Active ingredients: Venlafaxine
Efexor 37.5 mg prolonged-release hard capsules
Efexor 75 mg prolonged-release hard capsules
Efexor 150 mg prolonged-release hard capsules
Why is Efexor used? What is it for?
Efexor is an antidepressant belonging to a group of medicines called serotonin and norepinephrine reuptake inhibitors (SNRIs). This group of medicines is used to treat depression and other conditions, such as anxiety disorders. People who are depressed and / or anxious are believed to have lower levels of serotonin and noradrenaline in the brain. It is not fully known how antidepressants work, however they may help by raising the levels of serotonin and noradrenaline in the brain.
Efexor is a treatment for adults with depression. It is also a treatment for adults with the following anxiety disorders: generalized anxiety disorder, social anxiety disorder (fear of or avoidance of social situations) and panic disorder (panic attacks). Proper treatment of depression or anxiety disorders is important to help you get better. If left untreated, your condition may not go away and can become more severe and more difficult to treat
Contraindications When Efexor should not be used
Do not take Efexor
- if you are allergic to venlafaxine or any of the other ingredients of this medicine
- if you are taking or have taken within the last 14 days, any of the medicines known as irreversible monoamine oxidase inhibitors (MAOIs), used to treat depression or Parkinson's disease. Irreversible MAO together with Efexor, can lead to serious or even life-threatening side effects. In addition, you must wait at least 7 days after stopping treatment with Efexor before taking any MAOIs (see also the section called "Taking Efexor with other medicines" and the information in the same section on "Serotonin syndrome").
Precautions for use What you need to know before taking Efexor
If any of the following apply to your situation, tell your doctor before taking Efexor:
If you use other medicines which, taken together with Efexor, may increase the risk of developing a serotonin syndrome (see section "Taking Efexor with other medicines").
- If you have eye problems, such as certain types of glaucoma (increased pressure in the eye).
- If you have a history of high blood pressure.
- If you have a history of heart problems.
- If you have been told you have an abnormal heart rhythm.
- If you have a history of seizures.
- If you have a history of low sodium levels in your blood (hyponatremia).
- If you have a tendency to bruise or bleed easily (a history of bleeding disorders), or if you are using other medicines that may increase the risk of bleeding, such as warfarin (used to prevent blood clots).
- If you have a history or someone in your family has had mania or bipolar disorder (feeling over-excited or euphoric).
- If you have a history of aggressive behavior.
During the first few weeks of treatment Efexor may cause a feeling of restlessness or an inability to sit or stand still. If you have these symptoms, you should tell your doctor.
Thoughts of suicide and worsening of your depression or anxiety disorder
If you are depressed and / or have anxiety disorders, you can sometimes have thoughts of harming or killing yourself. These can increase when you first start using antidepressants, as it takes some time for all medicines like these to start working, usually around two weeks but sometimes longer.
You are more likely to think like this:
- If you have previously had thoughts about killing or harming yourself.
- If he is young. Information obtained from clinical trials has shown an increased risk of suicidal behavior in young people (less than 25 years old) with psychiatric disorders who had been treated with an antidepressant.
If you have thoughts of harming or killing yourself at any time, contact your doctor or go to a hospital immediately.
It may help to tell a close relative or friend that you are depressed or have an anxiety disorder, and ask them to read this leaflet. You may ask them to tell you if they think your depression or state is d "anxiety is getting worse, or if you are worried about changes in your behavior.
Dry mouth
Dry mouth is reported in 10% of patients treated with venlafaxine. This can increase the risk of dental caries. You must therefore pay particular attention to your oral hygiene.
Diabetes
Blood glucose levels can be affected by Efexor. Therefore, the dose of your diabetes therapy may need to be adjusted.
Use in children and adolescents under the age of 18
Efexor should normally not be used for children and adolescents under the age of 18. Furthermore, you should be aware that patients under the age of 18 have an increased risk of side effects, such as suicide attempt, suicidal thoughts and hostility (mainly aggression, oppositional behavior and anger) when taking this category of medicines. Despite this, your doctor may prescribe this medicine for patients under the age of 18, as they believe this is in their best interest. If your doctor has prescribed this medicine for a patient under 18, and you want to discuss this, please talk to your doctor. You should tell your doctor if any of the symptoms listed above develop or worsen when a patient under 18 is taking Efexor. Furthermore, the long-term safety effects of this medicine on growth, maturation and cognitive and behavioral development in this age group have not been demonstrated.
Interactions Which drugs or foods may change the effect of Efexor
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
Your doctor will decide whether you can use Efexor with other medicines.
Do not start or stop treatment with other medicines, including non-prescription medicines, herbal preparations, before asking your doctor or pharmacist.
- Monoamine oxidase inhibitors which are used to treat depression or Parkinson's disease should not be taken with Efexor. Tell your doctor if you have taken these medicines within the last 14 days (MAOIs: see section "Before taking Efexor")
Serotonin syndrome:
A potentially life-threatening condition or reactions such as Neuroleptic Malignant Syndrome (NMS) (see section "Possible side effects") may occur with venlafaxine treatment, especially when taken with other medicines.
Examples of these medicines include:
- Triptans (used for migraines)
- Other medicines to treat depression, for example SNRIs, SSRIs, tricyclics, or medicines containing lithium o Medicines containing linezolid, an antibiotic (used to treat infections)
- Medicines containing moclobemide, a MAOI (used to treat depression) or Medicines containing sibutramine (used for weight loss)
- Medicines containing tramadol, fentanyl, tapentadol, pethidine, or pentazocine (used to treat severe pain) or Medicines containing dextromethorphan (used to treat cough)
- Medicines containing methadone (used to treat opioid addiction or severe pain)
- Medicines containing methylene blue (used to treat high levels of methemoglobin in the blood)
- Preparations based on St. John's wort (also called Hypericum Perforatum, a natural remedy based on a medicinal plant used to treat mild depression)
- Products containing tryptophan (used for disorders such as sleep and depression)
- Antipsychotics (used to treat a disease with symptoms such as hearing, seeing or sensing things that are not real, wrong opinions, strange suspicions, confused reasoning and estrangement)
Signs and symptoms of serotonin syndrome may include a combination of: restlessness, hallucinations, loss of coordination, rapid heartbeat, increased body temperature, rapid changes in blood pressure, overactive reflexes, diarrhea, coma, nausea, vomiting
In its most severe form, serotonin syndrome may resemble Neuroleptic Malignant Syndrome (NMS). Signs and symptoms of NMS may include a combination of fever, rapid heart rate, sweating, severe muscle stiffness, confusion, increased muscle enzymes (determined by a "blood test).
If you think you have serotonin syndrome tell your doctor immediately or go to the nearest hospital emergency room.
You should tell your doctor if you are taking any medicines that can affect the heart rhythm.
