Zarelis - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Venlafaxine

Zarelis 37.5 mg Prolonged-release tablet
Zarelis 75 mg Prolonged-release tablet
Zarelis 150 mg Prolonged-release tablet
Zarelis 225 mg Prolonged-release tablet

Why is Zarelis used? What is it for?

Zarelis 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. Zarelis is a treatment for adults with depression.

Zarelis is also a treatment for adults with the following anxiety disorders: social anxiety disorder (fear of or avoidance of social situations). Appropriate treatment for depression or anxiety disorders is important to help you get better. If left untreated, your condition may not go away and may become more severe and more difficult to treat.

The venlafaxine contained in Zarelis is also authorized to treat other conditions not mentioned in this leaflet. Ask your doctor or pharmacist if you have any further questions.

Contraindications When Zarelis should not be used

Do not take Zarelis

  • if you are allergic to venlafaxine or any of the other ingredients of this medicine (listed in section 6).
  • if you are taking any of the medicines known as irreversible monoamine oxidase inhibitors (MAOIs), used to treat depression or Parkinson's disease, at any time or at any time within the last 14 days. of an irreversible MAOI together with Zarelis, can have serious or even life-threatening side effects. In addition, you must wait at least 7 days after stopping treatment with Zarelis before taking any irreversible MAOIs (see also the section entitled "Taking Zarelis with other medicines" and the information in that section relating to "Serotonin syndrome ").

Precautions for use What you need to know before taking Zarelis

Talk to your doctor before taking Zarelis.

  • If you use other medicines which, taken at the same time as Zarelis, may increase the risk of developing serotonin syndrome (see section "Taking Zarelis with other medicines").
  • If you have bloating, upset stomach or intestines which impair your ability to swallow or the passage of food in the gastrointestinal tract
  • 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 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 a tendency to bleed easily (bleeding disorders), or if you are using other medicines which may increase the risk of bleeding e.g. warfarin (used to prevent thrombosis)
  • If your cholesterol levels rise
  • If you have a history or someone in your family has suffered from mania or bipolar disorder (feeling over-excited or euphoric)
  • If you have a history of aggressive behavior.

Zarelis may cause a feeling of restlessness or an inability to sit or stand still during the first few weeks of treatment. If you have these symptoms, you should tell your doctor.

If you have any of these conditions, talk to your doctor before using Zarelis.

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 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 at any time you have thoughts of harming or killing yourself, 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 you think your depression or state d "anxiety is getting worse, or if you are worried about changes in your behavior.

Dry mouth

Dry mouth occurs in 10% of patients treated with venlafaxine. This can increase the risk of tooth decay. You must therefore pay particular attention to your oral hygiene.

Diabetes

If you have diabetes or a disease related to sugar (glucose) intake, which requires the administration of insulin or other drugs that lower blood sugar, the dosage of these drugs may need to be adjusted.

Use in children and adolescents under the age of 18

Zarelis should normally not be used for children and adolescents under the age of 18. In addition, 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 these types 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 Zarelis. Furthermore, the long-term effects of this medicine on growth, maturation and mental and behavioral development in this age group have not been demonstrated.

Interactions Which drugs or foods may change the effect of Zarelis

Other medicines and Zarelis

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, or might take any other medicines.

Your doctor will decide whether you can use Zarelis with other medicines.

Do not start or stop treatment with other medicines, including medicines obtained without a prescription and natural or 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 Zarelis. Tell your doctor if you have taken these medicines in the last 14 days (MAOIs: see "Before you take Zarelis").
  • Serotonin Syndrome: Serotonin Syndrome, a potentially life-threatening condition or Neuroleptic Malignant Syndrome type reactions (see "Possible Side Effects" section) may occur with venlafaxine treatment, especially when taken with other medicines. Examples of these medicines are:
  • Triptans (used for migraines)
  • Medicines to treat depression, for example serotonin and norepinephrine reuptake inhibitors (SNRIs, SSRIs), tricyclic antidepressants, or medicines containing lithium
  • Medicines containing linezolid, an antibiotic (used to treat infections)
  • Medicines containing moclobemide, a reversible MAOI (used to treat depression)
  • Medicines containing sibutramine (used for weight loss)
  • Medicines containing tramadol (a pain reliever)
  • 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 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 symptoms such as hearing, seeing or sensing things that are not there, having misconceptions, abnormal distrust, unusual suspiciousness or confused reasoning, or becoming estranged)

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 can manifest itself as neuroleptic malignant syndrome (NMS). Signs and symptoms of NMS may include fever, rapid heart rate, sweating, severe muscle stiffness, confusion, and increased muscle enzymes (assessed by a blood test). Tell your doctor immediately, or go to the nearest hospital emergency room if you think you have serotonin syndrome.

