natgillin/translations-raw huggingface dataset:
12 Elevated plasma prolactin levels were reported in 47.4% of adolescent patients.
Tratamentul îndelungat cu olanzapină (până 12 luni) pentru prevenirea recurenţ la pacienţ cu
4.9 Overdose
elor
Signs and symptoms Very common symptoms in overdose (> 10% incidence) include tachycardia, agitation/ aggressiveness, dysarthria, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma.
ii
Fatal outcomes have been reported for acute overdoses as low as 450 mg but survival has also been reported following acute overdose of 1,500 mg.
tulburare bipolară asociat la 39, 9% dintre pacienţ o creş de  a greutăii corporale faţ
66 Management of overdose There is no specific antidote for olanzapine.
de momentul iniţ tratamentului. ierii
Induction of emesis is not recommended.
Copii şadolescenţ
Standard procedures for management of overdose may be indicated (i. e. gastric lavage, administration of activated charcoal).
i
Cardiovascular monitoring is necessary to detect possible arrhythmias.
Chiar
Close medical supervision and monitoring should continue until the patient recovers.
dacă s- au efectuat studii clinice menite să
5.
nu
PHARMACOLOGICAL PROPERTIES
compare adolescenţ
5.1 Pharmacodynamic properties
din studiile iile
Pharmacotherapeutic group: antipsychotics: diazepines, oxazepines and thiazepines, ATC code:
clinice la adolescenţ fost comparate cu cele la populaţ adultă
N05AH03.
.
In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki; < 100 nM) for serotonin 5 HT2A/ 2C, 5 HT3, 5 HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors m1-m5; α adrenergic; and histamine H1 receptors.
ă
In a single oral dose (10 mg) Positron Emission tomography (PET) study in healthy volunteers, olanzapine produced a higher 5 HT2A than dopamine D2 receptor occupancy.
Urmă torul tabel sumarizează reacţ adverse raportate cu o frecvenţmai mare la pacienţ
In two of two placebo and two of three comparator controlled trials with over 2,900 schizophrenic patients presenting with both positive and negative symptoms, olanzapine was associated with statistically significantly greater improvements in negative as well as positive symptoms.
ă
In a multinationational, double-blind, comparative study of schizophrenia, schizoaffective, and related disorders which included 1,481 patients with varying degrees of associated depressive symptoms (baseline mean of 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective secondary analysis of baseline to endpoint mood score change demonstrated a statistically significant improvement (p=0.001) favouring olanzapine (-6.0) versus haloperidol (-3.1).
iile
In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks.
ii
67 of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in symptoms of mania than lithium or valproate monotherapy after 6 weeks.
adolescenţ( vârsta 13- 17 ani) faţde cei adulţ reacţ adverse identificate doar în cadrul studiilor
In a 12-month recurrence prevention study in manic episode patients who achieved remission on olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo on the primary endpoint of bipolar recurrence.
i
In a second 12-month recurrence prevention study in manic episode patients who achieved remission with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar recurrence (olanzapine 30.0%, lithium 38.3%; p = 0.055).
i sau
In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, defined according to syndromic (diagnostic) criteria.
ii
Olanzapine was used as a flexible dose starting with 2.5 and ranging up to 20 mg/ day.
la pacienţadolescenţ Creş
During treatment with olanzapine, adolescents gained significantly more weight compared with adults.
i
5.2 Pharmacokinetic properties
i.
Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours.
terea în greutate semnificativă punct de vedere clinic pare să din ilor ă
The absorption is not affected by food.
apară mai
Olanzapine is metabolized in the liver by conjugative and oxidative pathways.
frecvent în rândul adolescenţ faţde adulţ ce au avut expuneri comparabile.
The predominant pharmacologic activity is from the parent olanzapine.
Amploarea creş în greutate şproporţ pacienţ adolescenţ
After oral administration, the mean terminal elimination half-life of olanzapine in healthy subjects varied on the basis of age and gender.
ilor
The pharmacokinetic variability observed in the elderly is within the range for the non-elderly.
i care au avut creş în greutate semnificative clinic au teri
However, olanzapine (5-20 mg) demonstrated a comparable safety profile in female (n=467) as in male patients (n=869).
fost mai mari în cazul expunerii îndelungate (cel puţ 24 să mâni) decât în cazul expunerilor de scurtă durată
A mass balance study showed that approximately 57% of radiolabelled olanzapine appeared in urine, principally as metabolites.