Examples of these medicines include:
- Antiarrhythmics such as quinidine, amiodarone, sotalol or dofetilide (used to treat abnormal heart rhythms)
- Antipsychotics such as thioridazine (See also above: Serotonin Syndrome)
- Antibiotics such as erythromycin or moxifloxacin (used to treat bacterial infections)
- Antihistamines (used to treat allergies) The medicines listed below may also interfere with Efexor and should be used with caution. It is especially important that you tell your doctor or pharmacist if you are using medicines that contain:
- Ketoconazole (an antifungal medicine)
- Haloperidol or risperidone (to treat psychiatric disorders)
- Metoprolol (a beta blocker to treat high blood pressure and heart problems)
Taking Efexor with food and drink
You must take Efexor with food (see section "How to take Efexor"). You should not drink alcohol while you are taking Efexor.
Warnings It is important to know that:
Pregnancy and breastfeeding
Tell your doctor if you find that you are pregnant, or if you are trying to become pregnant. You should only use Efexor after discussing the potential benefits and potential risks to the fetus with your doctor.
Make sure your midwife and / or doctor know you are taking Efexor. When taken during pregnancy, similar drugs (called SSRIs) can increase the risk of a serious condition in newborns, called persistent pulmonary hypertension of the newborn (PPHN). This condition causes the baby to breathe quickly and have a bluish color.These symptoms usually begin during the first 24 hours of the baby's life.If this occurs you should contact your midwife and / or doctor immediately.
If you are using Efexor during pregnancy, other symptoms your baby may have at birth are difficulties with feeding and breathing. If you are concerned because you think your baby will have these symptoms at birth, please contact your doctor and / or midwife who will be able to assist you.
Efexor is excreted in breast milk. There is a risk of an effect on the baby. Therefore, you should discuss this with your doctor, who will decide whether you should stop breastfeeding or discontinue therapy with this medicine.
Driving and using machines
Do not drive or use any tools or machines until you understand what effects this medicine has on you.
Dose, Method and Time of Administration How to use Efexor: Posology
Always take Efexor exactly as your doctor has told you. If in doubt, you should consult your doctor or pharmacist.
The usual recommended starting dose for the treatment of depression, generalized anxiety disorder and social anxiety disorder is 75 mg per day. Your doctor may increase the dose gradually and, if necessary, up to a maximum dose of 375 mg per day for depression. If you are being treated for panic disorder, your doctor will start with a lower dose (37.5 mg) and then gradually increase the dose. The maximum dose for generalized anxiety disorder, social anxiety disorder and panic disorder is 225 mg per day.
Take Efexor at about the same time each day, in the morning or in the evening. The capsules must be swallowed whole with liquid and must not be opened, broken, chewed or dissolved.
You must take Efexor with food.
If you have liver or kidney problems, talk to your doctor, as the dose of this medicine may need to be adjusted. Do not stop taking this medicine without consulting your doctor (see section "If you stop taking Efexor").
Overdose What to do if you have taken too much Efexor
If you take more Efexor than you should
Contact your doctor or pharmacist immediately if you take more medicine than the amount prescribed by your doctor. Symptoms of a possible overdose may include rapid heartbeat, changes in consciousness (ranging from sleepiness to coma), blurred vision, fits and vomiting.
If you forget to take Efexor
If you forget to take a dose, take it as soon as you remember it. However, if you are due to take your next dose when you notice your missed dose, skip the missed dose and take only one dose as you usually do. Do not take more than the daily amount of Efexor that has been prescribed for you in a single day.
If you stop taking Efexor
Do not stop treatment or reduce the dose without your doctor's advice, even if you feel better. If your doctor thinks that you no longer need Efexor, he may ask you to reduce the dose gradually before stopping treatment completely. Side effects are known to occur when patients stop taking this medicine, especially when it is stopped abruptly or when the dose is reduced too quickly. Some patients may report symptoms such as tiredness, dizziness, light-headedness, headache, insomnia, nightmares, dry mouth, loss of appetite, nausea, diarrhea, nervousness, agitation, confusion, ringing in the ears, tingling or rarely feelings of shock. electric, weakness, sweating, seizures, or flu-like symptoms.
Your doctor will advise you on how you should gradually stop taking Efexor. If you experience any of these or any other symptoms that bother you, ask your doctor for further advice.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Efexor
Like all medicines, Efexor can cause side effects, although not everybody gets them. If any of the following happen, do not take more Efexor. Contact your doctor immediately, or go to the nearest hospital emergency room:
- Chest tightness, wheezing, difficulty swallowing or breathing.
- Swelling of the face, throat, hands or feet.
- Feeling nervous or anxious, dizziness, throbbing sensation, sudden redness of the skin and / or a feeling of warmth.
- Intense rash, itching, or hives (raised patches of red or pale skin that often itch).
- Signs and symptoms of serotonin syndrome may include agitation, hallucinations, loss of coordination, rapid heart rate, increased body temperature, rapid changes in blood pressure, overactive reflexes, diarrhea, coma, nausea, vomiting.
- In its most severe form, serotonin syndrome may resemble Neuroleptic Malignant Syndrome (NMS). Signs and symptoms of NMS may include a combination of fever, rapid heart rate, sweating, severe muscle stiffness, confusion, increased muscle enzymes (determined by a "blood test).
Other side effects that you should report to your doctor are:
- Cough, wheezing, shortness of breath and a high temperature.
- Black (tar-colored) stools or blood in stools.
- Yellow eyes or skin, itchy or dark urine, which may be symptoms of inflammation of the liver (hepatitis).
- Heart problems, such as fast or irregular heartbeat, increased blood pressure.
- Eye problems, such as blurred vision, dilated pupils.
- Problems of a nervous nature, such as dizziness, tingling, movement disorders, seizures.
- Psychiatric problems, such as hyperactivity and euphoria (feeling overly excited).
- Withdrawal syndrome (see section "How to take Efexor, If you stop taking Efexor").
- Prolonged bleeding - in case of cuts or wounds it may take a little longer than usual to stop bleeding.
Do not worry if you notice small white granules or beads in your stool after taking this medicine. Inside the Efexor capsules there are spheroids (small white spheres) that contain the active ingredient venlafaxine. These spheroids are released from the capsule into the stomach. As the spheroids travel the entire length of your gastrointestinal tract, venlafaxine is released slowly. . The spheroid coating does not dissolve and is found in the stool. Therefore, even if spheroids were noted in the faeces, the dose of medicine was absorbed.