The medicines listed below may also interfere with Zarelis 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, itraconazole, voriconazole, posaconazole (antifungal medicines)
  • clarithromycin, telithromycin (antibiotics used to treat infections)
  • atazanavir, indinavir, nelfinavir, ritonavir, saquinavir (used in the treatment of HIV infections)
  • haloperidol or risperidone (to treat psychiatric disorders)
  • metoprolol (a beta blocker to treat high blood pressure and heart problems).

Zarelis with food, drink and alcohol

You must take Zarelis with food (see section "How to take Zarelis"). You should not drink alcohol while you are taking Zarelis.

Warnings It is important to know that:

Pregnancy, breastfeeding and fertility

Tell your doctor if you find that you are pregnant, or if you are trying to become pregnant. You should only use Zarelis 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 Zarelis. When taken during pregnancy, SSRIs may increase the risk of a serious condition in babies, called persistent pulmonary hypertension of the newborn (PPHN), which causes the baby to "accelerate breathing and a bluish color. they usually occur 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.

If you are using Zarelis during pregnancy, tell your midwife and / or doctor as your baby may have some symptoms at birth. These symptoms usually start during the first 24 hours after birth.

These symptoms include irritability, tremor, hypotonia, constant crying, difficulty sleeping and feeding. If your baby has these symptoms at birth and you are unsure, contact your doctor and / or midwife who will be able to assist you.

Zarelis is excreted in breast milk. There is a risk of drug effects on the breastfed baby, which can cause crying, irritability and sleep disturbances. Drug withdrawal symptoms have been observed in infants after breastfeeding is discontinued. 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 effect Zarelis has on you. Important information about some of the ingredients of Zarelis This medicinal product contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, please inform him before taking Zarelis.

Dosage and method of use How to use Zarelis: Dosage

Always take this medicine exactly as your doctor has told you. If you are unsure, you should consult your doctor or pharmacist.

The usual recommended starting dose for the treatment of depression 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. The maximum dose for social anxiety disorder is 225 mg per day.

Take Zarelis at about the same time each day, in the morning or in the evening. The tablets must be swallowed whole with liquid and must not be opened, broken, chewed or dissolved. You must take Zarelis with food.

If you have liver or kidney problems, talk to your doctor, as your dose of Zarelis may need to be adjusted.

Do not stop taking Zarelis without consulting your doctor (see section "If you stop taking Zarelis").

Overdose What to do if you have taken too much Zarelis

If you take more Zarelis than you should

Contact your doctor or pharmacist immediately if you take more than the amount of this medicine that your doctor has prescribed for you.

Symptoms of a possible overdose may include rapid heart rate, changes in consciousness (ranging from sleepiness to coma), blurred vision, seizures and vomiting.

If you forget to take Zarelis

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 amount of Zarelis that has been prescribed for you in a single day.

If you stop taking Zarelis

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 Zarelis, he may ask you to reduce the dose gradually before stopping treatment completely. Side effects are known to occur when patients stop Zarelis treatment, especially when Zarelis is stopped abruptly or when the dose is reduced too quickly. Some patients may have symptoms such as tiredness, dizziness, confusion of mind, headache, insomnia, feeling that the surroundings are spinning around you (dizziness), nightmares, dry mouth, loss of appetite, nausea, diarrhea, nervousness, agitation, confusion, tinnitus (ringing in the ears), tingling or rarely feelings of electric shock, weakness, sweating, seizures or flu-like symptoms.

Your doctor will advise you on how you should gradually discontinue treatment with Zarelis. 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 Zarelis

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Do not worry if you notice a tablet in your stool after taking Zarelis. Venlafaxine is released slowly from the tablet as it travels the entire length of your gastrointestinal tract. The coating of the tablet does not dissolve, and is excreted in the faeces. Therefore, even if you notice a tablet in your faeces, the dose of venlafaxine was absorbed.

If any of the following happen, do not take more Zarelis. 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 red or pale patches of skin that often itch).
  • Signs and symptoms of serotonin syndrome which may include restlessness, 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 can manifest as Neuroleptic Malignant Syndrome (NMS). Signs and symptoms of NMS can include fever, rapid heart rate, sweating, severe muscle stiffness, confusion, and increased muscle enzymes (assessed by a blood test). Other side effects you should tell your doctor about include:

  • Cough, wheezing, shortness of breath and fever
  • Black (tarry) stools or blood in stools
  • Yellow skin or eyes, itchy, 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
  • Nervous problems such as dizziness, tingling, movement disorders, convulsions.
  • Psychiatric problems, such as hyperactivity and euphoria (feeling unusually overexcited)
  • Withdrawal symptoms (see section "How to take Zarelis, if you stop taking Zarelis")
  • Prolonged bleeding - if you cut or injure yourself, it may take longer than usual for the bleeding to stop.

