Zyprexa - 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: Olanzapine

ZYPREXA 2.5 mg coated tablets
ZYPREXA 5 mg coated tablets
ZYPREXA 7.5 mg coated tablets
ZYPREXA 10 mg coated tablets
ZYPREXA 15 mg coated tablets
ZYPREXA 20 mg coated tablets

Zyprexa package inserts are available for pack sizes:
  • ZYPREXA 2.5 mg coated tablets, ZYPREXA 5 mg coated tablets, ZYPREXA 7.5 mg coated tablets, ZYPREXA 10 mg coated tablets, ZYPREXA 15 mg coated tablets, ZYPREXA 20 mg coated tablets
  • ZYPREXA 10 mg powder for solution for injection

Why is Zyprexa used? What is it for?

ZYPREXA contains the active substance olanzapine. ZYPREXA belongs to a group of medicines called antipsychotics and is used to treat the following conditions:

  • schizophrenia, a disease with symptoms such as hearing, seeing or feeling things that are not there, misconceptions, unwarranted suspiciousness, and social withdrawal. People with this disease may also feel depressed, anxious or tense.
  • moderate to severe manic episode, a condition characterized by symptoms of arousal or euphoria

ZYPREXA has been shown to prevent recurrence of these symptoms in patients with bipolar disorder whose episode of mania has responded to olanzapine treatment.

Contraindications When Zyprexa should not be used

Do not take ZYPREXA

  • if you are allergic (hypersensitive) to olanzapine or any of the other ingredients of this medicine (listed in section 6). An allergic reaction can manifest itself as a rash, itching, swelling of the face, swelling of the lips, shortness of breath. If this has happened to you, please report it to your doctor.
  • if you have previously been diagnosed with an eye problem such as certain types of glaucoma (increased pressure in the eye).

Precautions for use What you need to know before taking Zyprexa

Talk to your doctor or pharmacist before taking ZYPREXA

  • The use of ZYPREXA in elderly patients with dementia is not recommended as it may cause serious side effects.
  • Medicines of this type can cause unusual movements especially of the face and tongue. If this happens after you have been given ZYPREXA please tell your doctor.
  • Very rarely, medicines of this type cause a 'combination of fever, faster breathing, sweating, muscle stiffness and drowsiness or sleepiness. If this happens, see your doctor right away.
  • Weight gain has been observed in patients taking ZYPREXA. You and your doctor need to monitor your weight regularly. If necessary, consider seeing a dietician or helping with a diet plan.
  • High blood sugar and fat values ​​(triglycerides and cholesterol) have been observed in patients taking ZYPREXA. Your doctor should order blood tests to check sugar and certain blood fat values ​​before you start taking ZYPREXA and regularly during treatment.
  • Tell your doctor if you or someone else in your family have had previous blood clots, as medicines like these have been associated with the formation of blood clots.

If you have any of the following conditions, please tell your doctor as soon as possible:

  • Stroke or transient ischemic attack (transient stroke symptoms) (TIA)
  • Parkinson's disease
  • Prostate problems
  • Intestinal blockage (paralytic ileus)
  • Diseases of the liver or kidneys
  • Diseases of the blood
  • Heart disease
  • Diabetes
  • Convulsions

If you have dementia, you or your caregiver should tell your doctor if you have had a stroke or transient ischemic attack in the past.

As a routine precaution, if you are over the age of 65, get your blood pressure checked by your doctor periodically.

Children and adolescents

ZYPREXA is not indicated for patients below 18 years of age.

Interactions Which drugs or foods may change the effect of Zyprexa

Only take other medicines while you are on ZYPREXA after your doctor tells you to.

You may feel sleepy if ZYPREXA is taken in combination with antidepressants or medicines taken for anxiety or to help you sleep (tranquilizers).

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

In particular, tell your doctor if you are taking:

  • Parkinson's disease medicines.
  • carbamazepine (an anti-epileptic and mood stabilizer), fluvoxamine (an antidepressant), ociprofloxacin (an antibiotic) - your dose of ZYPREXA may need to be adjusted.

ZYPREXA and alcohol

Do not drink any type of alcohol while taking ZYPREXA as taking ZYPREXA and alcohol at the same time can make you drowsy.

Warnings It is important to know that:

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. You should not take this medicine while breastfeeding, as small amounts of ZYPREXA can pass into breast milk.

The following symptoms may occur in newborn babies of mothers who have used ZYPREXA in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and / or weakness, sleepiness, agitation, breathing problems and difficulty in feeding. you have any of these symptoms you may need to contact your doctor.

Driving and using machines

When you take ZYPREXA there is a risk that you may get drowsy. If this happens do not drive or operate any tools or machines. Tell your doctor.

ZYPREXA contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Dose, Method and Time of Administration How to use Zyprexa: Posology

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

Your doctor will tell you how many ZYPREXA tablets to take and how long to continue taking them. The dose of ZYPREXA to be taken ranges from 5 mg to 20 mg per day. If your symptoms reappear, talk to your doctor but do not stop taking ZYPREXA unless your doctor tells you to.

You should take your ZYPREXA tablets once a day, following your doctor's instructions.

Try to take the tablets at the same time each day. It doesn't matter if you take them on a full stomach or on an empty stomach. ZYPREXA coated tablets are for oral use. Swallow the ZYPREXA tablets whole with water.

Overdose What to do if you have taken too much Zyprexa

If you take more ZYPREXA than you should

Patients who took more ZYPREXA than they should have experienced the following symptoms: rapid heart rate, agitation / aggression, speech problems, unusual movements (especially of the face or tongue) and a reduced level of consciousness. Other symptoms may be: acute confusion, seizures (epilepsy), coma, a combination of fever, faster breathing, sweating, muscle stiffness, drowsiness or sleepiness, slow breathing, decreased cough reflex, high or low blood pressure, changes heart rhythm. Contact your doctor or hospital immediately if you get any of the above symptoms. Show your doctor your pack of tablets.