Full list of side effects
Very common (affects more than 1 in 10 patients)
- Dizziness; headache
- Nausea; dry mouth
- Sweating (including night sweats)
- Common (affects 1 to 10 users in 100)
- Decreased appetite
- Confusion; feeling of detachment from oneself; absence of orgasm; decreased libido; nervousness; insomnia; abnormal dreams
- Drowsiness; tremor; tingling; increased muscle tone
- Visual disturbances including blurred vision; dilated pupils; inability of the eye to automatically change focus from distant to near objects
- Ringing in the ears (tinnitus)
- Palpitations
- Increased blood pressure hot flashes Yawning
- He retched; constipation; diarrhea
- Increased frequency of urination; difficulty passing urine
- Menstrual irregularities such as increased bleeding or increased bleeding irregularity; abnormal orgasm / ejaculation (males); erectile dysfunction (impotence)
- Weakness (asthenia); fatigue; chills
- Increased cholesterol
Uncommon (affects 1 to 10 users in 1,000)
- Hallucinations; feeling of detachment from reality; agitation; abnormal orgasm (females); absence of sensations or emotions; feeling of over-arousal; teeth grinding
- Feeling restless or unable to sit or stand still; fainting; involuntary movement of the muscles; impaired coordination and balance; sensation of altered taste
- Rapid heartbeat; feeling dizzy (especially when standing up too quickly)
- Shortness of breath
- Vomiting blood black tarry stools or blood in stools; which may be a sign of internal bleeding
- General swelling of the skin, especially in the area of the face, mouth, tongue and throat or hands and feet and / or itchy bumps (hives) may occur; sensitivity to sunlight; bruising; rash; loss abnormal hair
- Inability to pass urine
- Weight gain weight loss
Rare (affects 1 to 10 users in 10,000)
- Seizures
- Urinary incontinence
- Hyperactivity, competitive thoughts and decreased need for sleep (mania)
Frequency not known
- Reduced number of platelets in the blood, which leads to an increased risk of bruising or bleeding blood disorders which can lead to an increased risk of infection
- Swelling of the face or tongue, shortness of breath or difficulty in breathing, often with a skin rash (this can be a serious allergic reaction)
- Excessive water intake (known as SIADH)
- Decrease in blood sodium levels
- Suicidal ideation and suicidal behaviors: Cases of suicidal ideation and suicidal behaviors have been reported during treatment with venlafaxine or soon after stopping venlafaxine treatment (see section 2, Before taking Efexor)
- Disorientation and confusion often accompanied by hallucinations (delirium); aggression
- High fever with muscle stiffness, confusion or agitation, and sweating, or if you experience spasmodic movements of the muscles that you cannot control, this may indicate a serious condition known as neuroleptic malignant syndrome; feeling euphoric, sleepy, continuous and rapid eye movement, awkward movements, restlessness, feeling drunk, sweating or muscle stiffness, which are signs of serotonin syndrome; stiffness, spasms and involuntary movements of the muscles
- Intense eye pain and decreased or blurred vision
- Dizziness
- Lowering of blood pressure abnormal, rapid or irregular heartbeat, which can lead to fainting; unexpected bleeding, i.e. bleeding from the gums, blood in the urine or vomiting with blood, or unexpected bruising or rupture of the veins
- Cough, wheezing, shortness of breath and high temperature, which are symptoms of inflammation of the lungs associated with an increase in white blood cells (pulmonary eosinophilia)
- Severe abdominal or back pain (which may indicate a serious problem with the gut, liver or pancreas)
- Itching, yellow skin or eyes, dark urine, or flu-like symptoms, which are signs of inflammation of the liver (hepatitis); slight changes in blood levels of liver enzymes
- Skin rash, which can result in severe blistering and peeling of the skin itch; mild rash
- Unexplained pain, sensitivity to touch or muscle weakness (rhabdomyolysis)
- Abnormal production of breast milk
Sometimes Efexor causes side effects that you may not be aware of, such as increases in blood pressure or an abnormal heart beat; slight changes in blood levels of liver enzymes, sodium or cholesterol. More rarely, Efexor can reduce the function of the platelets in your blood, leading to an increased risk of bruising and bleeding. Therefore, your doctor may wish to have your blood checked occasionally, particularly if you have been taking Efexor for a long time.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Expiry and Retention
Keep Efexor out of the sight and reach of children.
Do not use Efexor after the expiry date which is stated on the carton.
Do not store above 30 ° C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
OTHER INFORMATION
What Efexor contains
The active ingredient is venlafaxine.
Efexor 37.5 mg:
Each prolonged-release capsule contains 42.43 mg of venlafaxine hydrochloride, equivalent to 37.5 mg of venlafaxine base.
The excipients are:
Capsule contents: microcrystalline cellulose, ethylcellulose, hypromellose, talc Capsule shell: gelatin, black, red and yellow iron oxides (E172), titanium dioxide (E171)
Capsule printing ink: lacquer, red iron oxide (E172), ammonium hydroxide, simethicone, propylene glycol
Efexor 75 mg:
Each prolonged-release capsule contains 84.85 mg of venlafaxine hydrochloride, equivalent to 75 mg of venlafaxine base.
The excipients are:
Capsule contents: microcrystalline cellulose, ethyl cellulose, hypromellose, talc
Capsule shell: gelatin, red and yellow iron oxides (E172), titanium dioxide (E171)
Capsule printing ink: lacquer, red iron oxide (E172), ammonium hydroxide, simethicone, propylene glycol
Efexor 150 mg:
Each prolonged-release capsule contains 169.7 mg of venlafaxine hydrochloride, equivalent to 150 mg of venlafaxine base.
The excipients are:
Capsule contents: microcrystalline cellulose, ethyl cellulose, hypromellose, talc
Capsule shell: gelatin, red and yellow iron oxides (E172), titanium dioxide (E171)
Capsule printing ink: lacquer, sodium hydroxide, povidone, titanium dioxide (E171), propylene glycol
What Efexor looks like and contents of the pack
Efexor 37.5 mg are light gray and peach opaque capsules printed in red with a "W" and strength "37.5".
Efexor 37.5 mg is available in packs containing 7, 10, 14, 20, 21, 28, 30, 35, 50, 60, 84, 100 capsules and in hospital packs containing 70 capsules (10x7, 1x70) or in bottles containing 7, 14, 20, 21, 35, 50, 100 capsules and in hospital bottles containing 70 capsules.
Efexor 75 mg are opaque peach capsules printed in red with a "W" and the strength "75".
Efexor 75 mg is available in packs containing 7, 10, 14, 15, 20, 28, 30, 50, 56, 60, 84, 98, 100 capsules and in hospital packs containing 500 (10x50) and 1000 (10x100) capsules or in bottles containing 14, 20, 50, 100 capsules and in hospital bottles containing 500 and 1000 capsules.
Efexor 150 mg are dark orange opaque capsules printed in white with a "W" and the strength "150".
Efexor 150 mg is available in packs containing 7, 10, 14, 15, 20, 28, 30, 50, 56, 60, 84, 98, 100 capsules and in hospital packs containing 500 (10x50) and 1000 (10x100) capsules or in bottles containing 14, 20, 50, 100 capsules and in hospital bottles containing 500 and 1000 capsules.
Not all pack sizes may be marketed.
Prolonged-release hard capsules
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
EFEXOR
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Venlafaxine 37.5 mg:
Each prolonged-release capsule contains 42.43 mg of venlafaxine hydrochloride, equivalent to 37.5 mg of venlafaxine base.
Venlafaxine 75 mg:
Each prolonged-release capsule contains 84.85 mg of venlafaxine hydrochloride, equivalent to 75 mg of venlafaxine base.
Venlafaxine 150 mg:
Each prolonged-release capsule contains 169.7 mg of venlafaxine hydrochloride, equivalent to 150 mg of venlafaxine base.
For the full list of excipients see section 6.1.
03.0 PHARMACEUTICAL FORM
Prolonged-release capsule, hard.
Venlafaxine 37.5 mg:
Hard gelatin capsule, type 3, with light gray opaque cap and peach opaque body, imprinted in red "W" and "37.5".