Full list of side effects

Very common (may affect more than 1 in 10 people)

  • Dizziness; headache
  • Nausea; dry mouth
  • Sweating (including night sweats)

Common (may affect up to 1 in 10 people)

  • Decreased appetite
  • Confusion; feeling separate (or detached) 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 focus on objects, from far to near
  • Ringing in the ears (tinnitus)
  • Palpitations
  • Increased blood pressure hot flashes
  • Yawns
  • He retched; constipation; diarrhea
  • Increased frequency of urge to urinate difficulty urinating
  • Menstrual irregularities such as increased bleeding, or increased irregular bleeding; abnormal
  • Abnormal ejaculation / orgasm (in males) erectile dysfunction (impotence)
  • Weakness (asthenia); fatigue; chills
  • Increased cholesterol

Uncommon (may affect up to 1 in 100 people)

  • Hallucinations; sense of estrangement from reality; agitation; abnormal orgasm (in females); absence of sensations or emotions; feeling of over-arousal; teeth grinding
  • Feeling restless or unable to sit or stand still; fainting; involuntary movements of the muscles; alteration of coordination and balance, alteration of taste
  • Acceleration of the heartbeat; feeling dizzy (especially when standing up too quickly)
  • Vomiting blood, black tarry stools or blood in the stool, which may be a symptom of "intestinal bleeding
  • There may be generalized swelling of the skin particularly of the face, mouth, tongue, throat and / or hands and feet, itchy rash (hives); sensitivity to sunlight; bruising; skin rashes; abnormal hair loss
  • Inability to urinate
  • Weight gain weight loss

Rare (may affect up to 1 in 1,000 people)

  • Convulsions or seizures
  • Urinary incontinence
  • Hyperactivity, runaway thoughts and reduced need for sleep (mania)

Not known (frequency cannot be estimated from the available data)

  • Reduction in blood platelets, which leads to an increased risk of bruising or bleeding; haematological changes which can lead to an increased risk of infection
  • Swelling of the face or tongue, shortness of breath or difficulty in breathing, often with skin rashes (severe 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 venlafaxine therapy or soon after treatment discontinuation (see section 2, Before taking Zarelis)
  • Disorientation and confusion often accompanied by hallucinations (delirium); aggression
  • High fever with muscle stiffness, confusion or agitation and sweating; if you experience spasmodic movements of your 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, for example bleeding from the gums, blood in the urine or vomit, or unexpected bruising or ruptured blood vessels (couperose)
  • Cough, wheezing, shortness of breath and fever, 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 and eyes, dark urine, or flu-like symptoms, which are symptoms of inflammation of the liver (hepatitis); small changes in blood levels of liver enzymes
  • Skin rash, which may lead to blistering and peeling of the skin itch; mild rash
  • Unexplained muscle pain, stiffness or weakness (rhabdomyolysis)
  • Abnormal breast milk secretion

Sometimes Zarelis causes side effects that you may not notice, such as increases in blood pressure or an abnormal heart beat; slight changes in blood levels of liver enzymes, sodium or cholesterol. More rarely, Zarelis can reduce the function of the platelets in your blood, leading to an increased risk of bruising and bleeding. Therefore, on certain occasions your doctor may wish to have your blood checked, particularly if you have been taking Zarelis for a long time.

If you get any side effects, please tell your doctor or pharmacist. This includes any side effects not listed in this leaflet.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the package. The expiry date refers to the last day of the month. Store at temperatures below 30ºC.

Blisters: Store in the original package to protect from moisture.

Plastic bottle: Keep the bottle tightly closed to protect the medicine from moisture.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Composition and pharmaceutical form

What Zarelis contains

The active ingredient is venlafaxine.

Each Zarelis 37.5, 75, 150 or 225 mg prolonged-release tablet contains venlafaxine hydrochloride corresponding to 37.5 mg, 75 mg, 150 mg or 225 mg of venlafaxine.

The other ingredients are:

Tablet core: Mannitol (E421), Povidone K-90, Macrogol 400, Microcrystalline cellulose, Silica, colloidal anhydrous, Magnesium stearate. Tablet coating: Cellulose acetate, Macrogol 400, Opadry Y 30 18037 (mixture of hypromellose, lactose monohydrate, titanium dioxide (E171) and triacetin).