If you forget to take ZYPREXA

Take the tablets as soon as you remember. Do not take a double dose in one day.

If you stop taking ZYPREXA

Do not stop taking the tablets as soon as you start to feel better. It is important that you continue taking ZYPREXA for as long as your doctor feels it is necessary.

If you suddenly stop taking ZYPREXA, symptoms such as sweating, unable to sleep, tremor, anxiety or nausea and vomiting may occur. Your doctor may advise you to gradually reduce the dose before stopping treatment.

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 Zyprexa

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

Tell your doctor immediately if you get:

  • unusual movements (a common side effect that may affect up to 1 in 10 people) mainly of the face or tongue;
  • blood clots in the veins (an uncommon side effect that may affect up to 1 in 100 people), especially in the lower limbs (symptoms include swelling, pain and redness of the leg), which can circulate through blood vessels to the lungs causing chest pain and difficulty in breathing. If you experience any of these symptoms, consult a doctor immediately;
  • an "association of fever, faster breathing, sweating, muscle stiffness and confusion or sleepiness (the frequency of this side effect cannot be estimated from the available data).

Very common side effects (may affect more than 1 in 10 patients) include weight gain; drowsiness; increased levels of prolactin in the blood. In the early stages of treatment, some people may feel dizzy or faint (with a slow heart rate), especially when getting up from a lying or sitting position. These effects usually subside spontaneously, but if they don't, tell your doctor.

Common side effects (may affect up to 1 in 10 people) include changes in the levels of some blood cells, circulating fats and temporary increases in liver enzymes in the early stages of treatment; increases in the level of sugar in the blood and urine; increases in blood uric acid and creatine phosphokinase levels; feeling of increased hunger; dizziness; restlessness; tremor unusual movements (dyskinesias); constipation; dry mouth; rash; loss of strength; extreme tiredness: water retention leading to swelling of the hands, ankles or feet; fever; joint pain and sexual dysfunction, such as decreased libido in males and females or erectile dysfunction in males.

Uncommon side effects (may affect up to 1 in 100 people) include hypersensitivity (eg swelling of the mouth and throat, itching, rash); diabetes or worsening of diabetes, occasionally associated with ketoacidosis (presence of ketone bodies in the blood and urine) or coma; seizures, usually associated with a history of seizures (epilepsy); muscle stiffness or spasms (including movement of the "eye); speech problems; slow heart rate; sensitivity to sunlight; nose bleeding; abdominal bloating; memory loss or forgetfulness; urinary incontinence; lack of the ability to urinate; hair loss; absence or reduction of menstrual cycles; and breast changes in males and females, such as abnormal growth or abnormal milk secretion.

Rare side effects (may affect up to 1 in 1,000 people) include a decrease in body temperature; changes in the rhythm of the heart; sudden unexplained death; inflammation of the pancreas causing severe stomach pain, fever and malaise; liver disease manifesting as yellowing of the skin and whites of the eyes; muscle disease presenting as unexplained aches and pains; and prolonged and / or painful erection.

During olanzapine treatment, elderly patients with dementia may suffer from stroke, pneumonia, urinary incontinence, falls, extreme tiredness, visual hallucinations, a rise in body temperature, redness of the skin, walking disturbances. Some fatal cases have been reported in this particular patient group.

In patients with Parkinson's disease ZYPREXA may lead to worsening of symptoms.

Reporting of side effects

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

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 carton.

ZYPREXA must be stored in its original packaging to keep it away from light and humidity.

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 ZYPREXA contains

The active ingredient is olanzapine. Each ZYPREXA tablet contains either 2.5 mg, or 5 mg, or 7.5 mg, or 10 mg, or 15 mg, or 20 mg of the active substance. The exact amount is stated on the package of ZYPREXA tablets.

The other components are

  • (tablet core) lactose monohydrate, hydroxypropylcellulose, polyvinylpyrrolidone, microcrystalline cellulose, magnesium stearate and
  • (tablet coating) hypromellose, titanium dioxide (E171), carnauba wax.

In addition, the different concentrations of ZYPREXA tablets also contain the following excipients:


TABLET DOSAGE OTHER EXCIPIENTS ZYPREXA 2.5 mg, 5 mg, 7.5 mg and 10 mg tablets (tablet coating) shellac, macrogol, propylene glycol, polysorbate 80 and indigo carmine dye (E132), anhydrous ethanol, isopropyl alcohol, butyl alcohol, ammonium hydroxide ZYPREXA 15 mg tablets (tablet coating) triacetin and indigo carmine dye (E132) ZYPREXA 20 mg tablets (tablet coating) macrogol and synthetic red iron oxide (E172)

What ZYPREXA looks like and contents of the pack

ZYPREXA 2.5 mg coated tablets are white imprinted with the name "LILLY" and a numeric identification code "4112".

ZYPREXA 5 mg coated tablets are white imprinted with the name "LILLY" and a numeric identification code "4115".

ZYPREXA 7.5 mg coated tablets are white imprinted with the name "LILLY" and a numeric identification code "4116".

ZYPREXA 10 mg coated tablets are white imprinted with the name "LILLY" and a numeric identification code "4117".

ZYPREXA 15 mg coated tablets are blue.

ZYPREXA 20 mg coated tablets are pink.

ZYPREXA is available in packs containing 28, 35, 56, 70 or 98 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.

More information about Zyprexa 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

ZYPREXA 5 MG COATED TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each coated tablet contains 5 mg olanzapine.

Excipient with known effect: Each coated tablet contains 156 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Coated tablet

Round-shaped, white coated tablet engraved with the name "LILLY" and a numeric identification code "4115".

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Adults

Olanzapine is indicated for the treatment of schizophrenia.

In patients who have demonstrated a positive response to initial treatment, continued olanzapine therapy allows clinical improvement to be maintained.

Olanzapine is indicated for the treatment of moderate to severe manic episode.

In patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated for the prevention of new disease episodes in patients with bipolar disorder (see section 5.1).

04.2 Posology and method of administration

Adults

Schizophrenia: The recommended starting dose of olanzapine is 10 mg / day.