În cadrul fiecă grupe de frecvenţ reacţ adverse sunt prezentate în ordinea descrescă
68 In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3 hr) was prolonged and clearance (18.0 l/ hr) was reduced analogous to non-smoking healthy subjects (48.8 hr and 14.1 l/ hr, respectively).
rei
In non-smoking versus smoking subjects (males and females) the mean elimination half-life was prolonged (38.6 versus 30.4 hr) and the clearance was reduced (18.6 versus 27.7 l/ hr).
,
The plasma clearance of olanzapine is lower in elderly versus young subjects, in females versus males, and in non-smokers versus smokers.
iile
In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the pharmacokinetic parameters among the three populations.
toare a
The plasma protein binding of olanzapine was about 93% over the concentration range of about 7 to about 1000 ng/ ml.
gravită Frecvenţevenimentelor enumerate este definită
Olanzapine is bound predominantly to albumin and α -acid-glycoprotein.
după cum urmeazăfoarte frecvente:
1
( 1% i 10%).
Paediatric population Adolescents (ages 13 to 17 years):
Foarte frecvente:
In clinical studies, the average olanzapine exposure was approximately 27% higher in adolescents.
Creş în greutate9, creş tere alimentar crescut. terea colesterolemiei11.
Such factors possibly contribute to the higher average exposure observed in adolescents.
Creş Tulbură ale sistemului nervos ri
5.3 Preclinical safety data
terea concentraţ
Acute (single-dose) toxicity Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity, coma, tremors, clonic convulsions, salivation, and depressed weight gain.
Tulbură hepatobiliare ri
The median lethal doses were approximately 210 mg/ kg (mice) and 175 mg/ kg (rats).
Creş ale valorilor transaminazelor hepatice (ALAT/ ASAT, vezi pct.
Dogs tolerated single oral doses up to 100 mg/ kg without mortality.
4. 4). teri Investigaţ diagnostice ii Foarte frecvente:
Clinical signs included sedation, ataxia, tremors, increased heart rate, labored respiration, miosis, and anorexia.
Scă derea valorilor bilirubinei totale, creş terea valorilor GGT, concentraţ plasmatice ii crescute ale prolactinei 12.
In monkeys, single oral doses up to 100 mg/ kg resulted in prostration and, at higher doses, semi-consciousness.
terea în greutate ≥ faţde masa corporală ială fost foarte frecventăiar creş 9
Repeated-dose toxicity In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects were CNS depression, anticholinergic effects, and peripheral haematological disorders.
faţde masa corporală ială fost frecventăÎn cazul expunerii îndelungate (cel puţ 24
Tolerance developed to the CNS depression.
să mâni), aproximativ jumă dintre pacienţ adolescenţ avut o creş în greutate ≥15% ş
Growth parameters were decreased at high doses.
66 aproape o treime o creş ≥25% faţde masa corporală ialăÎn cadrul pacienţ adolescenţ ă
Reversible effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and morphologic changes in vaginal epithelium and in mammary gland.
10
Haematologic toxicity:
Observată
Reversible neutropenia, thrombocytopenia, or anemia developed in a few dogs treated with 8 or 10 mg/ kg/ day (total olanzapine exposure [AUC] is 12- to 15-fold greater than that of a man given a 12-mg dose).
pentru valori iniţ normale în condiţ de repaus alimentar (< 1, 016 mmol/ l) care au iale ii
In cytopenic dogs, there were no adverse effects on progenitor and proliferating cells in the bone marrow.
atins valori crescute (≥1, 467 mmol/ l) şmodifică valorilor iniţ ale trigliceridelor în condiţ de
Reproductive toxicity Olanzapine had no teratogenic effects.
11
Sedation affected mating performance of male rats.
(≥1, 016 mmol/ l - < 1, 467 mmol/ l) la valori crescute (≥
Estrous cycles were affected at doses of 1.1 mg/ kg (3 times the maximum human dose) and reproduction parameters were influenced in rats given 3 mg/ kg (9 times the maximum human dose).
Modifică ale valorilor colesterolului total, normale iniţ în condiţ de repaus alimentar (<
In the offspring of rats given olanzapine, delays in fetal development and transient decreases in offspring activity levels were seen.
Modifică
69 Mutagenicity Olanzapine was not mutagenic or clastogenic in a full range of standard tests, which included bacterial mutation tests and in vitro and in vivo mammalian tests.
valorilor iniţ ale colesterolului total în condiţ de repaus alimentarde la valori limită
Carcinogenicity Based on the results of studies in mice and rats, it was concluded that olanzapine is not carcinogenic.