What Zarelis looks like and contents of the pack

37.5 mg prolonged-release tablets: round, biconvex, white tablets with a diameter of 7 mm

75 mg prolonged-release tablets: round, biconvex, white tablets with a diameter of 7.5 mm

150 mg prolonged-release tablets: round, biconvex, white tablets with a diameter of 9.5 mm

225 mg prolonged-release tablets: round, biconvex, white tablets with a diameter of 11 mm

Zarelis is available in blister packs of 10, 14, 20, 28, 30, 50, 56, 60, 100 and 500 tablets; and in plastic bottles of 10, 14, 20, 28, 30, 50, 56, 60, 100 and 500 tablets.

Not all pack sizes may be marketed

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.

Further information on Zarelis can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the primary packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER CIO 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

ZARELIS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Zarelis 37.5 mg prolonged-release tablets

One prolonged-release tablet contains 37.5 mg of venlafaxine (as hydrochloride)

Zarelis 75 mg prolonged-release tablets

One prolonged-release tablet contains 75 mg of venlafaxine (as hydrochloride)

Zarelis 150 mg prolonged-release tablets

One prolonged-release tablet contains 150 mg of venlafaxine (as hydrochloride)

Zarelis 225 mg prolonged-release tablets

One prolonged-release tablet contains 225 mg of venlafaxine (as hydrochloride)

Excipient with known effect: lactose 3.0 / 3.4 / 5.7 / 6.5 mg

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Prolonged-release tablets

37.5 mg prolonged-release tablets: round, biconvex, white tablets with a diameter of 7 mm

75 mg prolonged-release tablets: round, biconvex, white tablets with a diameter of 7.5 mm

150 mg prolonged-release tablets: round, biconvex, white tablets with a diameter of 9.5 mm

225 mg prolonged-release tablets: round, biconvex, white tablets with a diameter of 11 mm

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Treatment of major depressive episodes.

Prevention of recurrence of major depressive episodes.

Treatment of social anxiety disorder.

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 the severity of the symptoms so requires, dose increases can 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 may also be appropriate for the prevention of recurrence of major depressive episodes (MDE). In most cases, the recommended dose for preventing recurrence of MDE is the same as that used during the episode itself.

Treatment with antidepressant medicinal products should last for at least 6 months following disease remission.

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.

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). to 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 when treating patients with severe hepatic insufficiency; A dose reduction of more than 50% should be considered, and the potential benefits should be weighed against the risks.

Use in patients with renal insufficiency

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). or following discontinuation of treatment unbearable symptoms occur, 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 tablets be taken with food, at about the same time each day. The tablets should be swallowed whole with liquid and should not be divided, broken, chewed or dissolved.

Patients on venlafaxine immediate-release tablets may be switched to venlafaxine prolonged-release tablets 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 tablets once daily. Individual dosage adjustment may be required.

The prolonged-release tablets release the active ingredient into the digestive tract, maintaining the external form of the tablet which is eliminated unchanged in the faeces.

04.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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. Additionally, 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 of 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

Zarelis should not be used for the treatment of children and adolescents under 18 years of age.

Suicide-related behaviors (suicide attempts and suicidal ideation) 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 venlafaxine, as with other serotonergic drugs, a potentially life-threatening serotonin syndrome called Neuroleptic Malignant Syndrome (NMS) may develop, particularly with concomitant use of other serotonergic drugs (including SSRIs, SNRIs and triptans), or with drugs that inhibit the metabolism of serotonin, 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, blood pressure changes, hyperthermia), neuromuscular disorders (e.g., hyperreflexia, incoordination) and / or symptoms gastrointestinal (e.g. nausea, vomiting, diarrhea).

Serotonin syndrome in its most severe form may resemble the symptoms of NMS, which includes hyperthermia, muscle stiffness, autonomic instability with possible rapid changes in vital signs and mental status.

If treatment with venlafaxine in combination with other drugs that can affect the serotonergic and / or dopaminergic systems is clinically warranted, careful observation of the patient is recommended, particularly at the initiation of treatment and at dose increases.

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 narrow-angle glaucoma (narrow-angle glaucoma).

Blood pressure

Dose-dependent increases in blood pressure have been commonly reported with the use of venlafaxine. Serious cases of arterial hypertension requiring immediate treatment have been reported in post-marketing experience.

All patients should be carefully monitored for pre-existence of arterial hypertension 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 patients 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 history of recent 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. In patients taking venlafaxine, the risk of skin and mucosal bleeding, including gastrointestinal haemorrhage, may be increased. 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

In placebo-controlled clinical trials, clinically significant elevations in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients after treatment for at least three months. Measurement of serum cholesterol levels should be considered during prolonged treatment.

