency not known: Suicidal ideation and suicidal behaviour.

Cases of suicidal ideation and suicidal behaviours have been reported during venlafaxine therapy or early after treatment discontinuation (see also section 4.4).

Renal and urinary disorders - Common: urinary frequency. Uncommon: urinary retention.

Reproductive and breast disorders - Very common: anorgasmia, erectile dysfunction, abnormal ejaculation/orgasm. Common: decreased libido, impotence, menstrual cycle disorders. Uncommon: menorrhagia. Rare: galactorrhoea.

Respiratory system disorders - Common: dyspnoea, yawning. Very rare: pulmonary eosinophilia.

Skin and subcutaneous tissue disorders - Very common: sweating (including night sweats). Common: pruritus, rash. Uncommon: angioedema, maculopapular eruptions, urticaria, photosensitivity reactions, alopecia. Rare: erythema multiforme, Stevens Johnson syndrome.

Special senses - Common: abnormal vision/accommodation, mydriasis, tinnitus. Uncommon: altered taste sensation.

Adverse events from paediatric clinical trials

In clinical trials the following adverse events were reported at a frequency of at least 2 % of patients: abdominal pain, chest pain, tachycardia, anorexia, weight loss, constipation, dyspepsia, nausea, ecchymosis, epistaxis, mydriasis, myalgia, dizziness, emotional lability, tremor, hostility and suicidal ideation.

Withdrawal symptoms

Discontinuation of venlafaxine (particularly when abrupt) commonly leads to withdrawal symptoms (see also section 4.4).

4.9       Overdose

The most common symptom observed with higher dose that is drowsiness. In the case of severe overdosage seizures, mild sinus bradycardia occurs. Concomitant use of alcohol and other medicine may cause electrocardiogram exchanges (prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, impaired coordination, altered level of consciousness (ranging from somnolence to coma).

It is recommended a symptomatic therapy: ensure an adequate airway, oxygenation and ventilation. Monitoring of cardiac rhythm and other vital signs. If ingestion is recent the stomach should be emptied by gastric lavage, also activated charcoal is recommended. No specific antidotes for Venlaxor are known.

Pharmacotherapeutic group: Antidepressant. Code ATC: N06AX16

Venlaxor (venlafaxine) is a structurally novel antidepressant which is chemically unrelated to tricyclic, tetracyclic, or other available antidepressant agents. It is a racemate with two active enantiomers.

The mechanism of Venlaxor's antidepressant action in humans is believed to be associated with its potentiation of neurotransmitter activity in the central nervous system. Preclinical studies have shown that venlafaxine and its major metabolite, O-desmethylvenlafaxine, are potent neuronal serotonin and noradrenaline re-uptake inhibitors (SNRI) and weak inhibitors of dopamine reuptake. In addition, venlafaxine and O-desmethylvenlafaxine reduce β-adrenergic responsiveness in animals after both acute (single dose) and chronic administration. Venlafaxine and its major metabolite appear to be equipotent with respect to their overall action on neurotransmitter re-uptake.

Venlafaxine has virtually no affinity for rat brain muscarinic, histaminergic or adrenergic receptors in vitro. Pharmacologic activity at these receptors may be related to various side effects seen with other antidepressant drugs, such as anticholinergic, sedative and cardiovascular effects.

5.2       Pharmacokinetic properties

Venlafaxine is well absorbed and undergoes extensive first-pass metabolism. Mean peak plasma concentrations of venlafaxine range from approximately 33 to 172 ng/ml after 25 to 150 mg single doses, and are reached in approximately 2.4 hours. Venlafaxine is extensively metabolised in the liver. O-desmethylvenlafaxine is the major active metabolite of venlafaxine. The mean disposition half-life of venlafaxine and O-desmethylvenlafaxine is approximately 5 and 11 hours, respectively. Mean peak O-desmethylvenlafaxine plasma concentrations range from approximately 61 to 325 ng/ml and are reached in approximately 4.3 hours. Plasma concentrations of venlafaxine and O-desmethylvenlafaxine generally correlated well with dose levels. Venlafaxine and O-desmethylvenlafaxine are 27 % and    30 % bound to plasma proteins respectively. O-desmethylvenlafaxine, other minor venlafaxine metabolites, and non-metabolised venlafaxine are excreted primarily through the kidneys.

5.3       Preclinical safety data

Carcinogenesis. Studies in the animals (mice, rats) revealed no carcinogen particularities.

Mutagenicity. Venlafaxine and its active metabolite, O-desmethylvenlafaxine, did not show mutagenic activity.

Impairment of fertility. Reduced fertility was observed in a study in which both male and female rats were exposed to the major metabolite of venlafaxine (ODV). This exposure was approximately 2 to 3 times that of a human dose of 225mg/day.

Pregnancy. Studies in the animals (rats) revealed teratogenic properties.

Calcium hydrogen phosphate, anhydrous
Lactose, anhydrous
Sodium starch glycolate, type A
Magnesium stearate
Silica, colloidal anhydrous (Aerosil 200)
Red Iron Oxide, E 172

6.2       Incompatibilities
Not applicable.

6.3       Self- life
5 years.

6.4       Special precautions for storage
Do not store above 25 °C.

6.5       Nature and contents of container

10 tablets are packed per blister.
3 blisters are packed per cardboard box.

6.6       Special precautions for disposal and other handling

No special requirements.