Depression Symptoms Treatment

(British Approved Name Modified, US Adopted Name, rINNM)

Drug Nomenclature

INNs in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. InEurope.

European Pharmacopoeia, 6th ed. (Venlafaxine Hydrochlonde). A white or almost white powder. It exhibits polymorphism. Freely soluble in water and in methyl alcohol soluble in dehydrated alcohol slightly soluble or practically insoluble in acetone.

Adverse Effects and Treatment

Adverse effects that have been reported most frequently with venlafaxine include nausea, headache, insomnia, somnolence, dry mouth, dizziness, constipation, sexual dysfunction, asthenia, sweating, and nervousness. Other common adverse effects have included anorexia, diarrhoea, dyspepsia, abdominal pain, anxiety, urinary frequency, visual disturbances, mydriasis, vasodilatation, vomiting, tremor, paraesthesia, hypertonia, chills or fever, palpitations, weight gain or loss, increased serum-cholesterol, agitation, abnormal dreams, confusion, arthralgia, myalgia, tinnitus, pruritus, dyspnoea, yawning, and skin rashes. Dose-related increases in blood pressure have also been observed in some patients.

Less common effects have included reversible increases in liver enzymes, orthostatic hypotension, syncope, arrhythmias, tachycardia, mucous membrane bleeding, ecchymosis, hallucinations, bruxism, muscle spasm, myoclonus, alopecia, altered taste, urinary retention, menorrhagia, angioedema, and photo sensitivity reactions.

Convulsions, galactorrhoea, haemorrhage including gastrointestinal bleeding, anaphylaxis, hepatitis, erythema multiforme, Stevens-Johnson syndrome, ataxia, dysarthria, extrapyramidal disorders including psychomotor restlessness and akathisia, and activation of mania or hypomania have been reported rarely. Other rare adverse effects include blood dyscrasias such as agranulocytosis, aplastic anaemia, neutropenia, pancytopenia, and thrombocytopenia, prolongation of the QT interval and torsade de pointes, ventricular tachycardia or fibrillation, rhabdomyolysis, delirium, pancreatitis, and pulmonary eosinophilia.

Aggressive behaviour has developed with venlafaxine treatment particularly at the start and when stopping therapy. Suicidal ideation has been reported, particularly in children (see under Effects on Mental State, below).

Hyponatraemia possibly due to inappropriate secretion of antidiuretic hormone has been associated with the use of antidepressants, particularly in the elderly.

In overdosage, symptoms such as sweating, dizziness, somnolence, ECG changes, cardiac arrhythmias, and seizures may be noted. Treatment of overdosage includes consideration of the use of activated charcoal if more than 12.5 mg/kg has been ingested and the patient presents within 1 hour this should be followed by symptomatic and supportive therapy. Dialysis, haemo-perfusion, exchange perfusion, and measures to increase urine production are considered unlikely to be of benefit.

Effects on the endocrine system. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) with hyponatraemia may be more likely to occur with serotonergic antidepressants such as venlafaxine than with other antidepressants for further details, see under Fluoxetine.

Effects on the eyes. Acute angle-closure glaucoma developed in a 45-year-old woman 3 days after starting venlafaxine she recovered after iridotomy. In another case, a 35-year-old man presented with bilateral acute angle-closure glaucoma 10 days after starting venlafaxine. The patient had also experienced visual disturbances while on mirtazapine and sertraline.

Effects on the hair. Hair loss has been described in 3 women given venlafaxine. The effect was noticed by the patients within a few weeks to 5 months after starting treatment. One patient who noticed hair loss within 1 week of starting venlafaxine had experienced the same problem during previous fluoxetine treatment. In all 3 cases, hair loss abated soon after stopping venlafaxine. In 2 cases hair regrowth was reported within a few weeks, but the third report was unclear as to whether regrowth occurred.

Effects on the liver. Acute hepatitis developed in a 44-year-old woman about 6 months after starting venlafaxine she recovered once venlafaxine was withdrawn. In another report, acute hepatitis developed in a 78-year-old man about a month after venlafaxine was added to therapy. Again, symptoms resolved when the drug was stopped. Hepatitis was noted in a 60-year-old woman about a month after starting low-dose venlafaxine (75 mg daily) symptoms resolved when the drug was stopped and recurred on rechallenge. Hepatitis has also been attributed to low-dose venlafaxine (37.5 mg daily) in a patient with chronic hepatitis B other causes of hepatitis and relapse of viral hepatitis were excluded.