Episode of mania: The starting dose is 15 mg to be administered as a single daily dose as monotherapy or 10 mg / day in combination therapy (see section 5.1).

Prevention of new disease episodes in bipolar disorder: The recommended starting dosage is 10 mg / day. In patients receiving olanzapine for the treatment of manic episode, continue therapy at the same dosage for prevention of new episodes of illness. If a new depressive, manic, or mixed episode occurs, olanzapine treatment should be continued ( optimizing the dose as needed), with additional therapy to treat mood disorders, as clinically indicated.

During the treatment of schizophrenia, the episode of mania and the prevention of new episodes of illness in bipolar disorder, according to the clinical condition of the patient the daily dosage can subsequently be adjusted within a range of 5-20 mg. a dose higher than the initially recommended dosage is recommended only after an adequate period of clinical observation and should generally take place at intervals of not less than 24 hours. Olanzapine can be given without regard for meals as absorption is not affected by food. Gradual dose reduction should be considered when discontinuing olanzapine.

Particular populations

Elderly patients

Generally, a lower starting dose (5 mg / day) is not required, although dose reduction should be considered in patients 65 years of age and older when clinical situations advise (see section 4.4).

Patients with renal and / or hepatic insufficiency

A lower starting dose (5 mg) should be considered in these patients. In moderate hepatic insufficiency (Child-Pugh class A or B cirrhosis), the starting dose is 5 mg and any dose increase should be made with caution.

Smokers

In smokers relative to non-smokers, no changes in starting dose and dose range are usually necessary. The metabolism of olanzapine may be accelerated by smoking. Clinical monitoring is recommended and, if necessary, an increase in dose may be considered. olanzapine dosage (see section 4.5).

When there are multiple factors capable of slowing the metabolism (female patients, elderly, non-smokers), the possibility of decreasing the starting dose should be considered. Dosage increases when necessary should be done with caution in these patients (see sections 4.5 and 5.2).

Pediatric population

The use of olanzapine is not recommended in children and adolescents below 18 years of age due to a lack of safety and efficacy data. A greater magnitude of increase has been reported in short-term studies in adolescent patients. weight, lipid and prolactin alterations compared to studies in adult patients (see sections 4.4, 4.8, 5.1 and 5.2).

04.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Patients at known risk of narrow-angle glaucoma.

04.4 Special warnings and appropriate precautions for use

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to several weeks. During this period, patients should be closely monitored.

Psychosis and / or dementia-related behavioral disturbances

Olanzapine is not recommended for use in patients with dementia-related psychosis and / or behavioral disturbances due to an increased mortality and risk of cerebrovascular adverse events (EACV). In placebo-controlled clinical trials (6-12 weeks duration) in elderly patients (mean age 78 years) with dementia-related psychotic symptoms and / or behavioral disturbances, there was a two-fold increase in the incidence of deaths. among olanzapine-treated patients versus placebo-treated patients (3.5% vs. 1.5%, respectively).

The highest incidence of death was not associated with olanzapine dose (mean daily dose of 4.4 mg) or duration of treatment. Risk factors that may predispose this patient population to increased mortality include age over 65, dysphagia, sedation, malnutrition and dehydration, lung disease (eg pneumonia, including ab ingestis) or concomitant use of benzodiazepines. However, the incidence of death was higher in olanzapine-treated patients than in placebo-treated patients regardless of these risk factors.

In the same clinical studies, cerebrovascular adverse events (EACV, e.g. stroke, transient ischemic attack (TIA)), some of them fatal, were reported. A 3-fold increase in EACV was found in olanzapine-treated patients compared to placebo-treated patients (1.3% and 0.4%, respectively). All olanzapine and placebo treated patients who presented EACV had pre-existing risk factors. Age over 75 years and vascular / mixed dementia have been identified as risk factors for the onset of ACV during olanzapine treatment.

The efficacy of olanzapine was not established in these studies.

Parkinson's disease

The use of olanzapine in the treatment of dopamine agonist-induced psychosis is not recommended in patients with Parkinson's disease. During clinical trials, worsening of parkinsonian symptoms and hallucinations were reported more commonly and more frequently with olanzapine than with placebo. (see section 4.8), furthermore olanzapine was no more effective than placebo in the treatment of psychotic symptoms. In these studies, patients were required to be initially stable on the lowest effective dose of anti-Parkinson drugs (dopamine agonists) and that this anti-Parkinson treatment remained the same for drugs and dosages used throughout the duration. of study. Olanzapine was initially administered at doses of 2.5 mg / day with dose escalation up to a maximum of 15 mg / day based on the physician's judgment.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially life-threatening condition associated with antipsychotic treatment. Rare cases reported as NMS have also been reported with the use of olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and autonomic nervous system instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac arrhythmia) Additional manifestations may include increased creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure If a patient has signs and symptoms suggestive of NMS, or has unexplained high fever without other clinical manifestations of NMS, all medicines antipsychotics, including olanzapine, should be discontinued.

Hyperglycemia and diabetes

Hyperglycaemia and / or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma has been reported uncommonly, including some fatal cases (see section 4.8). Some cases have been described in which a previous increase in body mass could be a predisposing factor. Appropriate clinical monitoring is suggested in accordance with guidelines used for antipsychotics, such as blood glucose measurement at baseline, 12 weeks after starting olanzapine treatment and annually thereafter. Patients treated with any antipsychotic, including ZYPREXA, should be monitored for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus and risk factors for diabetes mellitus should be monitored regularly for worsening glycemic control. Weight should be monitored regularly, eg at baseline, 4, 8 and 12 weeks after starting olanzapine treatment and every three months thereafter.

Alterations of lipids

Undesirable alterations in lipids have been observed in olanzapine-treated patients in placebo-controlled clinical trials (see section 4.8). Lipid changes should be treated as clinically appropriate, particularly in dyslipidemic patients and in patients with risk factors for the development of lipid-induced diseases. Patients treated with any antipsychotic, including ZYPREXA, should be monitored regularly for lipid values ​​in accordance with the guidelines used for antipsychotics, for example at baseline, 12 weeks after starting olanzapine treatment and, thereafter, any 5 years.