Venlafaxine 75 mg:
Hard gelatin capsule, type 1, peach-colored, opaque, imprinted in red "W" and "75".
Venlafaxine 150 mg:
Hard gelatin capsule, type 0, dark orange, opaque, with white imprint "W" and "150".
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of major depressive episodes.
Prevention of relapses of major depressive episodes.
Treatment of generalized anxiety disorder.
Treatment of social anxiety disorder.
Treatment of panic disorder, with or without agoraphobia.
04.2 Posology and method of administration
Major depressive episodes
The recommended starting dose of prolonged-release venlafaxine is 75 mg once daily. Patients unresponsive to an initial dose of 75 mg / day may benefit from dose increases up to a maximum of 375 mg / day. Dosage increases can be made at intervals of 2 weeks or more. If clinically warranted due to the severity of symptoms, dose increases may be made at more frequent intervals, however not less than 4 days.
Due to the risk of dose-related adverse effects, dose increases should only be made after clinical evaluation (see section 4.4). The lowest effective dose should be maintained.
Patients should be treated for a sufficient period of time, usually several months or more. Treatment should be reassessed regularly on an individual basis. Long-term treatment for the prevention of relapse of major depressive episodes (MDE) may also be appropriate. In most cases, the recommended dose for prevention of MDE recurrence is the same as that used during the episode itself.
Treatment with antidepressant medications should last for at least 6 months following disease remission.
Generalized anxiety disorder
The recommended starting dose of prolonged-release venlafaxine is 75 mg per day, once daily. Patients unresponsive to an initial dose of 75 mg / day may benefit from dose increases up to a maximum of 225 mg / day. Dosage increases can be made at intervals of 2 weeks or more.
Due to the risk of dose-related adverse effects, dose increases should only be made after clinical evaluation (see section 4.4). The lowest effective dose should be maintained.
Patients should be treated for a sufficient period of time, usually several months or more. Treatment should be reassessed regularly on an individual basis.
Social anxiety disorder
The recommended dose of prolonged-release venlafaxine is 75 mg once daily. There is no evidence that higher doses bring greater benefits.
However, in individual patients unresponsive to the starting dose of 75 mg / day, increases up to the maximum dose of 225 mg / day may be considered. Dosage increases can be made at intervals of 2 weeks or more.
Due to the risk of dose-related adverse effects, dose increases should only be made after clinical evaluation (see section 4.4). The lowest effective dose should be maintained.
Patients should be treated for a sufficient period of time, usually several months or more. Treatment should be reassessed regularly on an individual basis.
Panic Disorder
It is recommended that a 37.5 mg daily dose of prolonged-release venlafaxine be used for 7 days. Thereafter, the dosage should be increased to 75 mg daily. Patients unresponsive to 75 mg / day may receive benefit from dose increases up to a maximum of 225 mg / day Dosage increases may be made at intervals of 2 weeks or more.
Due to the risk of dose-related adverse effects, dose increases should only be made after clinical evaluation (see section 4.4). The lowest effective dose should be maintained.
Patients should be treated for a sufficient period of time, usually several months or more. Treatment should be reassessed regularly on an individual basis.
Use in elderly patients
No specific dose adjustment of venlafaxine is considered necessary on the basis of age alone. However, caution should be exercised in the treatment of elderly patients (for example, due to the possibility of renal insufficiency, the potential for altered sensitivity and affinity). of neurotransmitters that occurs with age) The lowest effective dose should always be used, and patients should be closely monitored when a dose increase is required.
Use in children and adolescents under the age of 18
The use of venlafaxine is not recommended in children and adolescents.
Controlled clinical trials in children and adolescents with major depressive disorder have not demonstrated efficacy and do not support the use of venlafaxine in these patients (see sections 4.4 and 4.8).
The efficacy and safety of venlafaxine in other indications in children and adolescents below 18 years has not been established.
Use in patients with hepatic insufficiency
In patients with mild to moderate hepatic impairment, a 50% dose reduction should generally be considered. However, due to individual variability in clearance, individualisation of the dosage would be preferable.
There are limited data in patients with severe hepatic insufficiency. Caution is recommended and a dose reduction of more than 50% should be considered. The potential benefit should be weighed against the risks in the treatment of patients with severe hepatic impairment.
Use in patients with renal impairment
Although no dosage adjustment is necessary for patients with glomerular filtration rate (GFR) between 30 and 70 mL / minute, caution is recommended. For patients requiring hemodialysis and in patients with severe renal insufficiency (GFR
Withdrawal symptoms observed on discontinuation of venlafaxine treatment
Abrupt discontinuation of treatment should be avoided. When stopping venlafaxine, the dose should be reduced gradually over a period of at least 1-2 weeks in order to reduce the risk of withdrawal reactions (see sections 4.4 and 4.8). If unbearable symptoms occur following dose reduction or upon discontinuation of treatment, resuming the previously prescribed dose may be considered. Thereafter, the doctor may continue to decrease the dose, but more gradually.
Oral use.
It is recommended that the Venlafaxine prolonged-release capsules be taken with food, at approximately the same time each day. The capsules should be swallowed whole with liquid and should not be divided, broken, chewed or dissolved.
Patients on venlafaxine immediate-release tablets can be switched to venlafaxine prolonged-release capsules at the nearest equivalent daily dose. For example, taking venlafaxine 37.5 mg immediate-release tablets twice daily can be switched to taking venlafaxine 75 mg prolonged-release capsules once daily. Individual dosage adjustment may be required.
Venlafaxine extended-release capsules contain spheroids, which release the active substance slowly into the digestive tract. The insoluble portion of these spheroids is eliminated and can be found in the faeces.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Concomitant treatment with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serotonin syndrome with symptoms such as agitation, tremor and hyperthermia. Venlafaxine should not be started until at least 14 days have elapsed since stopping treatment with an irreversible MAOI.
Venlafaxine administration should be discontinued at least 7 days prior to initiation of treatment with an irreversible MAO inhibitor (see sections 4.4 and 4.5).
04.4 Special warnings and appropriate precautions for use
Suicide / suicidal thoughts or clinical worsening
Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first or immediate weeks of treatment, patients should be closely monitored until improvement occurs. It is clinical experience in general that the risk of suicide may increase in the early stages of improvement.
Other psychiatric conditions for which venlafaxine is prescribed may also be associated with an increased risk of suicide-related events. Furthermore, these conditions can be associated with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed with other psychiatric conditions.
Patients with a history of suicide-related events, or who exhibit a significant degree of suicidal ideation prior to initiation of treatment, are at increased risk for suicidal thoughts or suicide attempts, and should be closely monitored during treatment. Clinical trials conducted with antidepressant drugs in comparison with placebo in adult patients with psychiatric disorders, showed an increased risk of suicidal behavior in the age group below 25 years of patients treated with antidepressants compared to placebo.
Drug therapy with antidepressants should always be associated with close surveillance of patients, particularly those at high risk, especially in the initial stages of treatment and after dose changes. Patients (and caregivers) should be advised of the need to monitor for any clinical worsening, the onset of suicidal behavior or thoughts or unusual changes in behavior and to seek medical advice immediately if these symptoms occur.