For a report of hepatotoxicity in patients taking venlafaxine subsequent to an attempted overdose with sertraline.

Effects on mental state. An expert working group was convened in May 2003 by the UK CSM to consider the ongoing safety concerns of the SSRIs and, in particular, the risk of suicidal behaviour in children the safety of venlafaxine (another serotonergic antidepressant) was also considered. An interim report issued in September 2003 concluded that data from trials received by the CSM failed to show that venlafaxine was effective in the treatment of depressive illness in children under 18 years old and indicated that the risk of harmful outcome including self-harm and suicidal ideation was increased in those receiving venlafaxine when compared with placebo. The CSM recommended that venlafaxine should not be used to treat depressive illness in children under 18 years old. Similar warnings have also been issued in Canada, the EU, and the USA. (The final report of the CSM’s expert working group was published in December 2004.) The risk of suicide and suicide-related events with antidepressant treatment in adults including young adults is discussed under Fluoxetine.

Effects on the skin. Stevens-Johnson syndrome developed in a patient 12 days after beginning treatment with venlafaxine for recurrent depression. She had also been taking several other drugs for at least 6 months. Symptoms resolved on withdrawal of all medication and treatment with an intravenous corticosteroid.

Overdosage. Rare serious events including seizures and ECG changes have occurred after venlafaxine overdoses in some cases, death has ensued. Symptoms suggestive of serotonin toxicity may also develop.

Venlafaxine may not be as safe in overdose as some other serotonergic antidepressants. A review of UK data recording the number of deaths due to acute poisoning by a single drug, with or without alcohol, found the number of fatalities per million prescriptions (the fatal toxicity index) was higher for venlafaxine than for other serotonergic antidepressants, and was similar to that for some of the less toxic tricyclic antidepressants.

Serotonin syndrome. The serotonin syndrome is most often due to the additive adverse effects of two or more drugs that enhance serotonin activity at central receptors rarely, a single serotonergic drug may cause the syndrome. One such case was reported to have occurred in a 29-year-old woman who developed symptoms suggestive of serotonin syndrome 3 days after starting low-dose venlafaxine. However, this patient had been switched to venlafaxine the day after stopping imipramine treatment it is usually recommended that at least 3 weeks should elapse after stopping imipramine before starting another drug with serotonergic properties.

Precautions

Venlafaxine should not be used in patients with an identified very high risk of a serious ventricular arrhythmia or uncontrolled hypertension. Caution is advised in those with a recent history of myocardial infarction or whose condition might be exacerbated by an increase in heart rate. Due to the risk of dose-related increases in blood pressure, blood pressure measurement should be performed regularly during therapy. Measurement of serum-cholesterol levels should also be considered with long-term treatment.

Venlafaxine should be used with caution in patients with moderate to severe hepatic or renal impairment and dosage adjustment may be necessary. It should also be used with caution in patients with a history of epilepsy and avoided in those with unstable disease it should be stopped in any patient developing a seizure or if there is an increase in seizure frequency. Caution is also advised in patients with a history of bleeding disorders or of hypomania or mania. Patients with raised intra-ocular pressure or at risk of angle-closure glaucoma should be monitored closely. Patients who develop a rash, urticaria, or related allergic reaction with venlafaxine should be advised to contact their doctor.

Patients should be closely monitored during early antidepressant therapy until a significant improvement in depression is observed because suicide is an inherent risk in depressed patients. For further details, see under Depression. Suicidal thoughts and behaviour may also develop during early treatment with antidepressants for other disorders the same precautions observed when treating patients with depression should therefore be observed when treating patients with other disorders.

As with other antidepressants, venlafaxine may impair performance of skilled tasks and, if affected, patients should not drive or operate machinery. Patients, especially the elderly, should be warned of the risk of dizziness or unsteadiness due to orthostatic hypotension. Symptoms reported on abrupt withdrawal or dose reduction of venlafaxine include fatigue, somnolence, headache, nausea, vomiting, anorexia, palpitations, dizziness, dry mouth, diarrhoea, insomnia, agitation, anxiety, nervousness, confusion, hypomania, paraesthesia, sweating, and vertigo. It is therefore recommended that venlafaxine should be withdrawn gradually over at least one week after more than one week’s therapy patients receiving high-dose venlafaxine for longer than 6 weeks should be tapered over at least 2 weeks. All patients should also be monitored to minimise the risk of withdrawal reactions.