Co-administration with drugs indicated for weight loss

The safety and efficacy of venlafaxine therapy in combination with drugs indicated for weight loss, including phentermine, have not been demonstrated. Co-administration of venlafaxine and drugs indicated for weight loss is not recommended. Venlafaxine is not recommended. it is not indicated for weight loss either alone or 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 studies, adverse events observed upon discontinuation of treatment (during the dose reduction phase and after the end of treatment) 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 advisable to gradually reduce the administration of venlafaxine, stopping the treatment 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:

In diabetic patients, treatment with an SSRI or venlafaxine can impair glycemic control. The dosage of insulin and / or oral hypoglycaemics may need to be adjusted.

Risks of gastrointestinal obstruction

As the Zarelis prolonged-release tablet is not deformable and does not undergo substantial changes in shape in the gastrointestinal tract, it should not commonly be administered to patients with pre-existing severe gastrointestinal stenosis (pathological or iatrogenic) or to patients with dysphagia or who have significant difficulty in swallowing tablets.

There have been rare reports of obstructive symptoms associated with taking the drug in the non-deformable prolonged-release formulations in patients with pre-existing severe gastrointestinal tract stenosis.

Zarelis prolonged-release tablets, due to its prolonged-release technique, should only be administered to patients who are able to swallow the tablet whole (see section 4.2).

Zarelis prolonged-release tablets contain lactose.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, and glucose / galactose malabsorption syndrome should not take this medicine.

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 stopped 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 washout period of at least 14 days before starting venlafaxine treatment. It is recommended to stop taking venlafaxine 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, SNRIs). , lithium, sibutramine, tramadol or "St. John's wort [Hypericum perforatum]), with medicines that interfere with the metabolism of serotonin (such as MAOIs, e.g. methylene blue), or with serotonin precursors (such as tryptophan supplements). If concomitant treatment of venlafaxine and an SSRI, SNRI, or serotonin receptor agonist (triptan) is required, careful observation of the patient is recommended, especially at the start of treatment and at dose increases. The concomitant use of venlafaxine and 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 recommended if patient therapy includes concomitant use of venlafaxine and a CYP3A4 inhibitor.

Effect of venlafaxine on other medicinal products

Lithium

Serotonin syndrome may 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 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 does not affect the pharmacokinetics of imipramine and 2-OH-imipramine. A dose-dependent increase in AUC of 2-OH-desipramine of 2.5 to 4.5-fold was observed when venlafaxine was administered in single doses. 75 mg to 150 mg / day. Imipramine did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown. Caution should be exercised when concomitantly administered imipramine and venlafaxine.

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 overall pharmacokinetic profile of the active molecules (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 C 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 breastfeeding

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 data have suggested that the use of SSRIs during pregnancy, particularly towards term of pregnancy, may increase the risk of persistent pulmonary hypertension of the newborn (PPHN).

Although no studies have investigated the relationship between the use of SSRIs and persistent pulmonary hypertension of the newborn (PPHN), the potential risk with Zarelis cannot be excluded, given the 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.

There have been post-marketing reports of breastfed infants who experienced crying, irritability and sleep disturbances. Drug withdrawal symptoms have been observed in infants after breastfeeding is discontinued. A risk to the suckling child cannot be excluded. Therefore, a choice must be made whether to continue / discontinue breast-feeding or to continue / discontinue Zarelis therapy taking into account the benefit of breast-feeding for the child and the benefit of Zarelis 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 and

Body system Very common common Uncommon Rare Frequency not known Disorders of the blood and lymphatic system Thrombocytopenia and other blood dyscrasias, including agranulocytosis, aplastic anemia, neutropenia and pancytopenia. Disorders of the immune system Anaphylactic reaction Endocrine pathologies Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) Metabolism and nutrition disorders Decreased appetite Hyponatremia Psychiatric disorders Confusional state, depersonalization, anorgasmia, decreased libido, nervousness, insomnia, abnormal dreams Hallucination, derealization, agitation, abnormal orgasm (female), apathy, hypomania, bruxism Mania Suicidal ideation and suicidal behavior *, delirium, aggression ** Nervous system disorders Dizziness, migraine *** Somnolence, tremor, paraesthesia, hypertonia Akathisia / psychomotor restlessness, syncope, myoclonus, coordination disturbances, balance problems, dysgeusia Convulsions Neuroleptic malignant syndrome (NMS), serotonin syndrome, extrapyramidal disorders including dystonia and dyskinesia, tardive dyskinesia Eye disorders Visual changes, including blurred vision, mydriasis, accommodation disturbances Closed-angle glaucoma Ear and labyrinth disorders Tinnitus Vertigo Cardiac pathologies Palpitations Tachycardia Ventricular fibrillation, ventricular tachycardia (including Torsade de Pointes) Vascular pathologies Hypertension, vasodilation (mainly flushing) Orthostatic hypotension Hypotension, bleeding (bleeding of the mucous membranes) Respiratory, thoracic and mediastinal disorders Yawns Pulmonary eosinophilia Gastrointestinal disorders Nausea, dry mouth Vomiting, diarrhea, constipation Gastrointestinal bleeding Pancreatitis Hepatobiliary disorders Hepatitis, abnormal liver function tests Skin and subcutaneous tissue disorders Hyperhidrosis (including night sweats) Angioedema, photosensitivity reactions, ecchymosis, rash, alopecia Stevens Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, pruritus, urticaria Musculoskeletal and connective tissue disorders Rhabdomyolysis Renal and urinary disorders Dysuria (mainly, difficulty starting urination), pollakiuria Urinary retention Urinary incontinence Diseases of the reproductive system and breast Menstrual changes associated with increased bleeding or irregular discharge (eg menorrhagia, metrorrhagia), ejaculation disorders, erectile dysfunction General disorders and administration site conditions Asthenia, fatigue, chills Diagnostic tests Increased cholesterol in the blood Weight gain, weight decrease Prolonged QT on electrocardiogram, prolonged bleeding time, increased prolactinaemia