12 Concentraţ plasmatice crescute ale prolactinei au fost raportate la 47, 4% dintre pacienţ adolescenţ i.
PHARMACEUTICAL PARTICULARS
4. 9 Supradozare
6.1 List of excipients
Semne si simptome
Lactose monohydrate Powdered cellulose Pregelatinised maize starch Maize starch Colloidal anhydrous silica Magnesium stearate
Simptomele de supradozare foarte frecvente (incidenţ a > 10%) includ tahicardie, agitaţie/ agresivitate, disartrie, diferite simptome extrapiramidale şnivel de conş ă
6.2 Incompatibilities
tienţ redus, de la sedare până comă la
Not applicable.
.
6.3 Shelf life
ică
2 years.
S- au raportat
6.4 Special precautions for storage
i
This medicinal product does not require any special storage conditions.
cazuri letale în urma supradozajului acut cu numai 450 mg, dar s- a raportat şsupravieţ supradozaj acut cu 1500 mg.
6.5 Nature and contents of container
uirea după un o
Blister pack (OPA/ Al/ PVC, Al-foil):
Tratamentul supradozării
14, 28, 35, 56 or 70 tablets in a box.
Nu exista un antidot specific pentru olanzapinăNu se recomandă
Not all pack sizes may be marketed.
Se pot lua rsă
6.6 Special precautions for disposal
Administrarea concomitentă căa rbunelui activat reduce biodisponibilitatea orală a olanzapinei cu 50- 60%.
Any unused product or waste material should be disposed of in accordance with local requirements.
În funcţ de starea clinicăse va institui tratament simptomatic şmonitorizarea funcţ vitale,
7.
ie
KRKA, d. d., Novo mesto, Š marješ cesta 6, 8501 Novo mesto, Slovenia ka
, i
8.
ie, i
EU/ 1/ 07/ 415/ 022-026
iilor
9.
i i
Date of first authorisation:
inerea funcţ
27 September 2007.
respiratorii. iei
70 10.
Este necesară
DATE OF REVISION OF THE TEXT
monitorizarea cardiovascularăpentru depistarea,
Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http: / /www. emea. europa. eu
Supravegherea şmonitorizarea medicală recuperarea pacientului.
71 1.
i
Zalasta 20 mg tablets
atentă trebuie continuate pâna la
QUALITATIVE AND QUANTITATIVE COMPOSITION
PROPRIETĂ FARMACOLOGICE TI
Each tablet contains 20 mg olanzapine.
5. 1 Proprietă farmacodinamice ti
Excipient:
N05AH03
Each tablet contains 323.5 mg lactose.
i
For a full list of excipients, see section 6.1.
Olanzapina este un agent antipsihotic, antimaniacal şstabilizator al dispoziţ cu profil farmacologic larg, ce include mai multe sisteme de receptori.
3.
iei
PHARMACEUTICAL FORM
toarele afinitaţ ă receptori (Ki; < 100 nM):
Tablet.
i faţde
Tablets are round, slightly biconvex, slightly yellow tablets with possible individual yellow spots and an inscription “ 20”.
1
4.
la
CLINICAL PARTICULARS
tat aceasta exercită
4.1 Therapeutic indications
antagonism
Adults Olanzapine is indicated for the treatment of schizophrenia.
serotoninic (5 HT), dopaminic şcolinergic, în concordanţcu profilul afinită faţde receptori.
Olanzapine is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response.
ă
Olanzapine is indicated for the treatment of moderate to severe manic episode.
ţă ii
In patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated for the prevention of recurrence in patients with bipolar disorder (see section 5.1).
Olanzapina a micş un ră
4.2 Posology and method of administration
asupra că striate (A9) ilor
Adults Schizophrenia:
spuns de evitare condiţ
The recommended starting dose for olanzapine is 10 mg/ day.
activitate antipsihoticăîn doze mai mici decât cele ce produc catalepsie, efect ce indică
Manic episode:
secundare motorii.
The starting dose is 15 mg as a single daily dose in monotherapy or 10 mg daily in combination therapy (see section 5.1).
Spre deosebire de alţ i agenţi antipsihotici, olanzapina determină raspuns crescut un la un test „ anxiolitic “.
