Consumer medicine information

APO-Venlafaxine XR Capsules

Venlafaxine

BRAND INFORMATION

Brand name

APO-Venlafaxine XR

Active ingredient

Venlafaxine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Venlafaxine XR Capsules.

What is in this leaflet

This leaflet answers some common questions about venlafaxine. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may want to read it again.

What this medicine is used for

Venlafaxine is used to treat major depression, and to prevent it coming back. It is also used to treat panic attacks and anxiety.

Venlafaxine belongs to a group of medicines called serotonin-noradrenaline reuptake inhibitors (SNRIs).

Venlafaxine increases the level of serotonin and noradrenaline in the brain, helping to restore your feeling of wellness.

Depression may cause emotional and physical symptoms such as feeling low, poor appetite or lack of energy.

Excessive anxiety may cause you to feel constantly and uncontrollably worried and distressed. It may also make you feel irritable, and cause difficulty in thinking and sleeping.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed Venlafaxine XR for another reason.

This medicine is available only with a doctor's prescription.

This medicine is not addictive.

There is not enough information to recommend the use of this medicine for children under the age of 18 years.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

  • venlafaxine
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin

Do not take this medicine if you are taking other medicines called Monoamine Oxidase Inhibitors (MAOIs).

MAOIs may be used for the treatment of depression (phenelzine, tranylcypromine or moclobemide), Parkinson's disease (selegiline), infections (linezolid) or diagnosis of certain conditions/treatment of certain blood disorders (methylene blue).

Taking venlafaxine with a MAOI may cause a serious reaction with a sudden increase in body temperature, extremely high blood pressure and severe convulsions.

Do not take venlafaxine until 14 days after stopping most MAOIs, and do not take any MAOIs until more than one week after stopping venlafaxine. You may take venlafaxine 24 hours after stopping the reversible MAOI called moclobemide.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • epilepsy, fits or seizures
  • a personal or family history of bipolar disorder
  • a history of aggression
  • a history of restlessness or difficulty sitting still
  • drug abuse or misuse
  • blood pressure problems
  • diabetes
  • acute angle glaucoma or increased pressure in the eye
  • a tendency to bleed more than normal or other blood disorders
  • raised cholesterol levels or you are taking medicines to lower cholesterol
  • kidney or liver problems
  • low sodium levels in your blood, or a condition called SIADH (Syndrome of Inappropriate Antidiuretic Hormone Secretion)
  • thoughts or actions relating to self-harm or suicide
  • heart problems, especially conditions causing irregular heartbeats – your doctor may wish to do some heart tests such as an electrocardiogram (ECG) or blood tests during treatment with venlafaxine

Tell your doctor if you are pregnant or plan to become pregnant. There have been reports that babies exposed to venlafaxine and other antidepressants during the third trimester of pregnancy may develop complications after birth, including breathing difficulties, seizures and lack of oxygen in their blood.

Continuing treatment with venlafaxine or similar antidepressants during pregnancy should be strictly as directed by your doctor.

Do not take this medicine whilst pregnant until you and your doctor have discussed the risks and benefits involved.

Tell your doctor if you are breastfeeding. Venlafaxine passes into breast milk and there is a possibility that your baby may be affected. For this reason, the use of venlafaxine is not recommended if you are breastfeeding.

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

Taking other medicines

Tell your doctor and pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interact with venlafaxine. These include:

  • MAOIs (e.g. phenelzine, tranylcypromine, moclobemide, selegiline, linezolid or methylene blue).
    Do not take venlafaxine until 14 days after stopping most MAOIs, and do not take any MAOIs until more than one week after stopping venlafaxine.
    For moclobemide, do not take venlafaxine until at least 24 hours after stopping moclobemide, and do not take moclobemide until more than one week after stopping venlafaxine.
  • St John's wort (Hypericum perforatum) or tryptophan
  • dopamine agonists used to treat Parkinson's disease
  • any other medications for depression, anxiety, obsessive-compulsive disorder or premenstrual dysphoric disorder
  • haloperidol, risperidone, lithium or clozapine, used to treat mood disorders
  • tramadol, fentanyl, tapentadol, pethidine and methadone, strong pain killers
  • amphetamines, including those used to treat Attention Deficit Hyperactivity Disorder (e.g. dexamphetamine and lisdexamphetamine)
  • cimetidine, used to treat reflux
  • triptans, used to treat migraines
  • amiodarone or quinidine, used to treat irregular heartbeats
  • warfarin and clopidogrel, used to prevent blood clots
  • diuretics, also called fluid or water tablets
  • medicines used to treat diabetes

Your doctor may also wish to do some heart tests such as an electrocardiogram (ECG) or blood tests if you are using any of the following whilst taking venlafaxine:

  • warfarin, used to prevent blood clotting
  • indinavir, an antiviral medicine
  • linezolid or erythromycin, used to treat infections
  • ketoconazole or fluconazole, used as antifungal medicines
  • medicines used for weight loss (e.g. phentermine, sibutramine)
  • metoprolol, used to treat high blood pressure or angina
  • medications that can affect your heart beat
  • grapefruit juice

These medicines may be affected by venlafaxine or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

Other interactions not listed above may also occur.

How to take this medicine

Follow all directions given to you by your doctor or pharmacist carefully. They may differ to the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how much of this medicine you should take, depending on your condition and if you are taking any other medicines.

The usual starting dose is 75 mg taken once daily.

If necessary, after two weeks, your doctor may increase your dose. The maximum dose you should take in one day is 225 mg.

How to take it

Swallow the capsules whole with a glass of water. Do not divide, crush, chew or place the capsules in water.

Inside venlafaxine XR capsules, there are tablets that contain the venlafaxine. As the medicine travels the length of your gastrointestinal tract, venlafaxine is slowly released.

When to take it

Take this medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

Although you may begin to feel better after two weeks, it may take several weeks before you feel much better.

Even when you feel well again, you may need to keep taking venlafaxine for several months to make sure the benefits last.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is less than 12 hours until your next dose, skip the missed dose and take your next dose at the usual time.

Otherwise take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses. This may increase the chance of you experiencing side effects.

Contact your doctor if you have missed more than two doses in a row.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to the Emergency Department at your nearest hospital if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much venlafaxine, you may experience sleepiness, vomiting, dilated pupils, increased heart rate, changes in heart rhythm, seizure (fits), breathing difficulties or becoming unconscious.

While you are taking this medicine

Things you must do

Watch carefully for signs that your depression is getting worse, especially in the first few weeks of treatment or if your dose has changed.

Tell your doctor immediately if you experience any of the following symptoms, especially if they are severe, you have not had these symptoms before, or they happen very suddenly:

  • anxiety or agitation
  • panic attacks
  • difficulty sleeping
  • restlessness
  • irritability
  • aggressiveness, hostility or impulsiveness
  • overactivity or uninhibited behaviour
  • other unusual changes in behaviour
  • thoughts of suicide.

Tell your doctor immediately if you have any thoughts about suicide or doing harm to yourself.

All thoughts or talk about suicide or violence are serious. If you or someone you know is showing the following warning signs, either contact your doctor or a mental health advisor right away or go to the nearest hospital for treatment.

  • thoughts or talk about death or suicide.
  • thoughts or talk about self-harm or doing harm to others.
  • any recent attempts of self-harm.
  • an increase in aggressive behaviour, irritability or agitation.

If you are being treated for depression, discuss with your doctor any problems you may have and how you feel, especially any feelings of severe sadness, thoughts of suicide, bursts of unusual energy, anger or aggression, or if you become particularly agitated or restless.

If you are about to be started on any new medicine, tell your doctor that you are taking this medicine.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately. Make sure your midwife and/or doctor know immediately that you are pregnant and taking venlafaxine, as there is a possibility of problems developing in unborn children.

Symptoms such as feeding difficulty, vomiting, tremor, irritability and constant crying have been reported rarely in newborn babies after mothers have taken venlafaxine in the last 3 months of pregnancy.

In addition, when taken particularly in the last 3 months of pregnancy, medicines like venlafaxine may increase the risk of a serious condition in babies, called persistent pulmonary hypertension of the newborn (PPHN), making the baby breathe faster and appear bluish. These symptoms usually begin during the first 24 hours after the baby is born. If this happens to your baby, you should contact your midwife and/or doctor immediately.

Tell your doctor if you are breastfeeding or are planning to breastfeed.

Tell your doctor if you are about to have any blood tests.

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor may occasionally do tests (such as an electrocardiogram (ECG) or blood tests) to make sure the medicine is working and to prevent side effects. Some people (especially older people or those taking diuretics) may experience a lack of sodium in the blood when taking this medicine.

Tell your doctor if you get a headache or start to feel dizzy, confused, forgetful, weak, unsteady or unable to concentrate. Make sure to drink plenty of fluids.

Things you must not do

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not take your medicine to treat any other complaint unless your doctor tells you to

Do not stop taking your medicine, or change the dosage, without first checking with your doctor. Check with your doctor for the best way to slowly reduce the amount of venlafaxine you are taking before stopping completely, as this can reduce the possibility of these effects occurring.

Side effects from stopping treatment with venlafaxine suddenly may include headache, nausea and vomiting, insomnia, nervousness, anxiety, confusion and agitation, diarrhoea, sweating, flu-like symptoms, loss of appetite, dizziness, impaired coordination and balance, visual impairment, increased blood pressure, tremor, tingling or numbness of the hands and feet.