* 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 the overall analysis of clinical trial results, the incidence of headache with venlafaxine and placebo was 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 to gradually stop taking the drug, with 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 observed 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, arterial hypertension 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.

The following adverse reactions were particularly 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, induction of emesis is not recommended. 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 thought to be related to its ability to enhance 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 beta-adrenergic responsiveness after both acute (single dose) and chronic administration. Regarding their overall action on neurotransmitter uptake and interaction with receptors, venlafaxine and ODV are very similar to each other.

Venlafaxine has virtually no affinity in vitro for rat brain muscarinic, cholinergic, H1-histaminergic or alpha1-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 receptors and benzodiazepines.

Major depressive episodes

The efficacy of immediate-release venlafaxine in the treatment of major depressive episodes was demonstrated in five randomized, short-term, double-blind, placebo-controlled clinical trials of 4 to 6 weeks duration for doses up to 375 mg / The efficacy of prolonged-release venlafaxine in the treatment of major depressive episodes was demonstrated in two short-term placebo-controlled clinical trials of 8 and 12 weeks duration evaluating doses ranging from 75 to 225 mg / day. .

A longer-term study evaluated relapse in adult outpatients who responded to open-label prolonged-release venlafaxine (75, 150, or 225 mg / day) for 8 weeks. Patients were randomized to continue treatment with prolonged-release venlafaxine at the same dose, or with placebo, for up to 26 weeks.

A second long-term double-blind placebo-controlled study conducted over a period of 12 months in adult patients with recurrent episodes of major depression who had responded to venlafaxine treatment (100 to 200 mg / day, twice daily) at their last depressive episode demonstrated the efficacy of venlafaxine for the prevention of recurrent depressive episodes.

Generalized anxiety disorder

The efficacy of venlafaxine prolonged-release tablets for the treatment of Generalized Anxiety Disorder (GAD) was demonstrated in two 8-week fixed-dose placebo-controlled clinical trials (from 75 at 225 mg / day), a 6-month fixed-dose placebo-controlled clinical study (75 to 225 mg / day), and a 6-month variable-dose placebo-controlled study (37.5, 75 and 150 mg / day).

Although the 37.5 mg / day dose was also higher than placebo, this dose was not adequately effective when compared with the higher doses.

Social anxiety disorder

The efficacy of venlafaxine prolonged-release tablets for the treatment of social anxiety disorder was demonstrated in four multicentre, double-blind, placebo-controlled, parallel-group, 12-week, variable-dose studies and in a 6-month, double-blind, parallel-group, placebo-controlled, fixed / variable dose study conducted in adult outpatients. Patients received doses ranging from 75 to 225 mg / day. In the 6-month study, no greater efficacy was demonstrated in the 150-225 mg / day group compared to the 75 mg / day group.

Panic Disorder

The efficacy of venlafaxine prolonged-release tablets for the treatment of panic disorder was demonstrated in two 12-week double-blind placebo-controlled multicenter studies in adult outpatients with panic disorder, with or without agoraphobia. The starting dose was 37.5 mg / day for 7 days, followed by 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 double-blind, placebo-controlled, parallel-group study to evaluate long-term tolerability, efficacy and prevention of relapse in adult patients responding to open label treatment. Patients continued to receive the same prolonged-release venlafaxine dose they were taking at the end of the open phase of treatment (75, 150 or 225 mg).

05.2 Pharmacokinetic properties

Venlafaxine is extensively metabolised primarily 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. Venlafaxine el "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 hepatic first pass effect, the absolute bioavailability is between 40% and 45%. After 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. released from the prolonged-release tablet is absorbed more slowly, but at the same rate as 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 after intravenous administration is 4.4 ± 1.6 L / kg.