Anticholinergic activity

Although olanzapine has demonstrated anticholinergic activity in vitro, experience during clinical trials revealed a low incidence of related effects. However, in view of the lack of clinical experience with olanzapine in patients with concomitant diseases, caution is advised when prescribing to patients with prostatic hypertrophy, paralytic ileus and related diseases. .

Hepatic function

Transient and asymptomatic elevations of hepatic aminotransferases, ALT and AST, have frequently been observed, especially in the initial stages of treatment. Caution and periodic monitoring are advised in patients with elevated ALT and / or AST, in patients with signs and symptoms of hepatic insufficiency, in patients with pre-existing situations associated with limited hepatic functional reserve, as well as in cases of concomitant treatment with potentially hepatotoxic medicinal products. . In cases where a diagnosis of hepatitis (defined as hepatocellular injury, cholestatic, or both) has been made, olanzapine treatment should be discontinued.

Neutropenia

Caution is advised in patients with leukopenia and / or neutropenia of any origin, in patients taking medicinal products known to cause neutropenia, in patients with a history of iatrogenic myelotoxicity / myelosuppression, in patients with myelosuppression due to concomitant disease, radiotherapy or chemotherapy and finally in patients with hypereosinophilia situations or with myeloproliferative disease. Neutropenia has been reported frequently when olanzapine and valproate are co-administered (see section 4.8).

Discontinuation of treatment

When olanzapine is stopped abruptly, sweating, insomnia, tremor, anxiety, nausea or vomiting have been reported rarely (≥ 0.01%).

QT interval

In clinical studies, clinically significant prolongations of the corrected QT interval (Fridericia corrected QT interval [QTcF] ≥ 500 milliseconds [msec] at any time after baseline measurement in patients with baseline QTcF elderly in olanzapine treated patients , in patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalaemia or hypomagnesaemia.

Thromboembolism

Uncommon (≥ 0.1% and venous thromboembolism. A causal relationship between the occurrence of venous thromboembolism and treatment with olanzapine has not been established. However, since patients with schizophrenia often present with acquired risk factors for thromboembolism venous (VTE), all possible risk factors for VTE such as patient immobilization must be identified and preventive measures taken.

General activity of the Central Nervous System (CNS).

Due to the primary CNS effects of olanzapine, caution is recommended when the medicinal product is taken concomitantly with alcohol and other centrally acting medicinal products. Since olanzapine proves to possess in vitro a "dopamine antagonist activity, this medicinal product may antagonize the effects of direct and indirect dopamine agonists.

Convulsions

Olanzapine should be used with caution in patients with a history of seizures or who are subject to factors that may lower the seizure threshold. Seizures were not commonly seen in these patients treated with olanzapine. In the majority of these cases, the seizures or risk factors for the onset of epilepsy were described in the history.

Tardive dyskinesia

In comparative studies lasting one year or less, olanzapine treatment resulted in a statistically significant "lower incidence of treatment-induced tardive dyskinesias.

However, the risk of tardive dyskinesia increases with long-term treatment; therefore, if signs or symptoms of tardive dyskinesia occur in a patient receiving olanzapine, a dose reduction or discontinuation should be considered. These symptom manifestations may temporarily worsen or even arise after discontinuation of treatment.

Postural hypotension

Postural hypotension has sometimes been observed in clinical trials with olanzapine in elderly patients. It is recommended that blood pressure be checked periodically in patients over 65 years of age.

Sudden cardiac death

The event of sudden cardiac death was reported in postmarketing reports in olanzapine treated patients. In a retrospective observational cohort study, patients treated with olanzapine had an estimated 2-fold risk of presumed sudden cardiac death in patients treated with olanzapine. in treatment with antipsychotics. In the study, the risk with olanzapine was comparable to the risk assessed in an analysis that pooled atypical antipsychotics.

Pediatric population

The use of olanzapine is not indicated in the treatment of children and adolescents. Studies in patients aged 13 to 17 years have shown the occurrence of various adverse reactions, including weight gain, alterations in metabolic parameters and increases in blood levels. prolactin (see sections 4.8 and 5.1).

Lactose

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

04.5 Interactions with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Potential interactions involving olanzapine

Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.

Induction of CYP1A2

The metabolism of olanzapine may be accelerated by smoking and carbamazepine, which can lead to decreased olanzapine concentrations. Only a mild to moderate increase in olanzapine clearance was observed. Clinical consequences are likely to be limited, but clinical monitoring is recommended and an increase in olanzapine dosage may be considered if necessary (see section 4.2).

CYP1A2 inhibition

Fluvoxamine, a specific inhibitor of CYP1A2 activity, has been shown to significantly inhibit the metabolism of olanzapine. After administration of fluvoxamine the mean increase in olanzapine Cmax was 54% in non-smoking females and 77% in males. smokers, while the mean increase in olanzapine AUC was 52% in non-smoking females and 108% in smoking males, respectively. In patients who are using fluvoxamine or any other CYP1A2 inhibitor, as well as ciprofloxacin, olanzapine treatment should start at lower doses. If treatment with a CYP1A2 inhibitor is initiated, a dose reduction of olanzapine should be considered.

Decreased bioavailability

Activated charcoal reduces the bioavailability of oral olanzapine by 50-60% and should be taken at least 2 hours before or after olanzapine.

Fluoxetine (a CYP2D6 inhibitor), single doses of an antacid (aluminum, magnesium) or cimetidine do not significantly affect the pharmacokinetics of olanzapine.

Potential for olanzapine to affect other medicines

Olanzapine may oppose the effects of direct and indirect dopamine agonists. Olanzapine does not inhibit in vitro the main isoenzymes of CYP450 (for example 1A2, 2D6, 2C9, 2C19, 3A4). Therefore no particular interaction is to be expected as verified by the studies in vivo in which no inhibition of the metabolism of the following active substances was found: tricyclic antidepressant (mostly representing the CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19).