Slowly reducing your venlafaxine dose reduces the possibility of these effects occurring.

Some of these symptoms may impair driving, or the operation of dangerous machinery. Avoid these activities if you experience these symptoms.

Things to be careful of

Be careful driving or operating machinery until you know how this medicine affects you. Venlafaxine may make you feel drowsy.

Avoid drinking alcohol while you are taking venlafaxine.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking venlafaxine.

All medicines can have side effects.Sometimes they are serious but most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Tell your doctor or pharmacist if you notice any of the following:

  • stomach problems e.g. nausea, vomiting, loss of appetite, diarrhoea, constipation or wind
  • difficulty sleeping or abnormal dreams
  • yawning, feeling drowsy or sedated
  • paranoia or aggression
  • sexual function problems such as delayed ejaculation, erection problems, decreased sex drive or difficulties achieving orgasm (which may continue even after stopping treatment)
  • nervousness, teeth grinding
  • excessive enthusiasm or desire, delusions (mania)
  • fainting or dizziness after standing up
  • restlessness, agitation or difficulty sitting still
  • headache
  • heavy or irregular menstrual periods
  • sweating (including night sweats), hot flushes
  • rash, itchiness
  • hair loss
  • weight loss or weight gain
  • unusual milk production
  • dilated pupils, sensitivity to sunlight
  • ringing in the ears
  • altered taste, dry mouth, sore throat
  • increased blood pressure or blood cholesterol levels

The above list includes the more common side effects. Mostly, these are mild.

Tell your doctor as soon as possible if you notice any of the following:

  • blurred vision
  • cloudy urine, problems passing urine, passing urine more frequently, or being unable to control urination
  • muscle tremors, spasms, twitching, jerky movements or sustained muscle contractions
  • impaired coordination and balance
  • increase in bone fractures
  • abnormal facial movements such as tongue thrusting, repetitive chewing, jaw swinging, or grimacing
  • changes in muscle tone, muscle weakness or fatigue
  • a feeling of apathy or not caring about things or not being part of your body
  • hallucinations, confusion or agitation
  • excessively overactive
  • rapid heart beat
  • problems with breathing, cough
  • sensitivity to sunlight
  • bleeding or bruising more easily than normal
  • numbness, pins and needles

The above list includes serious side effects. You may need medical attention. Most of these side effects are rare.

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Emergency department at your nearest hospital:

  • fits or seizures, which may be accompanied by a fever
  • symptoms of sudden fever with sweating, rapid heartbeat and muscle stiffness, which may lead to loss of consciousness
  • palpitations, fainting, shortness of breath, chest pain or irregular heartbeat
  • dark, red or cola coloured urine, muscle weakness and tenderness, stiffness or aching
  • stomach pain, yellowing of the skin, nausea, fever, clammy skin and sweating
  • yellowing of the skin or eyes, fever, fatigue, loss of appetite, dark coloured urine or lightcoloured bowel movements
  • a severe skin reaction with painful red areas and large blisters, accompanied by fever and chills, aching muscles and generally feeling unwell.
  • symptoms of high fever, agitation, confusion, trembling and abrupt contractions of muscles
  • severe chills, fever, sore throat and mouth ulcers
  • black sticky bowel motions or bloody diarrhoea
  • shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin (signs of an allergic reaction)

The above list includes very serious side effects. These effects are usually very rare. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may occur in some patients.

Some of these side effects, such as increases in blood pressure or blood cholesterol levels, can only be found when your doctor does tests from time to time to check your progress.

Other side effects not listed above may occur in some patients.

Storage and disposal

Storage

Keep your medicine in its pack until it is time to take it. If you take your medicine out of its pack it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine left over.

Product description

What it looks like

75 mg capsules
Peach opaque/peach opaque size '1' hard gelatin capsules having thick and thin radial circular bands on the body and cap in red ink. The capsule is filled with white to off white, round, biconvex, film coated mini tablets. AUST R 286958.

150 mg capsules:
Dark orange/dark orange opaque size '0' hard gelatin capsules having thick and thin radial circular bands on the body and cap in white ink. The capsule is filled with white to off white, round, biconvex, film coated mini tablets. AUST R 286957.

Blister pack of 28 capsules.

*Not all strengths may be available.

Ingredients

Each capsule contains 75 or 150 mg of venlafaxine hydrochloride as the active ingredient.

It also contains the following:

  • microcrystalline cellulose
  • povidone
  • ethanol
  • purified talc
  • colloidal anhydrous silica
  • magnesium stearate
  • ethylcellulose
  • copovidone
  • brilliant blue FCF
  • allura red AC
  • sunset yellow FCF (only for 150 mg)
  • iron oxide black (only for 75 mg)
  • iron oxide red (only for 75 mg)
  • titanium dioxide
  • gelatin
  • TekPrint SB-0007P White Ink (150 mg capsules only)
  • TekPrint SB-1033 Red Ink (75 mg capsules only)

May contain trace amounts of phenylalanine and sulphites.

This medicine does not contain gluten, lactose, sucrose, tartrazine or any other azo dyes.

Sponsor

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel st
Cremorne VIC 3121
Australia
Tel: 1800 195 055

This leaflet was last updated in August 2023.

Published by MIMS September 2023

BRAND INFORMATION

Brand name

APO-Venlafaxine XR

Active ingredient

Venlafaxine

Schedule

S4

 

1 Name of Medicine

Venlafaxine hydrochloride.

2 Qualitative and Quantitative Composition

Each modified release capsule contains venlafaxine 75 mg (as 84.90 mg venlafaxine hydrochloride) or venlafaxine 150 mg (as 169.80 mg venlafaxine hydrochloride) as the active ingredient.

Excipients with known effect.

Gelatin (also contains sulfites and phenylalanine).
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Venlafaxine XR 75 mg modified release capsules.

Peach opaque/ peach opaque size 1 hard capsule with thick and thin radial circular band on the body and cap in red ink. The capsule is filled with white to off white, round, biconvex, film coated mini tablets.

Venlafaxine XR 150 mg modified release capsules.

Dark orange/ dark orange size 0 hard capsule with thick and thin radial circular band on the body and cap in white ink. The capsule is filled with white to off white, round, biconvex, film coated mini tablets.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of major depression, including prevention of relapse and recurrence where appropriate.
Generalised anxiety disorder.
Social anxiety disorder.
Panic disorder, including prevention of relapse.

4.2 Dose and Method of Administration

APO-Venlafaxine XR 75 mg and 150 mg modified release capsules are intended for oral administration.

Dosage.

Major depression, generalised anxiety disorder and social anxiety disorder.

The usual recommended dose for the treatment of major depression, generalised anxiety disorder or social anxiety disorder is 75 mg/day given once daily. After two weeks the dose may be increased to 150 mg/day given once daily if further clinical improvement is required. If needed, this can be increased up to 225 mg given once daily. Dose increments should be made at intervals of approximately two weeks or more, but not less than four days.
The recommended dose is based on results of clinical trials in which modified release venlafaxine was mostly given once daily in doses from 75 mg to 225 mg. Antidepressant activity with the 75 mg dose was observed after two weeks of treatment and anxiolytic activity was observed after one week.
It is recommended that venlafaxine XR be taken with food at approximately the same time each day. Each capsule must be swallowed whole with fluid. Do not divide, crush, chew or dissolve. Venlafaxine XR should be administered once daily.

Panic disorder.

The recommended dose is 75 mg of venlafaxine XR once daily. Treatment should be started with a dose of 37.5 mg per day for the first 4 to 7 days after which the dose should be increased to 75 mg once daily. An alternative venlafaxine product should be used to provide a 37.5 mg per day dose, as this strength is not available in this brand.
Patients not responding to the 75 mg/day dose may benefit from dose increases to a maximum of 225 mg/day, although there is no direct clinical trial evidence of any significant increase in efficacy with increase in dose. Dosage increases can be made in increments of 75 mg per day at intervals of approximately 2 weeks or more, but not less than 4 days.

Dosage adjustment.

Renal impairment.

Patients with renal and/or hepatic impairment should receive lower doses of venlafaxine XR. The total daily dose of venlafaxine should be reduced by 25% to 50% for patients with renal impairment with a glomerular filtration rate (GFR) of 10 to 70 mL/min. Haemodialysis clearances of both venlafaxine and O-desmethylvenlafaxine (ODV) in humans are low. The total daily dose of venlafaxine should be reduced by 50% in haemodialysis patients.

Hepatic impairment.

Patients with mild to moderate hepatic impairment should also have their dosage reduced by 50%. Further reductions in dosage should be considered for patients with more severe degrees of hepatic impairment. Because of individual variability in clearance in these patients, individualisation of dosage may be desirable.

Use in the elderly.

No adjustment in the usual dose is recommended for elderly patients solely because of their age. As with any antidepressant, however, caution should be exercised in treating the elderly. When individualising the dosage, extra care should be taken when increasing the dose.

Maintenance/ continuation/ extended treatment.