Abuse. A patient had an amfetamine-like “high” after taking crushed modified-release tablets of venlafaxine in doses of up to 3600 mg daily. He continued to ingest increasing amounts of venlafaxine until a 4050-mg dose produced chest pain. On evaluation he had a raised pulse and blood pressure but these returned to normal within a few days.

Breast feeding. Licensed product information recommends that venlafaxine should not be used in women who are breast feeding.

Venlafaxine and its metabolite O-desmethylvenlafaxine were both detected in breast milk in significant quantities in 3 women there were also measurable concentrations of desmethylven-lafaxine in the infants’ plasma. In another study by the same group the mean milk-to-plasma ratio in 6 breast-feeding women was calculated to be 2.5 for venlafaxine and 2.74 for O-desmethylvenlafaxine. Detectable plasma concentrations of venlafaxine were found only in 1 of 7 breast-fed infants while 4 had detectable O-desmethylvenlafaxine levels no adverse effects were reported in the infants. Nonetheless, the authors recommended caution when giving venlafaxine to breast-feeding women particularly for those feeding premature or very young neonates. The distribution of venlafaxine into breast milk and the presence of O-desmethylvenlafaxine in the serum of a further 5 breast-fed infants has also been reported. There were no detectable adverse effects in the infants, and the authors of 1 report suggested that women being treated for postpartum depression should not be generally discouraged from breast feeding. It has been suggested that venlafaxine in breast milk might alleviate a withdrawal syndrome in the neonate (see Pregnancy, below).

Children. Venlafaxine is associated with an increased risk of potentially suicidal behaviour when used for the treatment of depression in children and adolescents under 18 years old for further details, see under Effects on Mental State, above. US licensed product information also refers to studies that suggest that venlafaxine may adversely affect weight and height changes in children. In particular, the difference between the observed and the expected growth rate was larger for those children under 12 years of age than for older children.

Pregnancy. Licensed product information recommends that venlafaxine should not be used during pregnancy unless clearly necessary.

In a study of 150 women who took venlafaxine in the first trimester of pregnancy there were 125 live births, 18 spontaneous abortions, 7 therapeutic abortions, and 2 reports of major malformations (hypospadias and neural tube defect with club foot). Although the rate of spontaneous abortions was non-significantly higher in the venlafaxine group than in historical controls, the rate of major malformations was not greater than the baseline rate of 1 to 3%.

A neonatal withdrawal syndrome developed in the infant of a mother who had taken venlafaxine throughout her pregnancy symptoms included restlessness, hypertonia, irritability, and poor feeding. The infant recovered within 8 days. Seizures have been described in 2 neonates whose mothers were taking venlafaxine. Lip smacking and extensor limb posturing began at 30 minutes of age in 1 case, and multifocal myoclonic seizures occurred at 24 hours of age in the other both recovered and were well at 1 year of age. Serum-venlafaxine concentrations had not been measured and the authors were unsure whether the adverse effects in the neonates were due to withdrawal or toxicity. In a retrospective study of women who had taken SSRIs or venlafaxine during the third trimester (9 had taken venlafaxine), there were reports of adverse effects on the CNS and respiratory tract in the neonates, such as abnormal movements, tonus abnormalities, irritability, insomnia, indrawing, apnoea/bradycardia, and tachypnoea. The signs usually appeared on the first day of life and lasted for about 3 days in full-term neonates and about 5 days in those born prematurely.

Venlafaxine and its metabolite O-desmethylvenlafaxine are distributed into breast milk (see Breast Feeding, above), and it has been suggested that breast feeding might have helped to alleviate symptoms of a withdrawal syndrome in a neonate whose mother took venlafaxine throughout her pregnancy.

Renal impairment. The mean terminal disposition half-life of venlafaxine was prolonged from a mean of 3.8 hours in 18 healthy subj ects to 5.8 hours in 12 patients with mild to moderate renal impairment (creatinine clearance 10 to 70 mL/minute) and 10.6 hours in patients requiring haemodialysis corresponding values for O-desmethylvenlafaxine, the active major metabolite of venlafaxine, were 11.8, 16.8, and 28.5 hours, respectively. Because of the large intersubject variability, the change in disposition for venlafaxine and its active metabolite was evident only in patients with a creatinine clearance of less than 30 mL/minute drug clearance in these patients was reduced by about 55% and half-life more than doubled. It was calculated that for these patients half the usual daily dose could be given once daily. Similar recommendations are made in licensed drug information, see under Uses and Administration, below.