Olanzapine showed no drug interaction when administered concomitantly with lithium or biperidene.

Therapeutic monitoring of valproate plasma levels did not indicate that an adjustment of the valproate dose is required after co-administration with olanzapine.

General CNS activity

Caution should be exercised in patients who consume alcohol or receive medications that can cause CNS depression.

In patients with Parkinson's disease and dementia the concomitant use of olanzapine with anti-Parkinson medicinal products is not recommended (see section 4.4).

QT interval

Caution should be exercised if olanzapine is administered concomitantly with medicinal products known to cause an increase in the QT interval (see section 4.4).

04.6 Pregnancy and breastfeeding

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Patients should be advised of the need to inform their physician in the event of an existing or planned pregnancy while being treated with olanzapine. However, as experience in humans is limited, olanzapine should only be used in pregnancy if the potential benefit justifies a potential risk to the fetus.

Infants exposed to antipsychotics (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and / or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of restlessness, hypertonia, hypotonia, tremor, somnolence, difficulty breathing, or feeding disturbances. Consequently, neonates should be monitored closely.

Feeding time

In a study in healthy women during the breastfeeding period, olanzapine was excreted in breast milk. At the steady state the mean infant exposure (in mg / kg) was estimated to be 1.8% of the maternal dose of olanzapine (in mg / kg). Patients should be advised not to breastfeed while on olanzapine therapy.

Fertility

Effects on fertility are unknown (see section 5.3 for preclinical information)

04.7 Effects on ability to drive and use machines

No studies on the ability to drive and use machines have been performed. Since olanzapine may cause somnolence and dizziness, patients should be advised that caution should be exercised when operating machinery, including motor vehicles.

04.8 Undesirable effects

Summary of the safety profile

Adults

In clinical trials the most frequently reported adverse reactions associated with the use of olanzapine (observed in ≥ 1% of patients) were somnolence, weight gain, eosinophilia, increased levels of prolactin, cholesterol, glucose and triglycerides (see section 4.4), glycosuria, increased appetite, dizziness, akathisia, parkinsonism, leukopenia, neutropenia (see section 4.4), dyskinesia, orthostatic hypotension, anticholinergic effects, transient and asymptomatic elevations of hepatic aminotransferases (see section 4.4), rash, asthenia, fatigue, fever, arthralgia, increased alkaline phosphatase, elevated gamma glutamyltransferase, uric acid, creatine phosphokinase and edema.

Table of adverse reactions

The following table lists the adverse reactions and laboratory tests observed following spontaneous reports and during clinical trials. For each frequency group, adverse reactions are reported in order of decreasing severity. The listed frequency parameters are defined as follows: very common (≥1 / 10), common (≥1 / 100,

Very common common Uncommon Rare Not known Disorders of the blood and lymphatic system Eosinophilia, leukopenia10, neutropenia10 Thrombocytopenia 11 Disorders of the immune system Hypersensitivity 11 Metabolism and nutrition disorders Weight gain 1 Increased cholesterol levels2,3, increased glucose levels4, increased triglycerides2,5, glycosuria, increased appetite Development or exacerbation of diabetes occasionally associated with ketoacidosis or coma, including some fatal cases (see section 4.4) 11 Hypothermia 12 Nervous system disorders Drowsiness Dizziness, akathisia6, parkinsonism6, dyskinesia6 Seizures in which in most cases a history of seizures or the presence of risk factors for the onset of seizures11, dystonia (including oculogyric crisis) 11, tardive dyskinesia11, amnesia9, dysarthria were reported Neuroleptic malignant syndrome (see section 4.4) 12, withdrawal symptoms7,12 Cardiac pathologies Bradycardia, QTc interval prolongation (see section 4.4) Ventricular tachycardia / fibrillation, sudden death (see section 4.4) 11 Vascular pathologies Orthostatic hypotension 10 Thromboembolism (including pulmonary embolism and deep vein thrombosis) (see section 4.4) Respiratory, thoracic and mediastinal disorders Epistaxis 9 Gastrointestinal disorders Mild, transient anticholinergic effects including constipation and dry mouth Abdominal distension 9 Pancreatitis 11 Hepatobiliary disorders Transient and asymptomatic elevations of hepatic aminotransferases (ALT, AST), especially in the initial stages of treatment (see section 4.4) Hepatitis (understood as hepatocellular, cholestatic, or both) 11 Skin and subcutaneous tissue disorders rash photosensitivity reaction, alopecia pathologies of the musculoskeletal system and connective tissue arthralgia 9 rhabdomyolysis 11 kidney and urinary pathologies urinary incontinence, urinary retention, difficulty starting urination 11 difficulty starting urination conditions of pregnancy, puerperium and perinatal neonatal withdrawal syndrome (see section 4.6) pathologies of the reproductive system and breast erectile dysfunction in males, decreased libido in males and females amenorrhea, breast enlargement, galactorrhea in females, gynaecomastia / breast enlargement in males priapism 12 General disorders and administration site conditions asthenia, fatigue, edema, fever 10 diagnostic tests increased levels of prolactin 8 increased alkaline phosphatase10, elevated creatine phosphokinase11, elevated gamma glutamyltransferase10, elevated uric acid10 increase in total bilirubin

1 Clinically significant weight gain was observed in all categories of Body Mass Index (BMI) present at baseline. After short-term treatment (mean duration 47 days), weight gain ≥ 7% from baseline was very common (22.2%), body weight gain ≥ 15% from baseline was common (4.2%) and ≥ 25% body weight gain from baseline was uncommon (0.8%). With long-term exposure (at least 48 weeks), patients whose body weight had increased by ≥ 7%, ≥ 15% and ≥ 25% from baseline were very common (64.4%, 31, respectively, 7% and 12.3%).

2 Mean increases in fasting lipid values ​​(total cholesterol, LDL cholesterol and triglycerides) were greater in those patients who did not show evidence of lipid changes at baseline.