The physician should periodically re-evaluate the usefulness of long-term venlafaxine XR treatment for the individual patient. It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacological therapy. Whether the dose of antidepressant needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.
Usually, the dosage for prevention of relapse or for prevention of recurrence of a new episode is similar to that used during initial treatment. Patients should be regularly reassessed in order to evaluate the benefit of long-term therapy.
In social anxiety disorder, continuing therapeutic benefit has been established for periods of up to 6 months. The need for continuing medication in patients with social anxiety disorder who improve with venlafaxine XR treatment should be periodically assessed.
It is generally agreed that acute episodes of panic disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Longer-term efficacy was demonstrated in one study (Study 5) in which patients responding during 12 weeks of acute treatment with venlafaxine XR were assigned randomly to placebo or to the same dose of venlafaxine XR (75, 150, or 225 mg/day) during 6 months of maintenance treatment as they had received during the acute stabilization phase (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Panic disorder).

Discontinuing venlafaxine XR.

When venlafaxine XR at a dose of 75 mg/day or greater has been administered for more than one week is stopped, it is recommended whenever possible that the dose be tapered gradually to minimise the risk of discontinuation symptoms.
In clinical trials with venlafaxine XR, tapering was achieved by reducing the daily dose by 75 mg at one week intervals. To facilitate tapering below 75 mg, physicians may consider prescribing another brand of venlafaxine 37.5 mg capsules once daily (an alternative brand is needed as this brand does not come in a 37.5 mg dose). The time period required for tapering and the amount of dose reduction may depend on the dose, duration of therapy and the individual patient. Patients should be advised to consult their physician before abruptly discontinuing venlafaxine XR. In some patients, discontinuation may need to occur very gradually over periods of months or longer.

4.3 Contraindications

Hypersensitivity to venlafaxine or any excipients in the formulation.

Monoamine oxidase inhibitors (MAOIs).

Venlafaxine XR should not be used in combination with monoamine oxidase inhibitors (MAOIs) or reversible MAOIs (RIMA) (e.g. moclobemide, linezolid and intravenous methylene blue), or within 14 days of discontinuing treatment with a MAOI. Similarly, at least 7 days should be allowed after stopping venlafaxine XR before starting a MAOI. Cases of serious reactions, such as potentially life threatening serotonin syndrome (characterised by neuromuscular excitation, altered mental status and autonomic dysfunction) have been reported in patients receiving an SNRI in combination with MAOIs and RIMA, and in patients who have recently discontinued an SNRI and have been started on a MAOI (also see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Clinical worsening and suicide risk.

Patients with major depression, both adult and paediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behaviour (suicidality) or unusual changes in behaviour, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. Antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. As improvement may not occur during the first few weeks or more of treatment, patients should be monitored appropriately and observed closely for clinical worsening and suicidality, especially at the beginning of a course of treatment or at the time of dose changes, either increases or decreases.
Pooled analyses of short-term placebo controlled trials of antidepressant medicines (SSRIs and others) showed that these medicines increase the risk of suicidality in children, adolescents and young adults (ages 18 to 24 years) with major depression and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond the age of 24 years; there was a reduction in the risk of suicidality with antidepressants compared to placebo in adults aged 65 years and older.
The pooled analysis of placebo controlled trials in children and adolescents with major depression, obsessive compulsive disorder or other psychiatric disorders included a total of 24 short-term trials of nine antidepressant medicines in over 4,400 patients. The pooled analyses of placebo controlled trials in adults with major depression or other psychiatric disorders included a total of 295 short-term trials (median duration two months) of eleven antidepressant medicines in over 77,000 patients. There was considerable variation in risk of suicidality among medicines, but a tendency toward an increase in the younger patients for almost all medicines studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence with major depression.
No suicides occurred in any of the paediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about the medicine effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e. beyond several months. However, there is substantial evidence from placebo controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset or was not part of the patient's presenting symptoms (see Discontinuation effects below).
It is particularly important that appropriate monitoring be undertaken during the initial course of antidepressant treatment or at times of dose increase or decrease.
Patients with comorbid depression associated with other psychiatric or non-psychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality.
Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania and mania, have been reported in adults, adolescents and children being treated with antidepressants for major depression as well as for other indications, both psychiatric and non-psychiatric. Although a causal link between the emergence of such symptoms and either worsening of depression and/or emergence of suicidal impulses has not been established, there is concern that such symptoms may be precursors of emerging suicidality.
Prescriptions for venlafaxine XR should be written for the smallest quantity of capsules consistent with good patient management in order to reduce the possibility of overdosage.
This is particularly so at the times of treatment initiation or dosage change. Events reported in overdose include electrocardiogram changes (QRS prolongation, QT prolongation), cardiac arrhythmias (ventricular fibrillation; ventricular tachycardia, including torsades de pointes), convulsions and death (see Section 4.9 Overdose).

Information for patients and caregivers.

Patients, their families and their caregivers should be alerted about the need to monitor for the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behaviour, worsening of depression, and suicidal ideation, especially when initiating therapy or during any change in dose. Such symptoms should be reported to the patient's physician, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms (also see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

Akathisia/ psychomotor restlessness.

The use of venlafaxine 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.

Serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions.

As with other serotonergic agents, the development of serotonin syndrome, a potentially life threatening condition, or neuroleptic malignant syndrome (NMS)-like reaction may occur with venlafaxine treatment, particularly with concomitant use of other serotonergic drugs (including SSRIs, SNRIs, amphetamines, triptans, opioids (e.g. fentanyl, dextromethorphan, tramadol, tapentadol, pethidine, methadone and pentazocine)), and with drugs that impair metabolism of serotonin (e.g. MAOIs, including reversible MAOIs such as moclobemide, linezolid and intravenous methylene blue), or with antipsychotics or other dopamine antagonists (see Section 4.3 Contraindications).
Symptoms of serotonin syndrome may include mental status changes (e.g. agitation, confusion, hallucinations, and coma), autonomic instability (e.g. diaphoresis, tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination, myoclonus, tremor) and/or gastrointestinal symptoms (e.g. nausea, vomiting, and diarrhoea). Serotonin syndrome, in its most severe form, can resemble NMS, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
If concomitant treatment with venlafaxine and other agents that may affect the serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
The concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended.
Treatment with venlafaxine should be discontinued if serotonin syndrome or NMS-like reactions occur and supportive symptomatic treatment initiated.

Bone fractures.

Epidemiological studies show an increased risk of bone fractures in patients receiving serotonin reuptake inhibitors (SRIs) including venlafaxine. The mechanism leading to this risk is not fully understood.

Diabetes.

In patients with diabetes treatment with an SSRI may alter glycaemic control. Insulin and/or hypoglycaemic dosage may need to be adjusted.

Mydriasis and angle closure glaucoma.

Mydriasis may occur in association with venlafaxine. It is recommended that patients with raised intraocular pressure or patients at risk for acute narrow angle glaucoma (angle closure glaucoma) should be closely monitored.

Sustained hypertension.

Dose related increases in blood pressure have been reported in some patients treated with venlafaxine.
Among patients treated with venlafaxine 75 to 375 mg/day in premarketing depression studies, 3% (19/705) experienced sustained hypertension (defined as treatment emergent supine diastolic blood pressure [SDBP]: ≥ 90 mmHg and ≥ 10 mmHg above baseline for three consecutive on-therapy visits). Among patients treated with 37.5 to 225 mg per day of venlafaxine XR in pre-marketing GAD studies, 0.5% (5/1011) experienced sustained hypertension. Experience with the immediate release venlafaxine showed that sustained hypertension was dose related, increasing from 3 to 7% at 100 to 300 mg per day to 13% at doses above 300 mg per day. An insufficient number of patients received mean doses of venlafaxine XR over 300 mg per day to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.
In placebo controlled pre-marketing depression studies with venlafaxine 75 to 225 mg/day, a final on-drug mean increase in supine diastolic blood pressure (SDBP) of 1.2 mmHg was observed for venlafaxine treated patients compared with a mean decrease of 0.2 mmHg for placebo treated patients. In placebo controlled pre-marketing GAD studies with venlafaxine 37.5 to 225 mg per day up to 8 weeks or up to 6 months, a final on drug mean increase in SDBP of 0.3 mmHg was observed for venlafaxine treated patients compared with a mean decrease of 0.9 and 0.8 mmHg, respectively, for placebo treated patients. In pre-marketing social anxiety disorder studies up to 12 weeks, the final on-therapy mean change from baseline in SDBP was small, an increase of 0.78 mmHg, compared to a decrease of 1.41 mmHg in placebo treated patients. In a 6 month study, the final on-therapy mean increase from baseline in SDBP with venlafaxine 150 to 225 mg was 1.49 mmHg. The increase was significantly different from the 0.6 mmHg decrease with placebo and the 0.2 mmHg decrease with venlafaxine 75 mg.
In pre-marketing depression studies, 0.7% (5/705) of the venlafaxine treated patients discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 16 mmHg, SDBP). In pre-marketing GAD studies up to 8 weeks and up to 6 months, 0.7% (10/1381) and 1.3% (7/535) of the venlafaxine XR treated patients, respectively, discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 25 mmHg, SDBP up to 8 weeks; 8 to 28 mmHg up to 6 months).
Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience.
Sustained increases of SDBP could have adverse consequences. Therefore, it is recommended that patients receiving venlafaxine have regular monitoring of blood pressure.
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. Caution should be exercised in patients whose underlying conditions might be compromised by increases in blood pressure.

Increase in serum cholesterol.

Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine immediate release tablet treated patients and 0.0% of placebo treated patients for at least three months in placebo controlled clinical trials.
Treatment with venlafaxine for up to 12 weeks in premarketing placebo controlled depression trials was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 0.039 mmol/L (1.5 mg/dL). Venlafaxine XR treatment for up to 8 weeks and up to 6 months in pre-marketing placebo controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 0.026 mmol/L (1.0 mg/dL) and 0.059 mmol/L (2.3 mg/dL), respectively.
In the 12 week social anxiety disorder studies, small mean increases in fasting levels of total cholesterol (0.20 mmol/L, 4%) were seen in the venlafaxine XR treated group at the final on-therapy evaluation; the increases were significantly different from the changes in the placebo group. In a 6 month study, the final on-therapy mean increase in total cholesterol was higher (0.32 mmol/L, 7%) in the venlafaxine XR 150 to 225 mg group; however the total cholesterol value was only slightly increased (0.01 mmol/L) for the venlafaxine XR 75 mg group.
There were also significant mean increases from baseline in LDL, but not HDL for the venlafaxine XR 150 to 225 mg group. The final on-therapy increase of 0.213 mmol/L from baseline in LDL with venlafaxine XR 150 to 225 mg was significantly different from the small decrease with placebo (0.079 mmol/L) and the negligible increase with venlafaxine XR 75 mg (0.006 mmol/L).
Measurement of serum cholesterol levels should be considered during long-term treatment.

Hyponatraemia.

Cases of hyponatraemia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH) may occur with venlafaxine, usually in volume depleted or dehydrated patients.
Elderly patients, patients taking diuretics, and patients who are otherwise volume depleted may be at greater risk for this event.
Caution is advised in administering venlafaxine XR to patients with diseases or conditions that could affect haemodynamic responses or metabolism.

Use in patients with pre-existing heart disease.

Patients with a recent history of myocardial infarction or unstable heart disease were excluded from all venlafaxine clinical trials. However, patients with other pre-existing heart disease were not excluded, although they were neither separately analysed nor systematically studied.
Venlafaxine should be used with caution in patients with unstable heart disease (e.g. myocardial infarction; significant left ventricular dysfunction, ventricular arrhythmia). In these patients, assessment of the cardiovascular system (e.g. electrocardiogram [ECG]; serum electrolytes during diuretic treatment) should be considered during treatment with venlafaxine, particularly when the dose is increased beyond 150 - 200 mg daily.
Evaluation of the electrocardiograms for 769 patients who received immediate release venlafaxine in four to six week double blind, placebo controlled trials showed that the incidence of trial emergent conduction abnormalities did not differ from that with placebo.
The electrocardiograms for patients who received venlafaxine XR or placebo in the depression GAD and social anxiety disorder trials were analysed. The mean change from baseline in corrected QT interval (QTc) for venlafaxine XR treated patients in depression studies was increased relative to that for placebo treated patients (increase of 4.7 msec for venlafaxine XR and decrease of 1.9 msec for placebo). The mean change from baseline QTc for venlafaxine XR treated patients in the GAD studies did not differ significantly from placebo. The final on-therapy mean increase from baseline in QTc (3 msec) was significant for venlafaxine XR treated patients in the social anxiety disorder short-term studies. In the 6 month study, the final on-therapy mean increase from baseline in QTc with venlafaxine XR 150 to 225 mg (3 msec) was significant, but the increase was not significantly different from the small mean increase (0.5 msec) with placebo. The value for venlafaxine XR 75 mg was a 0.05 msec decrease.
Increases in heart rate may occur, particularly with higher doses. Therefore caution is advised in patients whose underlying conditions may be compromised by increases in heart rate.
The mean change from baseline in heart rate for venlafaxine XR treated patients in both the GAD and the depression studies was significantly higher than for placebo (a mean increase of 3-4 beats per minute for venlafaxine XR and 0-1 beat per minute for placebo in the GAD and depression studies respectively). In the pooled short-term social anxiety disorder studies, the final on-therapy mean increase from baseline in heart rate with venlafaxine XR was 5 beats per minute. In the 6 month study, the final on-therapy mean increases from baseline in heart rate were significant with venlafaxine XR 75 (2 beats per minute) and venlafaxine XR 150 to 225 mg (6 beats per minute); however only the increase with the higher dose was significantly different from the small increase with placebo (0.4 beats per minute). The clinical significance of these changes is unknown.

QTc prolongation/ torsade de pointes (TdP).

Cases of QTc prolongation, torsade de pointes (TdP), ventricular tachycardia and sudden death have been reported during the post-marketing use of venlafaxine. The majority of reports occurred in association with overdose or in patients with other risk factors for QTc prolongation/TdP. Therefore venlafaxine should be used with caution in patients with risk factors for QTc prolongation.

Discontinuation effects.

Discontinuation effects are well known to occur with antidepressants and sometimes these effects can be protracted and severe (see Section 4.8. Adverse Effects (Undesirable Effects)). Suicide/suicidal thoughts and aggression have been observed in patients during changes in venlafaxine dosing regimen, including during discontinuation (see Clinical worsening and suicide risk; Aggression). Discontinuation symptoms have been assessed both in patients with depression and in those with anxiety. Abrupt discontinuation, dose reduction or tapering of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment.
Symptoms reported included agitation, anorexia, anxiety, confusion, dry mouth, fatigue, paraesthesia, vertigo, hypomania, nausea, vomiting, dizziness, convulsion, headache, diarrhoea, sleep disturbance, insomnia, somnolence, sweating and nervousness. Where such symptoms occurred, they were usually self limiting, but in a few patients lasted for several weeks.
Discontinuation effects were systematically studied in a long-term fixed dose trial for generalised anxiety disorder; 24% and 11% of patients recorded the appearance of at least three withdrawal symptoms on abrupt discontinuation from 150 mg or 75 mg venlafaxine once daily, respectively, compared with 3% for placebo. The most commonly reported withdrawal symptoms on abrupt discontinuation were nausea, vomiting, dizziness, lightheadedness, and tinnitus from 150 mg venlafaxine once daily, and dizziness from 75 mg venlafaxine once daily.
In this study, severe withdrawal reactions were observed in 1.3% of patients discontinuing from 75 mg once daily (no patients requiring further drug treatment).
There is also a report of a withdrawal syndrome, confirmed by two challenges in a 32 year old woman who had received venlafaxine 300 mg daily for eight months. It is therefore recommended that the dosage of venlafaxine XR be tapered gradually and individually and the patients be closely monitored during discontinuation. The time period required for tapering and the amount of dose reduction may depend on the dose, duration of therapy and the individual patient (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)). In some patients, discontinuations could take months or longer.

Sexual dysfunction.

SNRIs may cause symptoms of sexual dysfunction (see Section 4.8 Adverse Effects (Undesirable Effects)). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SNRIs.

Altered weight.

Weight changes, either losses or gains, do not appear to present a clinically important feature of venlafaxine treatment. Clinically significant weight gain or loss was seen in less than 1% of patients treated with venlafaxine during clinical trials. A dose dependent weight loss (mean loss < 1 kg) was noted in some patients treated with venlafaxine during the first few months of venlafaxine treatment. After month 9, the mean weight began to increase slightly but significantly, an effect often seen with tricyclic antidepressant therapy. Significant weight loss (> 7 kg) was seen in 6 (0.3%) of 2,181 patients, compared to no patients treated with placebo and 0.2% of patients treated with a comparative antidepressant.
The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Coadministration of venlafaxine XR and weight loss agents is not recommended. Venlafaxine XR is not indicated for weight loss alone or in combination with other products.

Seizures.

Seizures have been reported with venlafaxine therapy and in overdosage. Venlafaxine XR, as with all antidepressants, should be introduced with care in patients with a history of seizure disorders. Venlafaxine XR should be discontinued in any patient who develops seizures (see Section 4.9 Overdose).

Mania/ hypomania and bipolar disorder.

Mania/ hypomania may occur in a small proportion of patients with mood disorders treated with antidepressants, including venlafaxine.
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/ manic episode in patients at risk for bipolar disorder. Whether any of the symptoms represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that venlafaxine XR is not approved for use in treating bipolar depression.
Aggression may occur in a small proportion of patients who have received antidepressants, including venlafaxine treatment, dose reduction or discontinuation.
Venlafaxine should be used cautiously in patients with a history of aggression.

Skin/ allergic reactions.

Patients should be advised to notify their physician if they develop a rash, hives or related allergic phenomena.

Abnormal bleeding.

Drugs that inhibit serotonin uptake may lead to abnormalities of platelet aggregation. Bleeding abnormalities have been reported with venlafaxine ranging from skin and mucous membrane bleeding and gastrointestinal haemorrhage, to life threatening haemorrhages. The risk may be increased in patients predisposed to bleeding, including patients on anti-coagulants and platelet inhibitors, and venlafaxine should be used cautiously in these patients.

Physical and psychological dependence.

Clinical studies have shown no evidence of drug seeking behaviour, development of tolerance or dose escalation over time among patients taking venlafaxine. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine (e.g. development of tolerance, increase in dose, drug seeking behaviour) (see Section 5 Pharmacological Properties).

Electroconvulsive therapy.

There are no clinical data establishing the benefit of venlafaxine XR combined with electroconvulsive therapy.

Use in renal impairment.

The total daily dose of venlafaxine must be reduced by 25 to 50% for patients with renal impairment with a glomerular filtration rate (GFR) of 10 to 70 mL/minute.
The total daily dose of venlafaxine must be reduced by 50% in haemodialysis patients. Because of individual variability in clearance in these patients, individualisation of dosage may be desirable.