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. 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 does not inhibit CYP1A2, CYP2C9, or CYP3A4.

Excretion

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%). Steady state (M ± SD) plasma clearance values ​​for venlafaxine and ODV are 1.3 ± 0.6 L / h / kg and 0.4 ± 0.2 L / h / kg.

Particular groups of patients

Age and gender

Age and gender do 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 subjects with mild or moderate hepatic impairment (Child-Pugh Classes A and B), the half-lives of venlafaxine and ODV are prolonged compared to normal subjects. Clearances of oral 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 dialysis patients, the elimination half-life of venlafaxine is prolonged by approximately 180% and clearance is reduced by approximately 57% compared to normal subjects, while the elimination half-life of ODV is prolonged by approximately 142. % and clearance is reduced by approximately 56%.

Dosage adjustment is required in patients with severe renal impairment and in hemodialysis patients (see section 4.2).

05.3 Preclinical safety data

Studies with venlafaxine in rats and mice produced no evidence for carcinogenesis.

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 a dose of 30 mg / kg / day, which corresponds to 4 times the human daily dose of 375 mg. The dose without these effects in the rat was 1.3 times the dose per l ". man. 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 corresponded to 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

Core of the tablet:

Mannitol (E421)

Povidone K-90

Macrogol 400

Microcrystalline cellulose

Anhydrous colloidal silica

Magnesium stearate

Coating:

Cellulose acetate

Macrogol 400

Opadry Y 30 18037 (mixture of hypromellose, lactose monohydrate, titanium dioxide (E172) and triacetin)

06.2 Incompatibility

Not relevant.

06.3 Period of validity

3 years.

06.4 Special precautions for storage

PVC-Polychlorotrifluoroethylene / Aluminum blisters: Store below 30 ° C. Store in the original package to protect from moisture.

HDPE bottle: Store below 30 ° C. Keep the bottle tightly closed to protect the contents from moisture.

06.5 Nature of the immediate packaging and contents of the package

PVC-Polychlorotrifluoroethylene / Aluminum blisters: Pack sizes: Prolonged-release tablets of 10, 14, 20, 28, 30, 50, 56, 60, 100 and 500 (for hospital use only).

HDPE bottle with desiccant silica gel contained in the cap: Pack sizes: Prolonged-release tablets of 10, 14, 20, 28, 30, 50, 56, 60, 100 and 500 (for hospital use only).

Not all pack sizes may be marketed.

06.6 Instructions for use and handling

No special instructions for disposal.

07.0 MARKETING AUTHORIZATION HOLDER

Viale F. Testi, 330

20126 Milan

Italy

08.0 MARKETING AUTHORIZATION NUMBER

PVC-Polychlorotrifluoroethylene / Aluminum blisters

37.5 mg prolonged-release tablets 10 tablets AIC 038316612 / M

37.5 mg prolonged-release tablets 14 tablets AIC 038316624 / M

37.5 mg prolonged-release tablets 20 tablets AIC 038316636 / M

37.5 mg prolonged-release tablets 28 tablets AIC 038316648 / M

37.5 mg prolonged-release tablets 30 tablets AIC 038316651 / M

37.5 mg prolonged-release tablets 50 tablets AIC 038316663 / M

37.5 mg prolonged-release tablets 56 tablets AIC 038316675 / M

37.5 mg prolonged-release tablets 60 tablets AIC 038316687 / M

37.5 mg prolonged-release tablets 100 tablets AIC 038316699 / M

37.5 mg prolonged-release tablets 500 tablets AIC 038316701 / M (hospital pack)

HDPE bottle

37.5 mg prolonged-release tablets 10 tablets AIC 038316713 / M

37.5 mg prolonged-release tablets 14 tablets AIC 038316725 / M

37.5 mg prolonged-release tablets 20 tablets AIC 038316737 / M

37.5 mg prolonged-release tablets 28 tablets AIC 038316749 / M

37.5 mg prolonged-release tablets 30 tablets AIC 038316752 / M

37.5 mg prolonged-release tablets 50 tablets AIC 038316764 / M

37.5 mg prolonged-release tablets 56 tablets AIC 038316776 / M

37.5 mg prolonged-release tablets 60 tablets AIC 038316788 / M

37.5 mg prolonged-release tablets 100 tablets AIC 038316790 / M

37.5 mg prolonged-release tablets 500 tablets AIC 038316802 / M (hospital pack)