Use in children and adolescents under the age of 18
Efexor should not be used to treat children and adolescents under 18 years of age.
Suicide-related behaviors (suicide attempts and suicidal thoughts) and hostility (mainly aggression, oppositional behavior and anger) were observed more frequently in clinical trials in children and adolescents treated with antidepressants than in those treated with placebo. If, based on medical need, a decision to treat is to be made, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, no long-term safety data are available for the growth, maturation and cognitive and behavioral development of children and adolescents.
Serotonin syndrome
With treatment with venlafaxine, as with other serotonergic drugs, a potentially life-threatening serotonin syndrome or reactions such as Neuroleptic Malignant Syndrome (NMS) may develop, particularly with concomitant use of other serotonergic drugs (including SSRIs, SNRIs). and triptans), with drugs that interfere with serotonin metabolism, such as MAO inhibitors (e.g. methylene blue), or with antipsychotics or other dopamine antagonists (see sections 4.3 and 4.5).
Symptoms of serotonin syndrome may include changes in mental status (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and / or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhea).
Serotonin syndrome in its most severe form can resemble NMS and is manifested by hyperthermia, muscle stiffness, autonomic instability with possible rapid fluctuation of vital signs and changes in mental status.
If concomitant treatment with venlafaxine and other drugs that may affect the dopaminergic and / or serotonergic neurotransmitter systems is clinically justified, careful observation of the patient is recommended, particularly during the initial phase of treatment and at dose increases.
The concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended.
Narrow angle glaucoma
In association with venlafaxine, mydriasis may occur. It is recommended to carefully monitor patients with increased intraocular pressure, or patients at risk for acute narrow-angle glaucoma (narrow-angle glaucoma).
Blood pressure
Dose-dependent increases in blood pressure have been commonly reported with the use of venlafaxine. Cases of elevated blood pressure requiring immediate treatment have been reported in post-marketing experience.
All patients should be closely monitored for cases of high blood pressure and pre-existing hypertension should be checked before initiating venlafaxine treatment. Blood pressure should be monitored periodically after initiation of treatment and after dose increases. Caution should be exercised in patients with pre-existing conditions that may be compromised by increases in blood pressure, such as those with impaired cardiac function.
Heart rate
An increase in heart rate may occur, particularly with higher dosages. Caution should be exercised in patients with pre-existing conditions that may be compromised by an increase in heart rate.
Heart disease and risk of arrhythmia
The use of venlafaxine has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Therefore venlafaxine should be used with caution in such patients.
In post-marketing experience, cases of fatal cardiac arrhythmia have been reported with the use of venlafaxine, especially in cases of overdose. Benefit and risk assessment should be considered before prescribing venlafaxine to patients at high risk for severe cardiac arrhythmia.
Convulsions
Convulsions may occur during venlafaxine therapy. Like all antidepressant drugs, venlafaxine should be used with caution in patients with a history of seizures, and affected patients should be carefully monitored. Treatment should be discontinued in patients who develop seizures.
Hyponatremia
Cases of hyponatremia and / or syndrome of inadequate antidiuretic hormone secretion (SIADH) may occur with the use of venlafaxine. This has occurred more frequently in fluid-depleted or dehydrated patients. Elderly patients, patients taking diuretics, and patients with fluid depletion for other reasons may be at increased risk for this event.
Abnormal bleeding
Medicines that inhibit serotonin uptake can lead to reduced platelet function. The risk of skin and mucosal bleeding, including gastrointestinal haemorrhage, may be increased in patients taking venlafaxine. As with other serotonin reuptake inhibitors, venlafaxine should be used with caution in patients prone to bleeding, including patients being treated with anticoagulants and platelet inhibitors.
Serum cholesterol
Clinically significant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients after at least three months of treatment in placebo-controlled clinical trials. Measurement of serum cholesterol levels should be considered during prolonged treatment.
Co-administration with weight loss agents
The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, has not been demonstrated. Co-administration of venlafaxine and weight loss agents is not recommended. Venlafaxine is not indicated. for weight loss neither alone nor in combination with other products.
Mania / hypomania
Mania / hypomania may occur in a small proportion of patients with mood disorders who have taken antidepressants, including venlafaxine. As with other antidepressants, venlafaxine should be used with caution in patients with a personal or family history of bipolar disorder.
Aggression
Aggression may occur in a small proportion of patients who have taken antidepressants, including venlafaxine. This was reported at treatment initiation, dose modification and treatment discontinuation.
As with other antidepressants, venlafaxine should be used with caution in patients with a history of aggression.
Suspension of treatment
Withdrawal symptoms are common when treatment is discontinued, especially in the event of abrupt discontinuation (see section 4.8). In clinical trials, adverse events observed on discontinuation of treatment (during and after dose reduction) occurred in approximately 31% of patients treated with venlafaxine and in 17% of patients taking placebo.
The risk of withdrawal symptoms may be dependent on several factors, including the duration and dose of therapy and the rate of dose reduction. The most commonly reported reactions are dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and / or vomiting, tremor and headache. Generally these symptoms are mild to moderate; however in some patients they may be severe in intensity. They usually occur within the first few days of stopping treatment, but very rare cases of such symptoms have been reported in patients who have inadvertently missed a dose. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, although in some individuals it may last longer (2-3 months or more). It is therefore recommended to gradually reduce venlafaxine administration when treatment is stopped over a period of several weeks or months, depending on the needs of each patient. (see section 4.2).
Akathisia / psychomotor restlessness
The use of venlafaxine has been associated with the development of akathisia, characterized by a subjectively unpleasant and stressful restlessness and need to move often accompanied by an inability to sit or stand still. It is more likely to occur within the first few weeks of treatment. In patients reporting these symptoms, increasing the dose may be harmful.
Dry mouth
10% of patients treated with venlafaxine report dry mouth. This can lead to an increased risk of caries and patients should be warned of the importance of dental hygiene.
Diabetes
Treatment with an SSRI or venlafaxine can alter blood glucose control in patients with diabetes. The dosage of insulin and / or oral hypoglycemic agents may need to be adjusted.
Interaction with drug laboratory tests
False positive immunological screening tests for phencyclidine (PCP) and amphetamine in urine have been reported in patients taking venlafaxine. This is due to the lack of specificity of the screening tests. False positive test results can be expected. for several days after stopping venlafaxine therapy. Confirmatory tests, such as gas chromatography / mass spectrometry, will distinguish venlafaxine from PCP and amphetamine.
04.5 Interactions with other medicinal products and other forms of interaction
Monoamine oxidase (I-MAO) inhibitors
Irreversible non-selective MAOIs
Venlafaxine should not be used in combination with non-selective irreversible MAOIs. Venlafaxine use should not be initiated for at least 14 days after stopping treatment with an irreversible non-selective MAOI. Venlafaxine treatment should be discontinued for at least 7 days before starting treatment with an irreversible non-selective MAOI (see sections 4.3 and 4.4).