3 Observed for fasting normal values ​​at baseline (borderline fasting cholesterol at baseline (≥ 5.17 -

4 Observed for fasting normal values ​​at baseline (borderline fasting blood glucose at baseline (≥ 5.56 -

5 Observed for normal fasting values ​​at baseline (

6 In clinical trials, the incidence of Parkinsonism and dystonia in olanzapine-treated patients was numerically higher, but not statistically significantly different from placebo. Olanzapine-treated patients had a lower "incidence" Parkinsonism, akathisia and dystonia compared to patients treated with fractional doses of haloperidol. In the absence of detailed anamnestic information regarding the presence of acute and late movement disorders of an extrapyramidal nature, it is not currently possible to conclude that olanzapine causes a minor occurrence of tardive dyskinesia and / or other late onset extrapyramidal syndromes.

7 Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and vomiting have been reported when olanzapine was stopped abruptly.

8 In clinical studies of up to 12 weeks, plasma prolactin concentrations exceeded the upper limit of the normal range in approximately 30% of olanzapine-treated patients who had normal baseline prolactin values. In most of these patients the increases were generally mild, and remained 2 times below the upper limit of the normal range.

9 Adverse event identified in clinical trials in the Integrated Database for olanzapine.

10 Established based on values ​​measured in clinical studies in the Integrated Database for olanzapine.

11 Adverse event identified in post-marketing spontaneous reports and with frequency determined using the Olanzapine Integrated Database.

12 Adverse event identified in post-marketing spontaneous reporting and with frequency estimated at the upper 95% confidence interval using the Olanzapine Integrated Database.

Long-term exposure (at least 48 weeks)

The percentage of patients who had clinically significant adverse changes in weight, glucose, total cholesterol / LDL / HDL or triglyceride gain increased over time. In adult patients who completed 9-12 months of therapy, the percentage increase average blood glucose decreased after about 6 months.

Additional information on particular categories of populations

In clinical trials in elderly patients with dementia, olanzapine treatment was associated with a higher incidence of death and cerebrovascular adverse reactions than placebo (see section 4.4). In this group of patients, very common adverse reactions associated with the use of olanzapine were walking disturbances and falls. Pneumonia, increased body temperature, lethargy, erythema, visual hallucinations and urinary incontinence were commonly observed.

In clinical trials of patients with iatrogenic psychosis (dopamine agonists) associated with Parkinson's disease, worsening of parkinsonian symptoms and hallucinations were reported very commonly and more frequently than with placebo.

In a clinical study in patients with bipolar mania, combination therapy of valproate and olanzapine resulted in an "incidence of neutropenia of 4.1%; elevated plasma levels of valproate could be a potential contributing factor. Olanzapine given with lithium or valproate has resulted in an increased incidence (≥ 10%) of tremor, dry mouth, increased appetite and weight gain. Speech disturbance has also been reported frequently. During treatment with olanzapine in combination with lithium or valproate, in case of acute treatment (up to 6 weeks) there was a ≥ 7% increase in starting body weight in 17.4% of patients. In patients with bipolar disorder, long-term treatment with olanzapine (up to 12 months) for prevention of new disease episodes was associated with a ≥ 7% increase in baseline body weight in 39.9% of patients.

Pediatric population

Olanzapine is not indicated for the treatment of children and adolescents under 18 years of age.

Although no clinical studies designed to compare adolescents with adults have been performed, the data obtained from studies in adolescent subjects were compared with those obtained from adult studies.

The following table summarizes the adverse reactions reported with a higher frequency in adolescent patients (aged 13-17 years) than in adult patients or adverse reactions reported only during short-term clinical trials in adolescent patients.Clinically significant weight gain (≥ 7%) appears to occur more commonly in the adolescent population than in adults for similar exposures. The magnitude of weight gain and the percentage of adolescent patients who had clinically significant weight gain were greater in long-term exposure (at least 24 weeks) than in short-term exposure.

For each frequency group, adverse reactions are reported in order of decreasing severity. The listed frequency parameters are defined as follows: very common (≥1 / 10), common (≥1 / 100,

Metabolism and nutrition disorders Very common: weight gain13, increased triglyceride levels14, increased appetite. common: increased cholesterol levels15. Nervous system disorders Very common: sedation (which includes: hypersomnia, lethargy, drowsiness). Gastrointestinal disorders Common: dry mouth. Hepatobiliary disorders Very common: elevations in hepatic aminotransferases (ALT / AST; see section 4.4). Diagnostic tests Very common: decreased total bilirubin, increased GGT, increased prolactin levels16

13 After short-term treatment (mean duration of 22 days), an increase in body weight (kg) ≥ 7% from baseline was very common (40.6%), an increase in body weight ≥ 15% from baseline baseline was common (7.1%) and ≥ 25% body weight gain from baseline was common (2.5%). With long-term exposure (at least 24 weeks), body weight from baseline increased by ≥ 7% in 89.4% of patients, by ≥ 15% in 55.3% of patients and of a value ≥ 25% in 29.1% of patients.

14 Observed for normal fasting values ​​at baseline (

15 Changes in total fasting cholesterol levels from normal to baseline (

16 Elevated prolactin levels were reported in 47.4% of adolescent patients.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. in "Annex V.

04.9 Overdose

Signs and symptoms

Very frequent symptoms of overdose (with incidence> 10%) include tachycardia, agitation / aggression, dysarthria, extrapyramidal manifestations of various types and a reduction in the level of consciousness ranging from sedation to coma.

Other clinically important sequelae of overdose include delirium, convulsion, coma, possible neuroleptic malignant syndrome, respiratory depression, aspiration, hypertension or hypotension, cardiac arrhythmias (

Treatment

There is no specific antidote for olanzapine. Induction of vomiting is not recommended. Standard procedures for the management of overdose may be indicated (eg gastric lavage, administration of activated charcoal). Concomitant administration of activated charcoal reduces the oral bioavailability of olanzapine by 50-60% .