Surgery. Serotonergic antidepressants such as venlafaxine may be associated with an increased risk of blood loss during surgery for further details, see under Fluoxetine.

Withd rawal. Withdrawal reactions may be more common with venlafaxine than with some other serotonergic antidepressants for further details, see under Fluoxetine. Withdrawal reactions may also be seen in neonates after maternal venlafaxine use, see under Pregnancy above.

Some cases of withdrawal reactions to venlafaxine have been reported.

Interactions

Although different antidepressants have been used together under expert supervision in refractory cases of depression, severe adverse reactions including the serotonin syndrome may occur. Sequential prescribing of different types of antidepressant may also produce adverse reactions, and an appropriate drug-free interval should elapse between stopping one type of antidepressant and starting another. Venlafaxine should not be used with MAOIs and at least 14 days should elapse between stopping an MAOI and starting treatment with venlafaxine. At least 7 days should elapse between stopping venlafaxine and starting any drug liable to provoke a serious reaction (e.g. phenelzine). For further details, see Antidepressants under Interactions of Phenelzine. Adverse effects such as the serotonin syndrome may also occur when venlafaxine is given with other drugs known to act on the same neurotransmitter, a consequence of synergistic interaction.

Venlafaxine has occasionally been associated with bleeding disorders and other effects on the blood caution is advised when giving venlafaxine with other drugs known to affect platelet function. Although cimetidine inhibits the first-pass hepatic metabolism of venlafaxine, it has no effect on the active metabolite Odesmethyfvenlafaxine, which is present in the plasma in much greater concentrations. Licensed product information therefore considers that when cimetidine and venlafaxine are used together, clinical monitoring may only be necessary in elderly patients and in those with hepatic impairment or pre-existing hypertension.

Conversion of venlafaxine to its equally active metabolite O-desmethylvenlafaxine is mediated by the cytochrome P450 isoenzyme C YP2D6. Therefore the potential exists for drugs that inhibit or act as a substrate for this enzyme to affect plasma concentrations of venlafaxine and its active metabolite. However, the US product information indicates that, as the total amount of active compounds is unaffected, no dosage adjustment is usually necessary for venlafaxine. Venlafaxine is also metabolised by CYP3A4 to the less active metabolite N-desmethylvenlafaxine. This is a relatively minor pathway and the potential for clinically significant interactions between venlafaxine and C YP3A4 inhibitors is considered to be small. However, potent inhibitors of C YP3A4 or drugs that inhibit both C YP2D6 and C YP3A4 could significantly increase venlafaxine concentrations in patients who are poor CYP2D6 metabolisers such combinations should therefore be used with caution.

Venlafaxine itself is considered to be a relatively weak inhibitor ofCYP2D6.

Antiarrhythmics. Psychosis with raised serum concentrations of venlafaxine and its metabolite O-desmethylvenlafaxine developed when propafenone therapy was started in a 67-year-old woman. There was improvement when venlafaxine was stopped and restarted at a reduced dose 50 mg daily was sufficient to maintain therapeutic serum concentrations.

Antibacterials. Tingling in the tip of the tongue, intense paraesthesia in the fingers, severe abdominal cramps, profuse diarrhoea, cold sweats, and uncontrolled shivering and tremor occurred when co-amoxiclav was started in a man taking venlafaxine. The reaction lasted for about 6 hours. It occurred again 2 months later after a single dose of co-amoxiclav. The patient reported that he had taken co-amoxiclav in the past without any reaction at a time when he was not taking venlafaxine. The mechanism for an interaction between venlafaxine and co-amoxiclav causing this serotonin syndrome is unknown. The author also suggested that many patients must have taken this combination without adverse effect, and found no other reports. Serotonin syndrome has been reported in an elderly patient taking venlafaxine, after 20 days of antibacterial treatment including linezolid In another report, serotonin syndrome developed 8 days after starting treatment with intravenous linezolid in a patient taking venlafaxine.

Antimigraine drugs. There have been rare reports of serotonin syndrome associated with the use of serotonin and noradrena-line reuptake inhibitors (SNRIs) with serotonin (5-HT1) agonists such as sumatriptan.