Reversible selective inhibitor of MAO-A (moclobemide)
The combination of venlafaxine with a reversible and selective MAOI, such as moclobemide, is not recommended due to the risk of serotonin syndrome. After treatment with a reversible MAOIs, a withdrawal period of less than 14 can be expected. days before starting venlafaxine treatment. It is recommended to stop taking venlafaxine for at least 7 days before starting treatment with a reversible MAOI (see section 4.4).
Reversible non-selective MAOIs (linezolid)
The antibiotic linezolid is a weak reversible and non-selective MAOI, and should not be prescribed to patients treated with venlafaxine (see section 4.4).
Serious adverse reactions have been reported in patients who had recently discontinued MAOI therapy and started venlafaxine therapy, or had recently discontinued venlafaxine therapy before starting MAOI therapy. These reactions included tremor, myoclonia, diaphoresis, nausea, vomiting, flushing, dizziness and hyperthermia with manifestations resembling neuroleptic malignant syndrome, convulsions and death.
Serotonin syndrome
As with other serotonergic drugs, serotonin syndrome, a potentially life-threatening condition, can occur with venlafaxine, especially with the concomitant use of other drugs that can modulate the serotonergic neurotransmission system (such as triptans, SSRIs, SNRI, lithium, sibutramine, tramadol or "St. John's wort [Hypericum perforatum]), with medicinal products that interfere with the metabolism of serotonin (such as MAOIs eg methylene blue), or with serotonin precursors (such as tryptophan supplements).
If concomitant treatment with venlafaxine and an SSRI, SNRI, or serotonin receptor agonist (triptan) is clinically justified, careful observation of the patient is recommended, especially at the start of treatment and at dose increases. The concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended (see section 4.4).
Medicines that affect the central nervous system (CNS)
The risk of using venlafaxine in combination with other CNS-acting medicinal products has not been systematically evaluated. Therefore, caution should be exercised when venlafaxine is taken in combination with other CNS-acting medicinal products.
Ethanol
Venlafaxine has been shown not to increase the impairment of mental and motor skills caused by ethanol. However, patients should be advised to avoid alcohol consumption while taking venlafaxine, as with all other CNS active medicinal products.
Effects of other medicinal products on venlafaxine
Ketoconazole (CYP3A4 inhibitor)
A pharmacokinetic study with ketoconazole in CYP2D6 strong metabolisers (MI) and poor metabolisers (MP) provided higher AUC results for both venlafaxine (70% and 21% in MP and MI subjects of CYP2D6, respectively) and O-desmethylvenlafaxine (33% and 23% in MP and MI subjects of CYP2D6, respectively) following administration of ketoconazole. Concomitant use of venlafaxine with CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, voriconazole, posaconazole, ketoconazole, nelfinavir, ritonavir, saquinavir, telithromycin) may therefore increase the levels of venlafaxyl-desmethyl and therefore. Caution is advised if patient therapy includes concomitant use of venlafaxine and a CYP3A4 inhibitor.
Effect of venlafaxine on other medicinal products
Lithium
Serotonin syndrome can occur with concomitant use of venlafaxine and lithium (see Serotonin syndrome).
Diazepam
Venlafaxine has no effect on the pharmacokinetics and pharmacodynamics of diazepam and its active metabolite, desmethyldiazepam. Diazepam does not appear to affect the pharmacokinetics of either venlafaxine or its active metabolite O-desmethylvenlafaxine. It is not known whether there is a pharmacokinetic and / or pharmacodynamic interaction with other benzodiazepines.
Imipramine
Venlafaxine did not affect the pharmacokinetics of "imipramine and 2-OH-imipramine. C" was a dose-dependent increase in AUC of 2-OH-desipramine 2.5 to 4.5-fold when venlafaxine was administered. daily in doses of 75 mg to 150 mg. Imipramine did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown. Caution should be exercised when imipramine and venlafaxine are administered concomitantly.
Haloperidol
A pharmacokinetic study with haloperidol showed a 42% decrease in total oral clearance, a 70% increase in AUC, an 88% increase in C but no change in the half-life of haloperidol. This should be taken into consideration in patients treated concomitantly with haloperidol and venlafaxine. The clinical significance of this interaction is unknown.
Risperidone
Venlafaxine increased the AUC of risperidone by 50%, but did not significantly change the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). The clinical significance of this interaction is unknown.
Metoprolol
Concomitant administration of venlafaxine and metoprolol to healthy volunteers in a pharmacokinetic interaction study for both medicinal products resulted in an approximately 30-40% increase in plasma concentrations of metoprolol, with no alteration in plasma concentrations of its active metabolite, l " α-hydroxymethoprolol. The clinical significance of this finding in hypertensive patients is unknown. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine. Co-administration of venlafaxine with metoprolol should be performed. with caution.
Indinavir
A pharmacokinetic study with indinavir showed a 28% reduction in AUC and a 36% reduction in Cmax of indinavir. Indinavir did not alter the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown.
04.6 Pregnancy and lactation
Pregnancy
There are no adequate data on the administration of venlafaxine to pregnant women.
Animal studies have shown reproductive toxicity (see section 5.3). The potential risk to humans is unknown. Venlafaxine should only be administered to pregnant women if the expected benefits outweigh any possible risk.
As with other serotonin reuptake inhibitors (SSRIs / SNRIs), withdrawal symptoms may occur in newborns if venlafaxine is used until birth or shortly before. Some infants exposed to venlafaxine at the end of the third trimester have developed complications that required artificial feeding, respiratory support, or prolonged hospitalization. Such complications can arise immediately upon delivery.
Epidemiological studies have suggested that the use of SSRIs in pregnancy, especially in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although there is no study on the association between PPHN and SNRI treatment, this potential risk cannot be excluded with venlafaxine, given its mechanism of action (inhibition of serotonin reuptake).
The following symptoms may be seen in newborns if mothers have taken an SSRI / SNRI towards term of pregnancy: irritability, tremor, hypotonia, persistent crying, and difficulty in sucking or falling asleep. These symptoms may be due to serotonergic effects or exposure symptoms. In most cases, these complications were observed immediately or within 24 hours after delivery.
Feeding time
Venlafaxine and its active metabolite, O-desmethylvenlafaxine, are excreted in human milk. Cases of breastfed infants who experienced crying, irritability and sleep disturbances were reported in post-marketing observation. Symptoms similar to those seen with discontinuation of venlafaxine were reported upon discontinuation of breastfeeding. a risk to the suckling child can be excluded.Therefore, a choice must be made whether to continue / discontinue breast-feeding or to continue / discontinue Efexor therapy taking into account the benefit of breast-feeding for the child and the benefit of Efexor therapy for the woman.
04.7 Effects on ability to drive and use machines
Any psychoactive medicine can impair judgment, thinking or motor skills. Therefore, patients taking venlafaxine should be advised to use caution when driving and operating hazardous machinery.
04.8 Undesirable effects
The most common (> 1/10) adverse reactions reported in clinical trials were nausea, dry mouth, headache and sweating (including night sweats).
Adverse reactions are listed below by system organ class and frequency.
Frequencies are defined as: very common (≥1 / 10), common (≥1 / 100,
* Cases of suicidal ideation and suicidal behaviors have been reported during venlafaxine therapy or immediately after treatment discontinuation (see section 4.4).