Based on the clinical picture, symptomatic treatment and monitoring of vital functions should be performed, including treatment of hypotension and circulatory collapse and maintenance of respiratory function. Do not use adrenaline, dopamine, or other sympathomimetic agents with beta-agonist activity since stimulation of beta receptors can cause a worsening of the hypotensive state. Cardiovascular activity should be monitored to recognize any arrhythmias. Monitoring and careful medical surveillance must continue until the patient is cured.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: psycholeptics, diazepines, oxazepines, thiazepines and oxepines.

ATC code: N05A H03.

Pharmacodynamic effects

Olanzapine is an antipsychotic, antimanic and mood stabilizing agent with a broad pharmacological profile on numerous receptor systems.

In pre-clinical studies olanzapine has been shown to possess an affinity spectrum (Ki serotonin 5-HT2A / 2C, 5-HT3, 5-HT6; dopamine D1, D2, D3, D4, D5; for muscarinic-type cholinergic receptors M1-M5; for those α1 adrenergic and H1 histamines. Animal behavioral studies with olanzapine indicated serotonergic, dopaminergic and cholinergic antagonism, which confirms the receptor affinity profile described above. Olanzapine showed greater affinity in vitro and increased activity in models in vivo for 5-HT2 serotonergic receptors compared to D2 dopaminergic receptors. Electrophysiological studies have shown that olanzapine selectively reduces the activity of mesolimbic dopaminergic neurons (A10), while having little effect on the striatal circuits (A9 neurons) involved in motor function. Olanzapine reduced the response in conditioned avoidance behavior (predictive test of " antipsychotic activity) at doses lower than those capable of inducing catalepsy (predictive test of motor side effects).

Unlike other antipsychotic agents, olanzapine increases response in an "anxiolytic" test. In a PET (Positron Emission Tomography) study in healthy volunteers with single oral doses (10 mg), olanzapine demonstrated a higher degree of affinity for 5HT2A receptors than for dopamine D2 receptors. In addition, a single photon emission computed tomography (SPECT) study in schizophrenic patients showed that patients who respond to olanzapine exhibit lesser degree of striatal D2 receptor blockade than patients who respond to some other antipsychotics and risperidone. , and comparable to that of patients who respond to clozapine.

Clinical efficacy

In controlled clinical trials, 2 versus placebo and 2 versus an active comparator conducted in over 2,900 schizophrenic patients who presented with both positive and negative symptoms, olanzapine was statistically superior in improving both positive and negative symptoms.

In a double-blind, international comparative study on schizophrenia, schizoaffective manifestations and related disorders, which included 1,481 patients with associated depressive symptoms of varying severity (with mean score of 16.6 detected at the start of the study according to the for Montgomery-Asberg depression), a "secondary prospective analysis of the change in mood score between the start and end of the study showed a statistically significant improvement (p = 0.001) obtained with olanzapine (-6.0). compared to that observed with haloperidol (-3.1).

In patients with mania or a mixed episode of bipolar disorder, olanzapine has been shown to be "superior to both placebo and valproate in reducing symptoms of mania for over 3 weeks."

Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the ratio of patients who achieved symptomatic remission from mania and depression after 6 and 12 weeks. In a combination therapy study in patients treated with lithium or valproate for a minimum of 2 weeks, the addition of 10 mg olanzapine (combination therapy with lithium or valproate) was superior in reducing the symptoms of mania after 6 weeks. compared to lithium or valproate monotherapy.

In a 12-month re-disease prevention study in manic episode patients who achieved remission on olanzapine and were then randomized to olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo at the primary endpoint. useful for evaluating new bipolar episodes Olanzapine also demonstrated a statistically significant advantage over placebo in terms of both new manic episode and new depressive episode.

In a second 12-month study on the prevention of re-episodes of disease in manic episode patients who achieved remission on a combination of olanzapine and lithium and were subsequently randomized to olanzapine or lithium alone, olanzapine was statistically unsatisfactory. lower than lithium at the primary endpoint useful for evaluating new bipolar episodes (olanzapine 30.0%, lithium 38.3%; p = 0.055).

In an 18-month study in manic or mixed episode patients stabilized with a combination therapy of olanzapine and a mood stabilizer (lithium or valproate), long-term combination therapy of olanzapine and lithium or valproate was not superior in statistically significant to lithium or valproate monotherapy in delaying the onset of new bipolar episodes, defined on the basis of diagnostic criteria.

Pediatric population

Controlled efficacy data in adolescents (13-17 years of age) are limited to short-term studies in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving fewer than 200 adolescents . Olanzapine was used in flexible dosing, starting with 2.5 mg / day and increasing to 20 mg / day. During olanzapine treatment, adolescents gained significantly more weight than adults. The magnitude of changes in total fasting cholesterol, LDL cholesterol, triglyceride and prolactin levels was greater in adolescents than in adults. There are no controlled data on maintenance of effect or long-term safety (see sections 4.4 and 4.8).

Long-term safety information is essentially limited to open, uncontrolled data.

05.2 Pharmacokinetic properties

Absorption

Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5-8 hours. Absorption is not affected by food intake. The absolute bioavailability following intravenous administration has not been determined.

Distribution

At serum concentrations ranging from 7 to 1,000 ng / ml, olanzapine is 93% bound to plasma proteins, mainly albumin and α1 acid glycoprotein.

Biotransformation

Olanzapine is metabolised in the liver mainly through conjugation and oxidation processes. The major circulating metabolite is 10-N-glucuronide, which does not cross the blood brain barrier.

Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites, both of which demonstrate lower pharmacological activity in vivocompared to olanzapine in animal studies. The predominant pharmacological activity is exerted by the unmetabolized olanzapine molecule.

Elimination

After oral administration, the mean elimination half-life of olanzapine in healthy volunteers varies with age and gender.