PVC-Polychlorotrifluoroethylene / Aluminum blisters

75 mg prolonged-release tablets 10 tablets AIC 038316016 / M

75 mg prolonged-release tablets 14 tablets AIC 038316028 / M

75 mg prolonged-release tablets 20 tablets AIC 038316030 / M

75 mg prolonged-release tablets 28 tablets AIC 038316042 / M

75 mg prolonged-release tablets 30 tablets AIC 038316055 / M

75 mg prolonged-release tablets 50 tablets AIC 038316067 / M

75 mg prolonged-release tablets 56 tablets AIC 038316079 / M

75 mg prolonged-release tablets 60 tablets AIC 038316081 / M

75 mg prolonged-release tablets 100 tablets AIC 038316093 / M

75 mg prolonged-release tablets 500 tablets AIC 038316105 / M (hospital pack)

HDPE bottle

75 mg prolonged-release tablets 10 tablets AIC 038316117 / M

75 mg prolonged-release tablets 14 tablets AIC 038316129 / M

75 mg prolonged-release tablets 20 tablets AIC 038316131 / M

75 mg prolonged-release tablets 28 tablets AIC 038316143 / M

75 mg prolonged-release tablets 30 tablets AIC 038316156 / M

75 mg prolonged-release tablets 50 tablets AIC 038316168 / M

75 mg prolonged-release tablets 56 tablets AIC 038316170 / M

75 mg prolonged-release tablets 60 tablets AIC 038316182 / M

75 mg prolonged-release tablets 100 tablets AIC 038316194 / M

75 mg prolonged-release tablets 500 tablets AIC 038316206 / M (hospital pack)

PVC-Polychlorotrifluoroethylene / Aluminum blisters

150 mg prolonged-release tablets 10 tablets AIC 038316218 / M

150 mg prolonged-release tablets 14 tablets AIC 038316220 / M

150 mg prolonged-release tablets 20 tablets AIC 038316232 / M

150 mg prolonged-release tablets 28 tablets AIC 038316244 / M

150 mg prolonged-release tablets 30 tablets AIC 038316257 / M

150 mg prolonged-release tablets 50 tablets AIC 038316269 / M

150 mg prolonged-release tablets 56 tablets AIC 038316271 / M

150 mg prolonged-release tablets 60 tablets AIC 038316283 / M

150 mg prolonged-release tablets 100 tablets AIC 038316295 / M

150 mg prolonged-release tablets 500 tablets AIC 038316307 / M (hospital pack)

HDPE bottle

150 mg prolonged-release tablets 10 tablets AIC 038316319 / M

150 mg prolonged-release tablets 14 tablets AIC 038316321 / M

150 mg prolonged-release tablets 20 tablets AIC 038316333 / M

150 mg prolonged-release tablets 28 tablets AIC 038316345 / M

150 mg prolonged-release tablets 30 tablets AIC 038316358 / M

150 mg prolonged-release tablets 50 tablets AIC 038316360 / M

150 mg prolonged-release tablets 56 tablets AIC 038316372 / M

150 mg prolonged-release tablets 60 tablets AIC 038316384 / M

150 mg prolonged-release tablets 100 tablets AIC 038316396 / M

150 mg prolonged-release tablets 500 tablets AIC 038316408 / M (hospital pack)

PVC-Polychlorotrifluoroethylene / Aluminum blisters

225 mg prolonged-release tablets 10 tablets AIC 038316410 / M

225 mg prolonged-release tablets 14 tablets AIC 038316422 / M

225 mg prolonged-release tablets 20 tablets AIC 038316434 / M

225 mg prolonged-release tablets 28 tablets AIC 038316446 / M

225 mg prolonged-release tablets 30 tablets AIC 038316459 / M

225 mg prolonged-release tablets 50 tablets AIC 038316461 / M

225 mg prolonged-release tablets 56 tablets AIC 038316473 / M

225 mg prolonged-release tablets 60 tablets AIC 038316485 / M

225 mg prolonged-release tablets 100 tablets AIC 038316497 / M

225 mg prolonged-release tablets 500 tablets AIC 038316509 / M (hospital pack)

HDPE bottle

225 mg prolonged-release tablets 10 tablets AIC 038316511 / M

225 mg prolonged-release tablets 14 tablets AIC 038316523 / M

225 mg prolonged-release tablets 20 tablets AIC 038316535 / M

225 mg prolonged-release tablets 28 tablets AIC 038316547 / M

225 mg prolonged-release tablets 30 tablets AIC 038316550 / M

225 mg prolonged-release tablets 50 tablets AIC 038316562 / M

225 mg prolonged-release tablets 56 tablets AIC 038316574 / M

225 mg prolonged-release tablets 60 tablets AIC 038316586 / M

225 mg prolonged-release tablets 100 tablets AIC 038316598 / M

225 mg prolonged-release tablets 500 tablets AIC 038316600 / M (hospital pack)

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

6 September 2010

10.0 DATE OF REVISION OF THE TEXT

April 2013

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

none:  gynecology antinutrients sexually transmitted diseases