** (see section 4.4)
*** In group clinical trials, the incidence of headache with venlafaxine and placebo were similar.
Discontinuation of venlafaxine treatment (especially when abrupt) commonly results in withdrawal symptoms. The most commonly reported reactions are dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and / or vomiting, tremor, dizziness, headache and flu syndrome. Generally these events are mild to moderate and self-limiting; however in some patients they may be severe and / or prolonged. Therefore it is recommended that patients should be gradually discontinued by taking a progressive dose reduction when venlafaxine treatment is no longer required (see sections 4.2 and 4.4).
Pediatric patients
In general, the adverse reaction profile of venlafaxine (in placebo-controlled clinical trials) in children and adolescents (aged 6-17 years) was similar to that seen in adults. As in adults, decreased appetite, weight loss, increased blood pressure and increased serum cholesterol have been observed (see section 4.4).
Suicidal ideation was observed as an adverse reaction in pediatric clinical trials. There were also increased cases of hostility and, especially in major depressive disorder, self-harm.
In particular, the following adverse reactions have been observed in pediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis and myalgia.
04.9 Overdose
In post-marketing experience, venlafaxine overdose has been reported predominantly in association with alcohol and / or other medicinal products. The most commonly reported events in overdose include tachycardia, changes in consciousness (ranging from somnolence to coma), mydriasis , convulsions and vomiting Other events such as changes in the electrocardiogram (eg QT interval prolongation, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, dizziness and death have been reported.
Published retrospective studies report that venlafaxine overdose may be associated with an increased risk of fatal outcomes compared to the risk reported with SSRI antidepressants, but lower than that reported with tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher number of suicidal risk factors than SSRI-treated patients. The degree to which the increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdose with respect to some characteristics of patients treated with venlafaxine is unclear. In order to reduce the risk of overdose, the minimum amount of medicine that allows for good patient management should be prescribed.
Recommended treatment
General supportive and symptomatic measures are recommended; Heart rhythm and vital signs should be monitored. In case of risk of aspiration, it is not recommended to induce emesis. Gastric lavage may be indicated if performed immediately after ingestion or in symptomatic patients. Administration of activated charcoal may also limit the absorption of the active substance. Forced diuresis, dialysis, haemoperfusion and exchange transfusion are unlikely to be of benefit. There is no known specific antidote for venlafaxine.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: other antidepressants.
ATC code: N06AX16.
The mechanism of venlafaxine's antidepressant activity in humans is believed to be related to its enhancement of neurotransmitter activity in the central nervous system. Preclinical studies have shown that venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV), are serotonin and noradrenaline reuptake inhibitors. Venlafaxine also weakly inhibits dopamine uptake. Venlafaxine and its active metabolite reduce β-adrenergic responsiveness after both acute (single dose) and chronic administration. Venlafaxine and ODV are very similar in their overall action on neurotransmitter uptake and receptor interaction.
Venlafaxine has virtually no affinity in vitro for rat brain muscarinic, cholinergic, H1-histaminergic or α1-adrenergic receptors. Pharmacological activity on these receptors may be associated with various side effects seen with other antidepressant drugs, such as anticholinergic, sedative and cardiovascular side effects.
Venlafaxine does not possess monoamine oxidase (MAO) inhibitory activity.
Education in vitro showed that venlafaxine has virtually no affinity for opiate and benzodiazepine sensitive receptors.
Major depressive episodes
The efficacy of immediate-release venlafaxine as a treatment for major depressive episodes was demonstrated in five randomized, double-blind, placebo-controlled, short-term clinical trials of 4 to 6 weeks duration for doses up to 375. mg / day. The efficacy of prolonged-release venlafaxine as a treatment for major depressive episodes was demonstrated in two placebo-controlled, short-term clinical trials of 8 and 12 weeks duration, which included a dose range of 75 at 225 mg / day.
In a longer-term study, adult patients who had responded to prolonged-release venlafaxine (75, 150, or 225 mg) during an 8-week open study were randomized to continue the same treatment with prolonged-release venlafaxine or placebo. , up to 26 weeks of observation for relapses.
In a second longer-term study, the efficacy of venlafaxine for the prevention of recurrent depressive episodes over a 12-month period was demonstrated in a double-blind placebo-controlled clinical trial with adult patients with recurrent episodes of major depression. who had responded to venlafaxine treatment (100 to 200 mg / day, twice daily) to their last depressive episode.
Generalized anxiety disorder
The efficacy of venlafaxine prolonged-release capsules for the treatment of Generalized Anxiety Disorder (GAD) was demonstrated in two 8-week placebo-controlled, fixed-dose clinical studies (75 to 225 mg / day), a 6-month, placebo-controlled, fixed-dose study (75 to 225 mg / day), and a 6-month placebo-controlled, variable-dose study (37.5, 75, and 150 mg / day). ), with adult patients.
Although superiority over placebo was also proven for the 37.5 mg / day dose, this dose was not as effective as for the higher doses.
Social anxiety disorder
The efficacy of venlafaxine prolonged-release capsules for the treatment of social anxiety disorder was demonstrated in four double-blind, parallel-group, 12-week, multicentre, placebo-controlled variable-dose studies and in one study. double-blind, parallel group, 6-month, placebo-controlled, fixed / variable dose, with adult patients. Patients received doses ranging from 75 to 225 mg / day. No greater efficacy was demonstrated in the 150-225 mg / day group compared to the 75 mg / day group in the 6-month study.
Panic Disorder
The efficacy of venlafaxine prolonged-release capsules for the treatment of panic disorder was demonstrated in two double-blind, 12-week, multicentre, placebo-controlled studies in adult patients with panic disorder, with or without agoraphobia. starting dose in the panic disorder studies was 37.5 mg / day for 7 days. Thereafter, patients received fixed doses of 75 or 150 mg / day in one study, and 75 or 225 mg / day in the other study.
Efficacy was also demonstrated in a long-term, double-blind, placebo-controlled, parallel group study to evaluate the safety, efficacy and long-term prevention of relapse in adult patients responding to open label treatment. . Patients continued to receive the same prolonged-release venlafaxine dose they had taken at the end of the open phase of treatment (75, 150 or 225 mg).
05.2 Pharmacokinetic properties
Venlafaxine is extensively metabolised, mainly to its active metabolite O-desmethylvenlafaxine (ODV). Mean ± SD plasma half-lives of venlafaxine and ODV are 5 ± 2 hours and 11 ± 2 hours, respectively. Steady-state concentrations of venlafaxine and ODV are achieved within 3 days of multiple dose oral therapy. ODVs show linear kinetics for dosages ranging from 75 to 450 mg / day.
Absorption
Following single oral doses of immediate-release venlafaxine, at least 92% of venlafaxine is absorbed. Due to the presystemic metabolism, the absolute bioavailability is between 40% and 45%. Following administration of immediate-release venlafaxine, peak plasma concentrations of venlafaxine and ODV occur within 2 and 3 hours, respectively. After administration of prolonged-release venlafaxine, peak plasma concentrations of venlafaxine and ODV occur within 5.5 and 9 hours, respectively. When administering the same daily doses of venlafaxine in immediate-release tablets or prolonged-release capsules, the prolonged-release capsule results in a slower rate of absorption, but the same extent of absorption compared to the immediate-release tablet. Food does not change the bioavailability of venlafaxine and ODV.