Antipsychotics. For mention of neuroleptic malignant syndrome developing in patients who received venlafaxine with antipsychotics see under Interactions in Chlorpromazine.

Gastrointestinal drugs. Signs suggestive of the serotonin syndrome that occurred after intravenous metoclopramide were attributed to an interaction with venlafaxine. The 32-year-old woman experienced confusion, agitation, generalised shaking, myoclonus, facial twitching, diaphoresis, horizontal nystagmus, and dilated pupils, that resolved within 2 days after stopping both drugs and treatment with diazepam.

Selegiline. Although it is generally recommended that venlafaxine should not be started for at least 14 days after stopping an MAOI, there is a report of serotonin syndrome developing when a patient began venlafaxine treatment 15 days after stopping selegiline, an MAO type B inhibitor.

Pharmacokinetics

Venlafaxine is readily absorbed from the gastrointestinal tract. After oral doses it undergoes extensive first-pass metabolism in the liver mainly to the active metabolite O-desmethylvenlafaxine formation of O-desmethyl venlafaxine is mediated by the cytochrome P450 isoenzyme CYP2D6. The isoenzyme CYP3A4 is also involved in the metabolism of venlafaxine. Other metabolites include N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine. Peak plasma concentrations of venlafaxine and Ode sm ethyl venlafaxine appear about 2 and 4 hours after a dose, respectively. Venlafaxine is 27% and O-desmethylvenlafaxine 30% bound to plasma proteins. The mean elimination half-life of venlafaxine and O-desmethylvenlafaxine is about 5 and 11 hours, respectively. Venlafaxine is excreted mainly in the urine, mainly in the form of its metabolites, either free or in conjugated form about 2% is excreted in the faeces. Venlafaxine and O-desmethylvenlafaxine have been detected in amniotic fluid and umbilical cord blood, and are distributed into breast milk.

Pregnancy. Venlafaxine and its metabolite, O-desmethylvenlafaxine, have been detected in amniotic fluid and umbilical cord blood. For adverse effects that have occurred in neonates of women who were taking venlafaxine during the third trimester, see Pregnancy, under Precautions, above.

Uses and Administration

Venlafaxine, a phenylethylamine derivative, is a serotonin and noradrenaline reuptake inhibitor (SNRI) it also weakly inhibits dopamine reuptake. It is reported to have little affinity for muscarinic, histaminergic, or α1-adrenergic receptors in vitro. Venlafaxine is given orally as the hydrochloride although doses are expressed in terms of the base venlafaxine hydrochloride 28.3 mg is equivalent to about 25 mg of venlafaxine.

Venlafaxine is used in the treatment of depression. The initial daily dose is equivalent to venlafaxine 75 mg in two or three divided doses with food. In the USA, it is suggested that some patients may be best started on 37.5 mg daily for the first 4 to 7 days before increasing the dose to 75 mg daily. The dose may be increased, if necessary, after several weeks to 150 mg daily. Further increases, to a maximum daily dose of 375 mg, may be made in increments of up to 75 mg at intervals of at least 2 to 4 days. Such doses may be required in severely depressed or hospitalised patients and should be gradually reduced to the minimum effective dose. Modified-release preparations are available for once-daily dosing.

Venlafaxine is also used, as a modified-release preparation, in the treatment of generalised anxiety disorder. The recommended initial dose is 75 mg once daily. In the USA it is suggested that some patients may be best begun with 37.5 mg daily for 4 to 7 days initially dosage may subsequently be adjusted in increments of up to 75 mg, at intervals of at least 4 days, to a maximum of 225 mg daily. Venlafaxine should be withdrawn gradually if there is no response after 8 weeks.

In the USA, modified-release venlafaxine is licensed for the treatment of social anxiety disorder in doses similar to those used for generalised anxiety disorder. It is also licensed in the USA for panic disorder with or without agoraphobia in doses of 37.5 mg once daily for the first 7 days, then increasing to 75 mg daily. Subsequent increases in increments of up to 75 mg may be made at intervals of at least 7 days, to a maximum dose of 225 mg daily.

Reduced doses may need to be given in hepatic or renal impairment, see below.

Venlafaxine should be withdrawn gradually to reduce the risk of withdrawal symptoms (see Precautions, above).