The mean half-life in elderly healthy volunteers (65 years and over) is increased (51.8 hours compared to 33.8 hours) and clearance reduced (17.5 vs 18.2 l / hour) compared to non-elderly subjects. The range of variability of the kinetic parameters in the elderly is similar to that found in the non-elderly. In 44 schizophrenic patients over 65 years of age, daily doses of 5 to 20 mg did not cause any particular adverse reaction profile.

The mean half-life in females is somewhat prolonged compared to males (36.7 versus 32.3 hours) and clearance is reduced (18.9 versus 27.3 l / h). Nevertheless olanzapine (5-20 mg) demonstrated the same safety profile in female (n = 467) and male (n = 869) patients.

Renal impairment

In patients with renal impairment (urine creatinine clearance, mainly in metabolised form.

Smokers

In smokers with mild hepatic impairment, the mean half-life is increased (39.3 hours) and drug clearance reduced (18.0 l / hour), similar to that found in healthy non-smokers (48.8 hours, respectively). and 14.1 l / hour).

In non-smokers, compared to smokers (males and females), the mean half-life is increased (38.6 versus 30.4 hours) and clearance reduced (18.6 versus 27.7 l / hour).

Plasma clearance of olanzapine appears to be lower in elderly than in young people, in female than in male subjects, and in non-smokers than in smokers.

However, the influence of factors such as age, sex or smoking on the clearance and plasma half-life of olanzapine is minimal compared to the range of variability found in the population.

In a study of Caucasian, Japanese and Chinese subjects, no differences in pharmacokinetic parameters were found between the three populations.

Pediatric population

Adolescents (13-17 years of age): The pharmacokinetic profile of olanzapine is similar in adolescents and adults. In clinical studies, the mean olanzapine exposure period was approximately 27% higher in adolescents. Demographic differences between adolescents and adults include lower average body weight and fewer adolescents were smokers. These factors likely contribute to the higher average exposure period observed in adolescents.

05.3 Preclinical safety data

Acute toxicity (single dose)

In rodents, signs of toxicity after oral administration were those typical of substances with high neuroleptic activity: hypoactivity, coma, tremors, clonic convulsions, salivation, decreased weight gain. The mean lethal dose observed in mice and rats was approximately 210 mg / kg and 175 mg / kg, respectively. In dogs, single oral doses up to 100 mg / kg were not fatal; clinical manifestations such as sedation, ataxia, tremors, increased heart rate were observed , difficulty breathing, miosis and anorexia In monkeys, single oral doses up to 100 mg / kg resulted in prostration and, with higher doses, in a state of semi-consciousness.

Repeated dose toxicity

In studies lasting up to 3 months in mice and up to 1 year in rats and dogs, the main effects observed were central nervous system depression, anticholinergic manifestations and peripheral haematological disorders. Tolerance has developed towards the depressive effects on the central nervous system. At high doses, growth parameters were decreased. Reversible effects, related to an increase in prolactin in rats, led to a decrease in the weight of the uterus and ovaries and morphological alterations of the vaginal epithelium and mammary gland.

Hematological toxicity

Effects on haematological parameters were found in each of the aforementioned animal species, including the reduction of circulating leukocytes which was found to be dose-related and non-specific in mice and rats, respectively; however, no signs of bone marrow toxicity were found.

Reversible neutropenia, thrombocytopenia and anemia developed in some dogs treated with 8 - 10 mg / kg per day (the area under the curve - AUC - is 12 to 15 times larger than that seen in a man treated with 12 mg. In cytopenic dogs, no adverse effects on stem and proliferative elements of the bone marrow were observed.

Reproductive toxicity

Olanzapine has no teratogenic effects. Sedation interferes with the mating abilities of male rats. Cycles of estrus were altered at doses of 1.1 mg / kg (3 times the maximum human dose) and reproduction parameters were affected in rats given 3 mg / kg (9 times the dose). maxim in man). The offspring of rats treated with olanzapine presented delayed fetal development and a transient reduction in activity levels.

Mutagenesis

Olanzapine is neither mutagenic nor capable of promoting cell division in a complete series of standard tests, including mutagenicity tests performed on both bacteria and mammalian tissues. in vivo and in vitro.

Carcinogenesis

Based on the results of studies carried out in mice and rats, it was concluded that olanzapine does not possess carcinogenic activity.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Core of the tablet

Lactose monohydrate

Hydroxypropylcellulose

Polyvinylpyrrolidone

Microcrystalline cellulose

Magnesium stearate

Tablet coating

Hypromellose

White colored mixture (hypromellose, titanium dioxide E171, macrogol, polysorbate 80)

Carnauba wax

Edible blue ink (shellac, anhydrous ethanol, isopropyl alcohol, butyl alcohol, propylene glycol, ammonium hydroxide, indigo carmine E132)

06.2 Incompatibility

Not relevant.

06.3 Period of validity

3 years.

06.4 Special precautions for storage

Store in the original package to keep it away from light and moisture.

06.5 Nature of the immediate packaging and contents of the package

Cold-sealed aluminum blister strips, contained in cartons of 28, 35, 56, 70 or 98 tablets each.

Not all pack sizes may be marketed.

06.6 Instructions for use and handling

No special instructions.

07.0 MARKETING AUTHORIZATION HOLDER

Eli Lilly Nederland BV, Grootslag 1-5, NL-3991 RA Houten, The Netherlands.

08.0 MARKETING AUTHORIZATION NUMBER

EU / 1/96/022/004 ZYPREXA - 5 mg - coated tablets - 28 tablets, per box.

033638038

EU / 1/96/022/020 ZYPREXA - 5 mg - coated tablets - 56 tablets, per box.

EU / 1/96/022/024 ZYPREXA - 5 mg - coated tablets - 35 tablets, per box.

EU / 1/96/022/030 ZYPREXA - 5 mg - coated tablets - 70 tablets, per box.

EU / 1/96/022/036 ZYPREXA - 5 mg - coated tablets - 98 tablets, per box.

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Date of first authorization: 27 September 1996

Date of last renewal: 27 September 2006

10.0 DATE OF REVISION OF THE TEXT

D.CCE May 2015

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

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