Distribution
At therapeutic concentrations, venlafaxine and ODV are minimally bound to human plasma proteins (27% and 30%, respectively). The steady-state volume of distribution of venlafaxine is 4.4 ± 1.6 L / kg after intravenous administration.
Metabolism
Venlafaxine undergoes significant hepatic metabolism. Education in vitro and in vivo indicate that venlafaxine is biotransformed to its most important active metabolite, ODV, by CYP2D6. Education in vitro and in vivo indicate that venlafaxine is metabolised to a less active secondary metabolite, N-desmethylvenlafaxine, by CYP3A4. Education in vitro and in vivo indicate that venlafaxine is a weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP1A2, CYP2C9, or CYP3A4.
Elimination
Venlafaxine and its metabolites are mainly excreted via the kidneys. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unmodified venlafaxine (5%), as unconjugated ODV (29%), as conjugated ODV (26%), or in the form of other metabolites inactive secondary (27%). The mean ± SD steady-state plasma clearance values for venlafaxine and ODV are 1.3 ± 0.6 L / h / kg and 0.4 ± 0.2 L / h, respectively. / kg.
Particular groups of patients
Age and gender
Subject age and gender did not significantly influence the pharmacokinetics of venlafaxine and ODV.
Strong / weak metabolisers of CYP2D6
Plasma concentrations of venlafaxine are higher in CYP2D6 poor metabolisers compared to strong metabolisers. Since the overall exposure (AUC) of venlafaxine and ODV is similar in weak and strong metabolisers, a different posology is not required for these two groups.
Patients with hepatic insufficiency
In Child-Pugh A (with mild hepatic insufficiency) and Child-Pugh B (with moderate hepatic insufficiency) subjects, the half-lives of venlafaxine and ODV were prolonged compared to normal subjects. Oral clearances of venlafaxine and ODV were both reduced. A large margin of variability between subjects was noted. There are limited data in patients with severe hepatic impairment (see section 4.2).
Patients with renal insufficiency
In patients on dialysis, the elimination half-life of venlafaxine was lengthened by approximately 180% and clearance was reduced by approximately 57% compared to normal subjects, while the elimination half-life of ODV was extended by approximately. 142% and clearance was reduced by approximately 56%. Dosage adjustment is necessary in patients with severe renal insufficiency and in patients requiring hemodialysis (see section 4.2).
05.3 Preclinical safety data
Studies with venlafaxine in rats and mice produced no evidence for carcinogenicity. Venlafaxine was not mutagenic in a broad spectrum of tests in vitro and in vivo.
Reproductive toxicity studies in animals have shown a decrease in pup weight in rats, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation. The cause of these deaths is unknown. These effects occurred at 30 mg / kg / day, which is 4 times the human daily dose of 375 mg venlafaxine (on a mg / kg basis). The no effect dose for these results was 1 , 3 times the dose for humans. The potential risk for humans is unknown.
Reduced fertility was observed in a study in which both male and female rats were exposed to ODV. This exposure was approximately 1 to 2 times the human dose of 375 mg / day of venlafaxine. The relevance of this data for humans is not known.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Venlafaxine 37.5 mg:
Capsule contents:
Microcrystalline cellulose
Ethylcellulose
Hypromellose
Talc
Capsule shell:
Jelly
Black, red and yellow iron oxides (E172)
Titanium dioxide (E171)
Capsule printing ink:
Lacquer
Red iron oxide (E172)
Ammonium hydroxide
Simethicone
Propylene glycol
Venlafaxine 75 mg:
Capsule contents:
Microcrystalline cellulose
Ethylcellulose
Hypromellose
Talc
Capsule shell:
Jelly
Red and yellow iron oxides (E172)
Titanium dioxide (E171)
Capsule printing ink:
Lacquer
Red iron oxide (E172)
Ammonium hydroxide
Simethicone
Propylene glycol
Venlafaxine 150 mg:
Capsule contents:
Microcrystalline cellulose
Ethylcellulose
Hypromellose
Talc
Capsule shell:
Jelly
Red and yellow iron oxides (E172)
Titanium dioxide (E171)
Capsule printing ink:
Lacquer
Propylene glycol
Sodium hydroxide
Povidone
Titanium dioxide (E171)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years
06.4 Special precautions for storage
Do not store above 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
Venlafaxine 37.5 mg:
Clear or opaque PVC / Aluminum or PVC / Aclar / Aluminum blisters in packs containing 7, 10, 14, 20, 21, 28, 30, 35, 50, 60, 84, 100 capsules; hospital packs containing 70 capsules (10x7 or 1x70)
PVC / Aluminum blisters in packs containing unit doses of 14, 28, 84, 100 capsules
High density polyethylene (HDPE) bottles containing 7, 14, 20, 21, 35, 50, 100 capsules; hospital bottles containing 70 capsules.
Venlafaxine 75 mg:
Clear or opaque PVC / Aluminum or PVC / Aclar / Aluminum blisters in packs containing 7, 10, 14, 15, 20, 28, 30, 50, 56, 60, 98, 100 capsules; hospital packs containing 500 (10x50) or 1000 capsules (10x100)
PVC / Aluminum blisters in packs containing unit doses of 14, 28, 84, 100 capsules
High density polyethylene (HDPE) bottles containing 14, 20, 50, 100 capsules; hospital bottles containing 500 or 1000 capsules.
Venlafaxine 150 mg:
Clear or opaque PVC / Aluminum or PVC / Aclar / Aluminum blisters in packs containing 7, 10, 14, 15, 20, 28, 30, 50, 56, 60, 98, 100 capsules; hospital packs containing 500 (10x50) or 1000 capsules (10x100)
PVC / Aluminum blisters in packs containing unit doses of 14, 28, 84, 100 capsules
High density polyethylene (HDPE) bottles containing 14, 20, 50, 100 capsules; hospital bottles containing 500 or 1000 capsules.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Pfizer Italia S.r.l.
Via Isonzo, 71 - 04100 Latina
08.0 MARKETING AUTHORIZATION NUMBER
Efexor 37.5 mg prolonged-release hard capsules: 7 hard capsules AIC n. 028831131
Efexor 37.5 mg prolonged-release hard capsules: 14 hard capsules AIC n. 028831117
Efexor 37.5 mg prolonged-release hard capsules: 28 hard capsules AIC n. 028831129
Efexor 75 mg prolonged-release hard capsules: 14 hard capsules AIC n. 028831055
Efexor 75 mg prolonged-release hard capsules: 28 hard capsules AIC n. 028831093
Efexor 150 mg prolonged-release hard capsules: 10 hard capsules AIC n. 028831067
Efexor 150 mg prolonged-release hard capsules: 28 hard capsules AIC n. 028831105
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 19 June 1998
Date of last renewal: 20 October 2009
10.0 DATE OF REVISION OF THE TEXT
2 April 2013