Use in hepatic impairment.

The total daily dose of venlafaxine must be reduced by 50% in patients with mild to moderate hepatic impairment. Reductions of more than 50% may be appropriate for some patients. Because of individual variability in clearance in these patients, individualisation of dosage may be desirable.

Use in the elderly.

No overall differences in effectiveness or safety were observed between elderly (aged 65 years and older) and younger patients. Venlafaxine XR does not appear to pose any exceptional safety problems for healthy elderly patients.
Effectiveness in elderly patients with social anxiety disorder has not been established.

Paediatric use.

Venlafaxine XR is not indicated for use in children and adolescents below 18 years of age as safety and effectiveness has not been demonstrated. Therefore, venlafaxine XR should not be used in this age group.
In paediatric clinical trials, the adverse reaction, suicidal ideation, was observed. There were also increased reports of hostility and, especially in major depressive disorder, self-harm (see Section 4.4 Special Warnings and Precautions for Use, Clinical worsening and suicide risk; Section 4.8 Adverse Effects (Undesirable Effects)).
As with adults, decreased appetite, weight loss, increased blood pressure and increased serum cholesterol have been observed in children and adolescents aged 6 to 17 years (see Section 4.8 Adverse Effects (Undesirable Effects)).

Effects on laboratory tests.

False positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/ mass spectrometry, will distinguish venlafaxine from PCP and amphetamine.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Venlafaxine and ODV are 27% and 30% bound to plasma proteins respectively; therefore interactions due to protein binding of venlafaxine and the major metabolite are not expected.

Monoamine oxidase inhibitors (MAOI).

Concomitant use of venlafaxine XR in patients taking MAOIs or reversible MAOIs (e.g. moclobemide, linezolid and intravenous methylene blue) is contraindicated (see Section 4.3 Contraindications).
Severe adverse reactions have been reported in patients who have recently been discontinued from a MAOI and started on venlafaxine, or have recently had venlafaxine therapy discontinued prior to initiation of a MAOI or when these two agents are coadministered. Reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome and/or serotonergic syndrome, seizures, and death.
Do not use venlafaxine XR in combination with a MAOI or reversible MAOIs, or within at least 14 days of discontinuing MAOI treatment. Allow at least 7 days after stopping venlafaxine XR before starting a MAOI.
The appropriate washout period should take into account the pharmacological properties of venlafaxine, ODV and the MAOI and the clinician's assessment of the individual patient.

Central nervous system active drugs.

The risk of using venlafaxine in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is advised when venlafaxine is taken in combination with other CNS active drugs.

Serotonin syndrome.

As with other serotonergic agents, serotonin syndrome, a potentially life threatening condition, may occur with venlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system. These can include triptans, SSRIs, other SNRIs, amphetamines, lithium, sibutramine, opioids (e.g. fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, pethidine, methadone and pentazocine) or St. John's Wort (Hypericum perforatum), with drugs which impair metabolism of serotonin (including MAOIs such as moclobemide), linezolid (an antibiotic which is a reversible nonselective MAOI) and intravenous methylene blue, or with serotonin precursors (such as tryptophan supplements). Serotonin syndrome symptoms may include mental status changes, autonomic instability, neuromuscular aberrations and/or gastrointestinal symptoms (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Serotonin syndrome has been reported in association with concomitant use with selective serotonin reuptake inhibitors (SSRIs). The decision to use venlafaxine in combination with SSRIs should include the advice of a psychiatrist.
If concomitant treatment of venlafaxine with an SSRI, an SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
As with other antidepressants, coadministration of venlafaxine XR and products containing St. John's Wort (Hypericum perforatum) is not recommended due to possible pharmacodynamic interactions.
No information is available on the use of venlafaxine XR in combination with opiates.
There have been reports of elevated clozapine levels in association with adverse events including seizures, following the administration of venlafaxine.

Drugs that prolong the QT interval.

The risk of QTc prolongation and/or ventricular arrhythmias (e.g. TdP) is increased with concomitant use of other drugs which prolong the QTc interval (e.g. some antipsychotics and antibiotics) (see Section 4.4 Special Warnings and Precautions for Use, QTc prolongation/ torsade de pointes (TdP)).

Ethanol.

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

Diazepam.

The pharmacokinetic profiles of venlafaxine and ODV were not altered when venlafaxine and diazepam were administered together to healthy volunteers. Venlafaxine had no effect on the pharmacokinetics of diazepam nor did it affect the psychomotor and psychometric effects induced by diazepam.

Lithium.

The steady-state pharmacokinetics of venlafaxine and ODV are not affected when lithium is coadministered. Venlafaxine also has no effect on the pharmacokinetics of lithium. (Also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Central nervous system active drugs). However, there have been reports of venlafaxine interaction with lithium resulting in increased lithium levels.

Haloperidol.

Venlafaxine administered under steady-state conditions (75 mg twice daily) to 24 healthy subjects decreased total oral clearance (Cl/F) of a single dose of haloperidol 2 mg by 42%, which resulted in a 70% increase in haloperidol AUC (area under the curve). In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown.

Risperidone.

Venlafaxine increased risperidone AUC by 32% but did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). The clinical significance of this interaction is unknown.

Indinavir.

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

Cimetidine.

At steady state cimetidine has been shown to inhibit the first-pass metabolism of venlafaxine but had no apparent effect on the formation or elimination of ODV, which is present in much greater quantity in the systemic circulation. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly in most patients. No dosage adjustment seems necessary when venlafaxine XR is coadministered with cimetidine. However, for elderly patients or patients with hepatic dysfunction, the interaction could potentially be more pronounced and for such patients clinical monitoring is indicated when venlafaxine XR is administered with cimetidine.

Metoprolol.

Concomitant administration of venlafaxine (50 mg every eight hours for five days) and metoprolol (100 mg every 24 hours for five days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30 to 40% without altering the plasma concentrations of its active metabolite, alpha-hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, ODV.
Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. Caution should be exercised with coadministration of venlafaxine and metoprolol.
Venlafaxine treatment has been associated with dose related increases in blood pressure in some patients. It is recommended that patients receiving venlafaxine XR have regular monitoring of blood pressure (see Section 4.4 Special Warnings and Precautions for Use, Sustained hypertension).

Antihypertensive and hypoglycaemic agents.

Retrospective analysis of study events occurring in patients taking venlafaxine concurrently with antihypertensive or hypoglycaemic agents in clinical trials provided no evidence suggesting incompatibility between treatment with venlafaxine and treatment with either antihypertensive or hypoglycaemic agents.

Drugs metabolised by cytochrome P450 isoenzymes.

In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6 and that venlafaxine does not inhibit CYP1A2, CYP2C9 or CYP3A4. Some of these findings have been confirmed with drug interaction studies between venlafaxine and imipramine (metabolised by CYP2D6) and diazepam (metabolised by CYP2C19). Therefore, venlafaxine XR is not expected to interact with other drugs metabolised by these isoenzymes.

Imipramine.

Venlafaxine did not affect the CYP2D6 mediated 2-hydroxylation of imipramine or its active metabolite desimipramine, which indicates that venlafaxine does not inhibit the CYP2D6 isoenzyme. However, the renal clearance of 2-hydroxydesimipramine was reduced with coadministration of venlafaxine.
Imipramine partially inhibited the CYP2D6 mediated formation of ODV, however, the total concentrations of active compounds (venlafaxine plus ODV) was not affected with imipramine administration. Additionally, in a clinical study involving CYP2D6 poor and CYP2D6 extensive metabolisers, the total sum of the two active species (venlafaxine and ODV) was similar in the two metaboliser groups. Therefore, no dosage adjustment is expected when venlafaxine is coadministered with a CYP2D6 inhibitor. However, desipramine AUC, Cmax and Cmin increased by about 35% in the presence of venlafaxine. There was an increase of 2-OH desipramine AUC by 2.5 to 4.5-fold. The clinical significance of this finding is unknown.

Potential for other drugs to affect venlafaxine.

The metabolic pathways for venlafaxine include CYP2D6 and CYP3A4.
In vitro and in vivo studies. In vitro and in vivo studies indicate that venlafaxine is metabolised predominantly to its active metabolite ODV by the cytochrome P450 enzyme CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore the potential exists for a drug interaction between drugs that inhibit CYP2D6 mediated metabolism (e.g. amiodarone and quinidine) and venlafaxine. CYP3A4 is a minor pathway relative to CYP2D6 in the metabolism of venlafaxine.

CYP2D6 inhibitors.

Concomitant use of CYP2D6 inhibitors and venlafaxine may reduce the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of ODV. As venlafaxine and ODV are both pharmacologically active, no dosage adjustment is required when venlafaxine is coadministered with CYP2D6 inhibitor.

CYP3A4 inhibitors.

Concomitant use of CYP3A4 inhibitors (such as erythromycin, fluconazole, ketoconazole and grape fruit juice) and venlafaxine may increase levels of venlafaxine and ODV. Therefore, caution is advised when combining venlafaxine and CYP3A4 inhibitor.
In vitro studies indicate that venlafaxine is likely metabolised to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. A pharmacokinetic study with ketoconazole (a CYP3A4 inhibitor) in extensive metabolisers (EM) and poor metabolisers (PM) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and ODV in most subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14 and 29% in EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects. AUC values for ODV increased by 23 and 33% in EM and PM subjects, respectively.