Administration in hepatic impairment. UK licensed product information considers that patients with mild hepatic impairment do not require a change in dose of venlafaxine. For those with moderate impairment, the dose should be reduced by half and given once daily. There are insufficient data to make any recommendations for patients with severe impairment.

Administration in renal impairment. The UK licensed product information states that, based on glomerular filtration rate (GFR), patients with mild renal impairment (GFR above 30 mL/minute) do not require a change in dose of venlafaxine. For those with moderate impairment (GFR 10 to 30 mL/minute), the dose should be reduced by 50% and once-daily dosage may be appropriate. There are insufficient data to make any recommendations for patients with severe impairment (GFR less than 10 mL/minute).

In the USA, it is recommended that patients with a GFR of 10 to 70 mL/minute reduce the dose of immediate-release venlafaxine by 25% and of modified-release venlafaxine by 25 to 50% regardless of preparation, in those undergoing haemodialysis, the dose should be reduced by 50% and withheld until the dialysis is completed.

Anxiety disorders. Venlafaxine is used in the treatment of generalised anxiety disorder and social anxiety disorder (see under Phobic Disorders) it may also be of use in a variety of other types of anxiety disorders including the treatment of obsessive-compulsive disorder, panic disorder, and post-traumatic stress disorder.

Depression. As discussed, there is very little difference in efficacy between the different groups of antidepressant drugs, and choice is often made on the basis of adverse effect profile. In December 2004 the UK CSM recommended that, because of the risk of adverse cardiovascular effects and toxicity in overdosage (see above), venlafaxine treatment should be begun and maintained under specialist supervision only. After an assessment of further safety evidence, these restrictions were revised in May 2006 and specialist supervision was considered only necessary when starting venlafaxine treatment in severely depressed or hospitalised patients who require doses of 300 mg daily or above. However, it was also advised that venlafaxine should be considered a second-line treatment, after the SSRIs. The O-desmethyl metabolite of venlafaxine, desvenlafaxine, is also used in depression. References.

Hot flushes. For the reference to the use of venlafaxine in the treatment of hot flushes, see under Fluoxetine.

Hyperactivity. When drug therapy is indicated for attention deficit hyperactivity disorder initial treatment is usually with a central stimulant. Antidepressants may be used for patients who fail to respond to, or who are intolerant of, central stimulants in open studies venlafaxine has been reported to be effective in both adults and children although in one study some patients experienced a worsening of symptoms.

Migraine. Retrospective analysis in patients with tension-type headache or migraine indicated that venlafaxine, as a modified-release preparation, had potential for headache prophylaxis. A more recent randomised placebo-controlled study also supports the use of modified-release venlafaxine in the prophylaxis of migraine.

Pain. Venlafaxine may be of benefit in the treatment of neuropathic pain syndromes including painful diabetic neuropathy. It has also shown some promise in the treatment of fibromyalgia (see Soft-tissue Rheumatism).

Proprietary Preparations

Argentina: Efexor Elafax Ganavax Mezine Quilarex Sesaren

Australia: Efexor

Austria: Efectin

Belgium: Efexor

Brazil: Efexor Venlaxin Venlift

Canada: Effexor

Chile: Depurol Efexor Nervix Norpilen Senexon Sentidol Sesaren Subelan Venlax

Czech Republic: Argofan Convalemin Efectin Elify Faxiprol Lafaxon Mollome Olvexya Velaxin

Denmark: Efexor

Finland: Efexor

France: Effexor

Germany: Trevilor

Greece: Arvifax Efexor

Hong Kong: Efexor

Hungary: Efectin Olwexya Velaxin

India: Flavix Venlor Vexor

Indonesia: Efexor

Ireland: Efexor

Israel: Efexor Venla Viepax

Italy: Efexor Faxine

Malaysia: Efexor

Mexico: Efexor Odven SBK

The Netherlands: Efexor

Norway: Efexor

New Zealand: Efexor

Philippines: Efexor

Poland: Efectin Velafax Velaxin

Portugal: Desinax Efexor Genexin Venxin Xapnev Zarelix

Russia: Efevelone Velafax Velaxin

South Africa: Efexor Venlor

Singapore: Efexor

Spain: Dobupal Vandral

Sweden: Efexor

Switzerland: Efexor

Thailand: Efexor

Turkey: Efexor

UK: Efexor

USA: Effexor

Venezuela: Efexor Idoxen Sesaren.