Preventing recurrence in bipolar disorder:
Într- un studiu de tomografie cu emisie de pozitroni (PET) la voluntari să toş olanzapina, nă i, administrată doză
The recommended starting dose is 10 mg/ day.
oralăunică mg) a avut un grad mai mare de ocupare a receptorilor 5- HT2A, (10
For patients who have been receiving olanzapine for treatment of manic episode, continue therapy for preventing recurrence at the same dose.
decât a celor dopaminici D2.
If a new manic, mixed, or depressive episode occurs, olanzapine treatment should be continued (with dose optimisation as needed), with supplementary therapy to treat mood symptoms, as clinically indicated.
În plus, un studiu de imagisticăSPECT la pacienţ schizofrenie a i cu ară că tat pacienţ responsivi la olanzapină un grad de ocupare a receptorilor striaţD2 mai mic
An increase to a dose greater than the recommended starting dose is advised only after appropriate clinical reassessment and should generally occur at intervals of not less than 24 hours.
decât pacienţ responsivi la alte antipsihotice şla risperidonădar comparabil cu cei responsivi la clozapină.
72 Olanzapine can be given without regards for meals as absorption is not affected by food.
studii placebo controlate, precum şîn două În cele două
Gradual tapering of the dose should be considered when discontinuing olanzapine.
dintre cele trei studii comparative, efectuate
Children and adolescents Olanzapine is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy.
la peste 2900 de pacienţ schizofrenie, cu simptome pozitive şnegative, olanzapina a determinat
A greater magnitude of weight gain, lipid and prolactin alterations has been reported in short term studies of adolescent patients than in studies of adult patients (see sections 4.4, 4.8, 5.1 and 5.2).
amelioră superioare, semnificativ statistic, atât pentru simptomele negative, cât şpentru cele pozitive.
Elderly A lower starting dose (5 mg/ day) is not routinely indicated but should be considered for those 65 and over when clinical factors warrant (see also section 4.4).
i
Renal and/ or hepatic impairment A lower starting dose (5 mg) should be considered for such patients.
Într- un studiu al schizofreniei şal tulbură asociate, multinaţ
In cases of moderate hepatic insufficiency (cirrhosis, Child-Pugh Class A or B), the starting dose should be 5 mg and only increased with caution.
ional, dublu- orb, comparativ, la care
Gender The starting dose and dose range need not be routinely altered for female patients relative to male patients.
au participat 1. 481 pacienţ grade variate de simptome depresive asociate (media bazală 16, 6 pe
Smokers The starting dose and dose range need not be routinely altered for non-smokers relative to smokers.
de
Dose escalation, when indicated, should be conservative in such patients.
Scala de Evaluare a Depresiei Montgomery- Asberg), o analiză
(See sections 4.5 and 5.2.)
prospectivă
4.3 Contraindications
modifică a
Hypersensitivity to the active substance or to any of the excipients.
simptomelor iniţ până sfârş tratamentului, a demonstrat o ameliorare semnificativă
Patients with known risk for narrow-angle glaucoma.
statistic
4.4 Special warnings and precautions for use
(p=0. 001) mai bună olanzapină
Patients should be closely monitored during this period.
(- 6. 0) decât haloperidol (- 3. 1).
In placebo-controlled clinical trials (6-12 weeks duration) of elderly patients (mean age 78 years) with dementia-related psychosis and/ or disturbed behaviours, there was a 2-fold increase in the incidence of death in olanzapine-treated patients compared to patients treated with placebo (3.5% vs.
La pacienţ cu episod maniacal sau mixt din tulburarile bipolare, olanzapina a demonstrat eficacitate ii superioară ă placebo şfaţde valproatul semisodic (divalproex) în privinţreducerii iă
1.5%, respectively).
simptomelor
There was a 3-fold increase in CVAE in patients treated
maniacale, după să mâni
0.4%, respectively).
de tratament.
The efficacy of olanzapine was not established in these trials.
Olanzapina a demonstrat, de asemenea, 3 ptă
Olanzapine was started at 2.5 mg/ day and titrated to a maximum of 15 mg/ day based on investigator judgement.
eficacitate comparabilă haloperidolul în ceea ce priveş proporţ pacienţ cu remisiune
Neuroleptic Malignant Syndrome (NMS) NMS is a potentially life-threatening condition associated with antipsychotic medicinal product.
simptomatică maniei şa depresiei după ş12 să mâni de tratament.
Rare cases reported as NMS have also been received in association with olanzapine.