CYP2D6 and CYP3A4 inhibitors.

The concomitant use of venlafaxine with drug treatment(s) that potentially inhibits both CYP2D6 and CYP3A4, the primary metabolising enzymes for venlafaxine, has not been studied. However, this concomitant use would be expected to increase venlafaxine plasma concentrations. Therefore, caution is advised if a patient's therapy includes venlafaxine and any agent(s) that produces simultaneous inhibition of these two enzyme systems. In patients with unstable heart disease receiving these combinations, assessment of the cardiovascular system (e.g. ECG; serum electrolytes during diuretic treatment) should be considered during treatment with venlafaxine (see Section 4.4 Special Warnings and Precautions for Use, Use in patients with pre-existing heart disease).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to two times the maximum recommended human dose on a mg/m2 basis.
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 two to three times that of a human dose of 225 mg/day. The human relevance of this finding is unknown.
Signs of pharmacological toxicity were seen in paternal and maternal rats given venlafaxine doses of 30 and 60 mg/kg/day, but no adverse effect was noted in fertility or general reproductive performance. Decreased foetal size and pup weight at birth with 60 mg/kg/day may be correlated with maternal toxicity.

Teratogenicity.

In a rat teratology study, venlafaxine was given orally at dosages up to 80 mg/kg/day (approximately 11 times the maximum recommended human dose). Foetotoxicity evidenced by growth retardation was slightly increased at 80 mg/kg/day, an effect that may be related to maternal toxicity at this dose level. Foetal survival and morphologic development were not affected. In another teratology study, rabbits were given venlafaxine dosages up to 90 mg/kg/day. Foetotoxicity evidenced by resorption and foetal loss was slightly increased at 90 mg/kg/day (approximately 12 times the maximum recommended human dose). These effects could be correlated with maternal toxicity. No venlafaxine associated teratogenic effect was noted in either species at any dosage, though there was an increased incidence of 'W'-shaped apex of the heart in the rabbit study. In these studies, animal exposure to the main human metabolite ODV was less, and estimated exposure to venlafaxine was approximately 6-fold more than would be expected in humans taking the recommended therapeutic and maximum doses. In rats, estimated exposure to venlafaxine was more than the expected human exposure. No teratogenic effect was seen.
In a perinatal toxicity study in rats after oral dosing of dams with 30 mg/kg or more, decreased pup survival following birth was observed. This effect is secondary to treatment decreased maternal care, and is also seen with other antidepressants.
(Category B2)
The safety of venlafaxine in human pregnancy has not been established. There are no adequate and well controlled studies in pregnant women. Venlafaxine must only be administered to pregnant women if the expected benefits outweigh the possible risks. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. If venlafaxine is used until or shortly before birth, discontinuation effects in the newborn should be considered.
Some neonates exposed to venlafaxine, other serotonin and noradrenaline reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) late in the third trimester have developed complications requiring prolonged hospitalisation, respiratory support or tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypotonia, hypertonia, hyper-reflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome.
Epidemiological data have suggested that the use of SSRI's in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated an association of PPHN to SNRI treatment, this potential risk cannot be ruled out with venlafaxine, taking into account the related mechanism of action (inhibition of the reuptake of serotonin).
A prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy showed that women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. During pregnancy both major depression and antidepressant medications may present risks to the mother and the neonate. The benefits and choice of specific therapy must be weighed against the risks.
Epidemiological studies suggest that exposure to SNRIs in mid to late pregnancy may increase the risk for preeclampsia. Exposure to SNRIs near delivery may increase the risk for postpartum haemorrhage.
 Venlafaxine and/or its metabolites are secreted in milk of lactating rats at concentrations higher than those found in the plasma of the dam. Venlafaxine and its metabolites have been shown to pass into human milk. The total dose of venlafaxine and O-desmethylvenlafaxine ingested by breastfed infants can be as high as 9.2% of maternal intake. Therefore, the use of venlafaxine XR in breastfeeding women cannot be recommended. Exposed infants should be observed closely.

4.7 Effects on Ability to Drive and Use Machines

Although venlafaxine has been shown not to affect psychomotor, cognitive or complex behaviour performance in healthy volunteers, any psychoactive medication may impair judgement, thinking or motor skills, and patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the treatment does not affect them adversely.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

The information included in the adverse reactions clinical trials subsection are those that were observed in short-term, placebo controlled studies with modified release venlafaxine and has been based on data from a pool of three 8 and 12 week controlled clinical trials in major depressive disorder (dose range of 75 - 225 mg/day), on data up to 8 weeks from a pool of five controlled clinical trials in generalised anxiety disorder with venlafaxine XR (dose range 37.5 - 225 mg/day), on data up to 12 weeks from a pool of five controlled clinical trials in social anxiety disorder (dose range of 75 - 225 mg/day), and on data up to 12 weeks from a pool of four controlled clinical trials in panic disorder (dose range of 75 - 225 mg/day).
The adverse events occurring at an incidence greater than or equal to 2% among modified release venlafaxine treated patients or at an incidence greater than the placebo treated patients are provided in Table 1. The table shows the percentage of patients who had at least one episode of an event at some time during the treatment. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials.
Below are adverse reactions from combined analyses of the clinical studies for major depression, generalised anxiety disorder, social anxiety disorder, and panic disorder. The adverse reactions have been presented using the Council for International Organizations of Medical Sciences (CIOMS) frequency categories: common: ≥ 1%; uncommon: ≥ 0.1% and < 1%; rare: ≥ 0.01% and < 0.1%; very rare: < 0.01%.

General disorders and administration site conditions.

Common: asthenia, fatigue.
Uncommon: mucosal haemorrhage.

Immune system disorders.

Rare: anaphylactic reaction.

Cardiac disorders.

Common: tachycardia.

Vascular disorders.

Common: hypertension, hot flush.
Uncommon: hypotension, orthostatic hypotension.

Endocrine disorders.

Rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Gastrointestinal disorders.

Very common: constipation, nausea, dry mouth.
Common: vomiting.
Uncommon: gastrointestinal bleeding.

Hepatobiliary disorders.

Uncommon: liver function test abnormal.

Blood and lymphatic system disorders.

Rare: thrombocytopenia.

Endocrine disorders.

Rare: inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders.

Common: decreased appetite.
Uncommon: hyponatraemia.

Investigations.

Common: blood cholesterol increased, weight decreased, weight increased.
Rare: bleeding time prolonged.

Musculoskeletal and connective tissue disorders.

Common: hypertonia.

Psychiatric disorders.

Very common: insomnia.
Common: abnormal dreams, libido decreased, anorgasmia, nervousness, abnormal orgasm (males).
Uncommon: mania, hypomania, hallucination, abnormal orgasm (females), bruxism, apathy.

Nervous system disorders.

Very common: dizziness, sedation.
Common: paraesthesia, tremor, dysgeusia.
Uncommon: myoclonus syncope.
Rare: convulsion, neuroleptic malignant syndrome (NMS), serotonergic syndrome.

Respiratory, thoracic and mediastinal disorders.

Common: yawning.

Skin and subcutaneous tissue disorders.

Very common: hyperhidrosis.
Common: rash.
Uncommon: ecchymosis, photosensitivity reaction.

Eye disorders.

Common: accommodation disorder, mydriasis, visual impairment.

Renal and urinary disorders.

Common: urinary hesitation, urinary retention.

Reproductive system and breast disorders.

Common: ejaculation disorder, erectile dysfunction.
Uncommon: menorrhagia.

Discontinuation symptoms.

Discontinuation effects are well known to occur with antidepressants and it is therefore recommended that the dosage is tapered gradually and the patient monitored (see Section 4.2 Dose and Method of Administration). The following symptoms have been reported in association with abrupt discontinuation or dose reduction, or tapering of treatment: hypomania, anxiety, agitation, nervousness, confusion, insomnia or other sleep disturbances, fatigue, somnolence, paraesthesia, dizziness, convulsion, vertigo, headache, flu-like symptoms, tinnitus, impaired coordination and balance, tremor, sweating, dry mouth, anorexia, diarrhoea, nausea, vomiting, visual impairment and hypertension. In pre-marketing studies, the majority of discontinuation reactions were mild and resolved without treatment (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use). There have been reports of serious discontinuation symptoms, and sometimes these effects can be protracted and severe.
In the social anxiety disorder pooled short-term studies, the most common taper/ post-study emergent adverse events were dizziness (13%), nausea (7%), insomnia (3%), nervousness (3%) and asthenia (2%). In the 6 month study, the most common taper/ post-study treatment emergent adverse events were dizziness (21% and 16%) and nausea (7% and 10%) for venlafaxine XR 75 mg and venlafaxine XR 150-225 mg, respectively.

Paediatric patients.

(See Section 4.4 Special Warnings and Precautions for Use, Clinical worsening and suicide risk, Paediatric use).
In general, the adverse reaction profile of venlafaxine in placebo controlled clinical trials in children and adolescents (aged 6 to 17) was similar to that seen for adults.
As with adults, decreased appetite, weight loss, increased blood pressure and increased serum cholesterol were observed. Additionally, the following adverse reactions were observed: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis and myalgia.
In paediatric clinical trials, there were increased reports of hostility and, especially in major depression, suicide related adverse events such as suicidal ideation and self harm.

Post-marketing reports.