Într– un studiu de terapie
Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).
i trataţ
Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
litiu sau valproat, timp de minimum 2 să mâni, i cu
If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine must be discontinued.
olanzapinei 10 mg (în tratament combinat cu litiu sau valproat) a dus, după să mâni de tratament, 6 ptă la o reducere mai mare a simptomelor maniacale, decat în cazul monoterapiei cu litiu sau cu valproat.
In some cases, a prior increase in body weight has been reported which may be a predisposing factor.
Într- un studiu de prevenire a recurenţ episoadelor maniacale de 12 luni la pacienţîn remisie pe
Lipid alterations Undesirable alterations in lipids have been observed in olanzapine-treated patients in placebo- controlled clinical trials (see section 4.8).
elor
Anticholinergic activity While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinical trials revealed a low incidence of related events.
i
In the event of elevated ALT and/ or AST during treatment, follow- up should be organised and dose reduction should be considered.
tratament cu olanzapinăş care au fost apoi randomizaţ pe olanzapinăsau placebo, olanzapina a
74 Neutropenia Caution should be exercised in patients with low leukocyte and/ or neutrophil counts for any reason, in patients receiving medicines known to cause neutropenia, in patients with a history of drug-induced bone marrow depression/ toxicity, in patients with bone marrow depression caused by concomitant illness, radiation therapy or chemotherapy and in patients with hypereosinophilic conditions or with myeloproliferative disease.
i
Discontinuation of treatment Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported very rarely (< 0.01%) when olanzapine is stopped abruptly.
ăde
QT interval In clinical trials, clinically meaningful QTc prolongations (Fridericia QT correction [QTcF] ≥ 500 milliseconds [msec] at any time post baseline in patients with baseline QTcF < 500 msec) were uncommon (0.1% to 1%) in patients treated with olanzapine, with no significant differences in associated cardiac events compared to placebo.
i
Thromboembolism Temporal association of olanzapine treatment and venous thromboembolism has very rarely (< 0.01%) been reported.
demonstrat o superioritate semnificativăstatistic faţ placebo pe parametrul principal - recurenţ
A causal relationship between the occurrence of venous thromboembolism and treatment with olanzapine has not been established.
ăde tulbură bipolare.
However, since patients with schizophrenia often present with acquired risk factors for venous thromboembolism all possible risk factors of VTE e. g. immobilisation of patients, should be identified and preventive measures undertaken.
Olanzapina a demonstrat de asemenea un avantaj semnificativ statistic faţ rii placebo în prevenirea recurenţ episoadelor maniacale sau depresive. elor Într- un al doilea studiu de 12 luni de prevenire a recurenţ episoadelor maniacale la pacienti aflaţ
As it exhibits in vitro dopamine antagonism, olanzapine may antagonize the effects of direct and indirect dopamine agonists.
în remisie pe tratament cu o asociere de olanzapină i litiu, şcare au fost apoi randomizaţpe
In most of these cases, a history of seizures or risk factors for seizures was reported.
olanzapină litiu în monoterapie, olanzapina nu a fost inferioară
These symptoms can temporally deteriorate or even arise after discontinuation of treatment.
statistic litiului, pe parametrul
As with other antipsychotics, it is recommended that blood pressure is measured periodically in patients over 65 years.
principal - recurenţtulbură bipolare (olanzapina 30, 0%, litiu 38, 3%; p=0, 055)
Use in children and adolescents under 18 years of age Olanzapine is not indicated for use in the treatment of children and adolescents.
de tratament combinat, de 18 luni, în episoade maniacale sau mixte la pacienţ ş
75 Lactose Zalasta tablets contain lactose.
i stabilizaţ i
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
cu olanzapină i un stabilizator de dispoziţ (litiu sau valproat), tratamentul combinat de lungă
4.5 Interaction with other medicinal products and other forms of interaction
ş
Interaction studies have only been performed in adults.
ie
Potential interactions affecting olanzapine Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.
durată
Induction of CYP1A2 The metabolism of olanzapine may be induced by smoking and carbamazepine, which may lead to reduced olanzapine concentrations.
cu olanzapină i litiu sau valproat nu a fost superior, semnificativ statistic, monoterapiei cu litiu sau valproat în amânarea recurenţ bipolare, definită
Only slight to moderate increase in olanzapine clearance has been observed.
conform criteriilor diagnostice.
The mean increase in olanzapine AUC was 52% and 108% respectively.
Copii şadolescenţ
A lower starting dose of olanzapine should be considered in patients who are using fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin.
i