Below are adverse reactions derived from post-marketing spontaneous reports in patients with major depression, generalised anxiety disorder, social anxiety disorder and panic disorder. Adverse reactions are shown in CIOMS frequency categories: common: ≥ 1%; uncommon: ≥ 0.1% and < 1%; rare: ≥ 0.01% and < 0.1%; very rare: < 0.01%; unknown: cannot be estimated from the available data.

General disorders and administration site conditions.

Common: chills.

Cardiac disorders.

Common: palpitations.
Rare: electrocardiogram QT prolonged, ventricular fibrillation, ventricular tachycardia, torsade de pointes, stress cardiomyopathy (takotsubo cardiomyopathy).

Gastrointestinal disorders.

Common: diarrhoea.
Uncommon: gastrointestinal haemorrhage.
Rare: pancreatitis.

Hepatobiliary disorders.

Rare: hepatitis.

Blood and lymphatic system disorders.

Rare: agranulocytosis, aplastic anaemia, neutropenia and pancytopenia.

Endocrine disorders.

Very rare: blood prolactin increased.

Musculoskeletal and connective tissue disorders.

Rare: rhabdomyolysis.

Psychiatric disorders.

Common: agitation, confusion, depersonalisation.
Rare: delirium.

Nervous system disorders.

Very common: headache.
Common: akathisia.
Uncommon: impaired coordination and balance, dyskinesia.
Rare: dystonia.
Very rare: tardive dyskinesia.
Unknown: psychotic disorder, paranoia, aggression.

Respiratory, thoracic and mediastinal disorders.

Common: dyspnoea.
Rare: pulmonary eosinophilia, interstitial lung disease.

Skin and subcutaneous tissue disorders.

Common: night sweats, pruritus.
Uncommon: alopecia, urticaria, angioedema.
Rare: erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Eye disorders.

Rare: angle closure glaucoma.

Ear and labyrinth disorders.

Common: tinnitus.

Renal and urinary disorders.

Common: pollakiuria.
Uncommon: proteinuria, urinary incontinence.

Reproductive system and breast disorders.

Common: menstrual disorders associated with increased bleeding or increased irregular bleeding (e.g. menorrhagia, metrorrhagia), pollakiuria.

Injury, poisoning and procedural complications.

Uncommon: bone fracture.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

In managing overdosage, consider the possibility of multiple medication involvement. The physician should consider contacting the Poison Information Centre on the treatment of any overdose (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Symptoms.

During premarketing trials, most patients who have overdosed with venlafaxine were asymptomatic. Of the remainder, somnolence was the most commonly reported symptom. Mild sinus tachycardia and mydriasis have also been reported.
There were no reports of seizures, respiratory distress, significant cardiac disturbances or significant laboratory test result abnormalities among any of the cases reported to date. However, seizures and respiratory distress occurred in one additional patient in an ongoing study who ingested an estimated 2.75 g of venlafaxine with naproxen and thyroxine. Generalised convulsions and coma resulted and emergency resuscitation was required. Recovery was good without sequelae.
In post-marketing experience, overdose with venlafaxine was reported predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdose include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, vomiting and seizures. Other events reported included electrocardiogram changes (e.g. prolongation of QT interval, bundle branch block, QRS prolongation), ventricular fibrillation, ventricular tachycardia (including torsades de pointes), bradycardia, hypotension, vertigo and death. Serotonin toxicity has been reported in association with venlafaxine overdose.

Fatal overdoses.

Published 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.
Epidemiological studies have shown that venlafaxine is prescribed to patients with a higher pre-existing burden of suicide risk factors than patients prescribed SSRIs. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage as opposed to some characteristics of venlafaxine treated patients is not clear. Prescriptions of venlafaxine should be written for the smallest quantity of drug consistent with good patient management, in order to reduce the risk of overdose (see Section 4.4 Special Warnings and Precautions for Use, Clinical worsening and suicide risk).

Management of overdoses.

General supportive and symptomatic measures are recommended. Ensure an adequate airway, oxygenation and ventilation. Cardiac rhythm and vital signs must be monitored. Administration of activated charcoal may also limit drug absorption.
Where there is a risk of aspiration, induction of emesis is not recommended. No specific antidotes for venlafaxine are known. Forced diuresis, dialysis, haemoperfusion and exchange transfusion are unlikely to be of benefit.
Venlafaxine and ODV are not considered dialysable because haemodialysis clearance of both compounds is low.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Venlafaxine is a structurally novel antidepressant for oral administration; it is chemically unrelated to tricyclic, tetracyclic or other available antidepressant agents.
The antidepressant action of venlafaxine 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 (ODV), are potent inhibitors of serotonin and noradrenaline reuptake, and also weakly inhibit dopamine reuptake. Venlafaxine is a racemate. The R-enantiomer is relatively more potent than the S-enantiomer with regard to inhibition of noradrenaline reuptake; the S-enantiomer is more potent regarding inhibition of serotonin reuptake. Both enantiomers are more potent on serotonin compared to noradrenaline reuptake. The enantiomers of ODV also inhibit both noradrenaline and serotonin reuptake, with the R-enantiomer being more potent.
Venlafaxine and its major metabolite appear to be equipotent with respect to their overall action on neurotransmitter reuptake and receptor binding. Studies in animals show that tricyclic antidepressants may reduce beta-adrenergic receptor responsiveness following chronic administration. In contrast, venlafaxine and ODV reduce beta-adrenergic responsiveness after both acute (single dose) and chronic administration.
Venlafaxine has no significant affinity for rat brain muscarinic, H1-histaminergic or alpha1-adrenergic receptors in vitro. Pharmacological activity at these receptors is potentially associated with various sedative, cardiovascular and anticholinergic effects seen with other psychotropic drugs. Venlafaxine does not possess monoamine oxidase (MAO) inhibitory activity.
In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP) or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine also does not produce noradrenaline release from brain slices. It has no significant central nervous system (CNS) stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability.

Cardiac electrophysiology.

In a dedicated thorough QTc study in healthy subjects, venlafaxine did not prolong the QT interval to any clinically relevant extent at a dose of 450 mg/day (given as 225 mg twice a day).

Clinical trials.

Major depression.

Three double blind, placebo controlled trials, of up to 12 weeks duration, have examined the clinical efficacy of modified release venlafaxine in the treatment of major depression. One of these studies also incorporated an active comparator, paroxetine. These studies showed modified release venlafaxine to have greater efficacy than both placebo and paroxetine in reducing depression.

Generalised anxiety disorder.

Five placebo controlled trials were conducted to evaluate the efficacy of modified release venlafaxine in the treatment of anxiety. Two trials were eight week studies, utilising modified release venlafaxine doses of 75 mg, 150 mg and 225 mg/day and of 75 mg and 150 mg/day. In one of these, buspirone was found not to be significantly different to placebo or to modified release venlafaxine. However, modified release venlafaxine was found to be superior to placebo. Two other trials were the first eight weeks of two long term studies, utilising modified release venlafaxine doses of 75 mg-225 mg/day and of 37.5 mg, 75 mg and 150 mg/day.
Four studies demonstrated superiority of modified release venlafaxine over placebo on at least five of the following efficacy scales: HAM-A total score, the HAM-A psychic anxiety factor, the Hospital Anxiety and Depression (HAD) anxiety subscale, and the CGI severity of illness scale, as well as the HAM-A anxious mood and tension item. Two of these four studies continued for up to six months. These two studies, which utilised modified release venlafaxine doses of 75 mg-225 mg/day and 37.5 mg, 75 mg and 150 mg/day demonstrated superiority of modified release venlafaxine over placebo on the HAM-A total score, HAM-A psychic anxiety factor, the HAD anxiety factor, and the CGI severity of illness scale, as well as the HAM-A anxious mood item.
The fifth trial was a short-term (8 week) comparison of the efficacy of 2 fixed doses of modified release venlafaxine (75 mg and 150 mg) with placebo and diazepam followed by a comparison of the long-term (6 month) efficacy of modified release venlafaxine and placebo in the prevention of relapse. The most important results were the primary efficacy variables at week 8 using an LOCF analysis. These demonstrated no significant differences between either venlafaxine and placebo, or diazepam and placebo for any of the primary efficacy variables. In view of this failure to demonstrate any effectiveness of either venlafaxine or diazepam over placebo, the long-term outcomes of this study are not of clinical or theoretical value. In conclusion, this study showed no anxiolytic effect of either diazepam or placebo in the short-term (8 week phase). See Table 2.

Depression relapse/ recurrence.

A long-term study of depressed outpatients who had responded to modified release venlafaxine during an initial 8 week open label treatment phase and were randomly assigned to continuation on venlafaxine or placebo for 6 months demonstrated a significantly lower relapse rate for patients taking venlafaxine compared with those on placebo.
In a second long-term study, outpatients with a history of recurrent depression who had responded to the immediate release form of venlafaxine by eight weeks and maintained improvement during an initial six month open label treatment phase were randomly assigned to maintenance therapy on immediate release venlafaxine or placebo for 12 months. Significantly fewer patients taking immediate release venlafaxine compared with those on placebo had a reappearance of depression.

Social anxiety disorder.

The efficacy of modified release venlafaxine as a treatment for social anxiety disorder (also known as social phobia) was established in four double blind, parallel group, 12 week, multi-centre, placebo controlled, flexible dose studies and one double blind, parallel group, 6 month, fixed/ flexible dose study in adult outpatients meeting the Diagnostic and Statistical Manual (DSM)-IV criteria for social anxiety disorder. Patients received doses in a range of 75-225 mg/day. Efficacy was assessed with the Liebowitz Social Anxiety Scale (LSAS). The LSAS measures the relationship of impairment because of social anxiety disorder symptoms by evaluating a patient's fear and avoidance in a broad range of situations (i.e. 13 performance and 11 social interaction situations). Psychometric studies have shown the LSAS to be a valid and reliable measure of social anxiety.1 The LSAS scale has also been shown to be sensitive to differences between active and placebo treatments.2
1 Clark DB, et al. Systematic assessment of social phobia in clinical practice. Depress and Anxiety 1997;6:47-61.
2 Davidson JRT, et al. Treatment of social phobia with clonazepam and placebo. J Clin Psychopharmacol. 1993;13:423-428.
The results of these trials are presented in Table 3. In these five trials, modified release venlafaxine was significantly more effective than placebo on change from baseline to endpoint on the LSAS total score.

Panic disorder.

The efficacy of modified release venlafaxine capsules as a treatment for panic disorder was established in two double blind, 12 week, multicentre, placebo controlled studies in adult outpatients meeting DSM-IV criteria for panic disorder, with or without agoraphobia. Patients received fixed doses of 75 or 150 mg/day in one study (Study 1) and 75 or 225 mg/day in the other study (Study 2).
In one flexible dose study (Study 3) (75 mg to 225 mg daily doses), the primary outcome, the percentage of patients free of full symptom panic attacks, approached significance (p = 0.056). In this study, modified release venlafaxine was significantly more effective than placebo for the two key secondary outcomes, (1) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score, and (2) percentage of patients rated as responders (much improved or very much improved) in the Clinical Global Impressions (CGI) Improvement scale.
In another flexible dose study (Study 4) (dose range 75 mg to 225 mg per day), modified release venlafaxine was not significantly more effective than placebo for the primary outcome, the percentage of patients free of full symptom panic attacks, but it was significantly more effective than placebo for the secondary outcome, percentage of patients rated as responders (much improved or very much improved) in the Clinical Impressions (CGI) Improvement scale.
Efficacy was assessed on the basis of outcomes in three variables: (1) percentage of patients free of full symptom panic attacks on the Panic and Anticipatory Anxiety Scale (PAAS), (2) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score, and (3) percentage of patients rated as responders (much improved or very much improved) in the Clinical Global Impressions (CGI) Improvement scale. In Studies 1 and 2, modified release venlafaxine was significantly more effective than placebo in all three variables. See Table 4.
Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies.
In a longer-term study (Study 5), adult outpatients meeting DSM-IV criteria for panic disorder who had responded during a 12 week open phase with modified release venlafaxine (75 to 225 mg/day) were randomly assigned to continue the same venlafaxine dose (75, 150, or 225 mg) or switch to placebo for observation for relapse during a 6 month double blind phase. Response during the open phase was defined as ≥ 1 full symptom panic attack per week during the last 2 weeks of the open phase and a CGI Improvement score of 1 (very much improved) or 2 (much improved). Relapse during the double blind phase was defined as having 2 or more full symptom panic attacks per week for 2 consecutive weeks or having discontinued due to loss of effectiveness. Patients receiving continued modified release venlafaxine treatment experienced significantly lower relapse rates over the subsequent 6 months compared with those receiving placebo. See Table 5.

5.2 Pharmacokinetic Properties

Steady-state concentrations of venlafaxine and ODV are attained within three days of oral multiple dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg/day. Mean ± SD steady-state plasma clearances of venlafaxine and ODV are 1.3 ± 0.6 and 0.4 ± 0.2 L/hour/kg, respectively; apparent elimination half-life is 5 ± 2 and 11 ± 2 hours, respectively; and apparent (steady-state) volume of distribution is 7.5 ± 3.7 and 5.7 ± 1.8 L/kg, respectively.

Absorption.

On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed, indicating that absorption of venlafaxine is nearly complete. However, the presystemic metabolism of venlafaxine (which primarily forms the active metabolite ODV) reduces the absolute bioavailability of venlafaxine to 42 ± 15%.
After administration of modified release venlafaxine (150 mg daily), the peak plasma concentrations (Cmax) of venlafaxine (150 nanogram/mL) and ODV (260 nanogram/mL) are attained within 6.0 ± 1.5 and 8.8 ± 2.2 hours, respectively.
The rate of absorption of venlafaxine from the modified release venlafaxine capsule is slower than its rate of elimination.
Therefore, the apparent elimination half-life of venlafaxine following administration of modified release venlafaxine (15 ± 6 hours) is actually the absorption half-life instead of the true disposition half-life (5 ± 2 hours) observed following administration of an immediate release tablet.
When equal doses of venlafaxine, administered either as an immediate release tablet taken in divided doses or as a modified release capsule, were taken once a day, the exposure (AUC, area under the concentration curve) to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower following treatment with the modified release venlafaxine capsule. Therefore, the modified release venlafaxine capsule provides a slower rate of absorption, but the same extent of absorption (i.e. AUC), as the venlafaxine immediate release tablet.
No accumulation of venlafaxine or ODV has been observed during chronic administration in healthy subjects.

Food-drug interactions.

Administration of venlafaxine XR with food has no effect on the absorption of venlafaxine or on the subsequent formation of ODV.

Distribution.

The degree of binding of venlafaxine to human plasma proteins is 27 ± 2% at concentrations ranging from 2.5 to 2215 nanogram/mL, and the degree of ODV binding to human plasma proteins is 30 ± 12% at concentrations ranging from 100 to 500 nanogram/mL. Protein binding induced drug interactions with concomitantly administered venlafaxine are not expected. Following intravenous administration, the steady-state volume of distribution of venlafaxine is 4.4 ± 1.9 L/kg, indicating that venlafaxine distributes well beyond the total body water.

Metabolism.

Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver. The primary metabolite of venlafaxine is ODV, but venlafaxine is also metabolised to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine and other minor metabolites. In vitro studies indicate that the formation of ODV is catalysed by CYP2D6 and that the formation of N-desmethylvenlafaxine is catalysed by CYP3A3/4. The results of the in vitro studies have been confirmed in a clinical study with subjects who are CYP2D6 poor and CYP2D6 extensive metabolisers. However, despite the metabolic differences between the CYP2D6 poor and CYP2D6 extensive metabolisers, the total exposure to the sum of the two active species (venlafaxine and ODV) was similar in the two metaboliser groups. Therefore, CYP2D6 poor and CYP2D6 extensive metabolisers can be treated with the same regimen of venlafaxine XR (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, CYP2D6 inhibitors).

Excretion.

Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours after a single radiolabelled dose as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%) or other minor inactive metabolites (27%), and 92% of the radioactive dose is recovered within 72 hours. Therefore, renal elimination of venlafaxine and its metabolites is the primary route of excretion.

Special populations.

Gender and age.

Subject age and sex do not significantly affect the pharmacokinetics of venlafaxine. A 20% reduction in clearance was noted for ODV in subjects over 60 years old; this was probably caused by the decrease in renal function that typically occurs with ageing.

Renal impairment.

In patients with moderate to severe impairment of renal function, the total clearance of both venlafaxine and ODV was reduced, and t1/2 was prolonged. The reduction in total clearance was most pronounced in subjects with creatinine clearance less than 30 mL/min.

Hepatic impairment.

In some patients with compensated hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered. The reduction in both the metabolism of venlafaxine and elimination of ODV resulted in higher plasma concentrations of both venlafaxine and ODV.

5.3 Preclinical Safety Data

Genotoxicity.

There was no evidence of gene mutation or chromosomal change in a series of genotoxicity assays using venlafaxine and the main human metabolite ODV.

Carcinogenicity.

Venlafaxine was given by oral gavage to mice and rats for 18 and 24 months, respectively, at dosages up to 120 mg/kg/day. There were no clear drug related oncogenic effects in either species. In these studies, animal exposure to the main human metabolite ODV was less and exposure to venlafaxine was more than would be expected in humans taking the recommended therapeutic and maximum doses.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, povidone, ethanol, purified talc, colloidal anhydrous silica, magnesium stearate, ethylcellulose, copovidone, brilliant blue FCF, allura red AC, sunset yellow FCF (only for 150 mg), iron oxide black (only for 75 mg), iron oxide red (only for 75 mg), titanium dioxide, gelatin, TekPrint SB-0007P White Ink (150 mg capsules only), TekPrint SB-1033 Red Ink (75 mg capsules only).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

APO-Venlafaxine XR 75 mg modified release capsules.

Blister pack - PVC/PCTFE (Aclar)/Al and PVC/PVDC/Al pack of 28 modified release capsules.

APO-Venlafaxine XR 150 mg modified release capsules.

Blister pack - PVC/PCTFE (Aclar)/Al and PVC/PVDC/Al pack of 28 modified release capsules.
Not all strengths may be available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Venlafaxine hydrochloride is a white to off white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride).
Venlafaxine XR capsules are a modified release formulation, which release the active constituent venlafaxine hydrochloride from a tablet or tablets within the capsule. Drug is released by a combination of swelling of the hydrophilic polymer (hypromellose), diffusion and erosion.

Chemical structure.


Chemical name: 1-[(1RS)-2-(Dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride.
Molecular formula: C17H27NO2.HCl. Molecular weight: 313.87.

CAS number.

99300-78-4.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes