ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
ZYPREXA VELOTAB 5 mg orodispersible tablets
ZYPREXA VELOTAB 10 mg orodispersible tablets
ZYPREXA VELOTAB 15 mg orodispersible tablets
ZYPREXA VELOTAB 20 mg orodispersible tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
ZYPREXA VELOTAB 5 mg orodispersible tablets
Each orodispersible tablet contains 5 mg olanzapine.
Excipients with known effect: Each orodispersible tablet contains
0.60 mg aspartame (E951),
0.1125 mg sodium methyl parahydroxybenzoate (E219),
0.0375 mg sodium propyl parahydroxybenzoate (E217).
ZYPREXA VELOTAB 10 mg orodispersible tablets
Each orodispersible tablet contains 10 mg olanzapine.
Excipients with known effect: Each orodispersible tablet contains
0.80 mg aspartame (E951),
0.15 mg sodium methyl parahydroxybenzoate (E219),
0.05 mg sodium propyl parahydroxybenzoate (E217).
ZYPREXA VELOTAB 15 mg orodispersible tablets
Each orodispersible tablet contains 15 mg olanzapine.
Excipients with known effect: Each orodispersible tablet contains
1.20 mg aspartame (E951),
0.225 mg sodium methyl parahydroxybenzoate (E219),
0.075 mg sodium propyl parahydroxybenzoate (E217).
ZYPREXA VELOTAB 20 mg orodispersible tablets
Each orodispersible tablet contains 20 mg olanzapine.
Excipients with known effect: Each orodispersible tablet contains
1.60 mg aspartame (E951),
0.30 mg sodium methyl parahydroxybenzoate (E219),
0.10 mg sodium propyl parahydroxybenzoate (E217).
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Orodispersible tablet
Yellow, round, freeze dried, rapid-dispersing preparation to be placed in the mouth or alternatively to
be dispersed in water or other suitable beverage for administration.
3
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Adults
Olanzapine is indicated for the treatment of schizophrenia.
Olanzapine is effective in maintaining the clinical improvement during continuation therapy in
patients who have shown an initial treatment response.
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 recurrence in patients with bipolar disorder (see section 5.1).
4.2 Posology and method of administration
Adults
Schizophrenia: The recommended starting dose for olanzapine is 10 mg/day.
Manic episode: The starting dose is 15 mg as a single daily dose in monotherapy or 10 mg daily in
combination therapy (see section 5.1).
Preventing recurrence in bipolar disorder: The recommended starting dose is 10 mg/day. For patients
who have been receiving olanzapine for treatment of manic episode, continue therapy for preventing
recurrence at the same dose. 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.
During treatment for schizophrenia, manic episode and recurrence prevention in bipolar disorder, daily
dosage may subsequently be adjusted on the basis of individual clinical status within the range 5-
20 mg/day. 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.
Olanzapine can be given without regards for meals as absorption is not affected by food. Gradual
tapering of the dose should be considered when discontinuing olanzapine.
ZYPREXA VELOTAB orodispersible tablet should be placed in the mouth, where it will rapidly
disperse in saliva, so it can be easily swallowed. Removal of the intact orodispersible tablet from the
mouth is difficult. Since the orodispersible tablet is fragile, it should be taken immediately on opening
the blister. Alternatively, it may be dispersed in a full glass of water or other suitable beverage (orange
juice, apple juice, milk or coffee) immediately before administration.
Olanzapine orodispersible tablet is bioequivalent to olanzapine coated tablets, with a similar rate and
extent of absorption. It has the same dosage and frequency of administration as olanzapine coated
tablets. Olanzapine orodispersible tablets may be used as an alternative to olanzapine coated tablets.
Special populations
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 section 4.4).
Renal and/or hepatic impairment
A lower starting dose (5 mg) should be considered for such patients. 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.
4
Smokers
The starting dose and dose range need not be routinely altered for non-smokers relative to smokers. The
metabolism of olanzapine may be induced by smoking. Clinical monitoring is recommended and an
increase of olanzapine dose may be considered if necessary (see section 4.5).
When more than one factor is present which might result in slower metabolism (female gender,
geriatric age, non-smoking status), consideration should be given to decreasing the starting dose. Dose
escalation, when indicated, should be conservative in such patients.
In cases where dose increments of 2.5 mg are considered necessary, ZYPREXA coated tablets should
be used.
(See sections 4.5 and 5.2.)
Paediatric population
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. 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).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients with known risk of narrow-angle glaucoma.
4.4 Special warnings and precautions for use
During antipsychotic treatment, improvement in the patient's clinical condition may take several days
to some weeks. Patients should be closely monitored during this period.
Dementia-related psychosis and/or behavioural disturbances
Olanzapine is not recommended for use in patients with dementia-related psychosis and/or behavioural
disturbances because of an increase in mortality and the risk of cerebrovascular accident. In placebocontrolled clinical trials (6-12 weeks duration) of elderly patients (mean age 78 years) with dementiarelated 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. 1.5 %, respectively).
The higher incidence of death was not associated with olanzapine dose (mean daily dose 4.4 mg) or
duration of treatment. Risk factors that may predispose this patient population to increased mortality
include age > 65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g.,
pneumonia, with or without aspiration), or concomitant use of benzodiazepines. However, the
incidence of death was higher in olanzapine-treated than in placebo-treated patients independent of
these risk factors.
In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischemic
attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated
with olanzapine compared to patients treated with placebo (1.3 % vs. 0.4 %, respectively). All
olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing
risk factors. Age > 75 years and vascular/mixed type dementia were identified as risk factors for
CVAE in association with olanzapine treatment. The efficacy of olanzapine was not established in
these trials.
Parkinson's disease
The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with
Parkinson's disease is not recommended. In clinical trials, worsening of Parkinsonian symptomatology
and hallucinations were reported very commonly and more frequently than with placebo (see section
4.8), and olanzapine was not more effective than placebo in the treatment of psychotic symptoms. In
5
these trials, patients were initially required to be stable on the lowest effective dose of antiParkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian
medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and
titrated to a maximum of 15 mg/day based on investigator judgement.
Neuroleptic Malignant Syndrome (NMS)
NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. Rare
cases reported as NMS have also been received in association with olanzapine. 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). Additional
signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal
failure. 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.
Hyperglycaemia 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). In
some cases, a prior increase in body weight has been reported which may be a predisposing factor.
Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines, e.g.
measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually
thereafter. Patients treated with any antipsychotic medicines, including ZYPREXA VELOTAB,
should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria,
polyphagia, and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus
should be monitored regularly for worsening of glucose control. Weight should be monitored
regularly, e.g. at baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly
thereafter.
Lipid alterations
Undesirable alterations in lipids have been observed in olanzapine-treated patients in placebocontrolled clinical trials (see section 4.8). Lipid alterations should be managed as clinically
appropriate, particularly in dyslipidemic patients and in patients with risk factors for the development
of lipids disorders. Patients treated with any antipsychotic medicines, including ZYPREXA
VELOTAB, should be monitored regularly for lipids in accordance with utilised antipsychotic
guidelines, e.g. at baseline, 12 weeks after starting olanzapine treatment and every 5 years thereafter.
Anticholinergic activity
While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinical trials
revealed a low incidence of related events. However, as clinical experience with olanzapine in patients
with concomitant illness is limited, caution is advised when prescribing for patients with prostatic
hypertrophy, or paralytic ileus and related conditions.
Hepatic function
Transient, asymptomatic elevations of hepatic aminotransferases, ALT, AST have been seen
commonly, especially in early treatment. Caution should be exercised and follow-up organised in
patients with elevated ALT and/or AST, in patients with signs and symptoms of hepatic impairment,
in patients with pre-existing conditions associated with limited hepatic functional reserve, and in
patients who are being treated with potentially hepatotoxic medicines. In cases where hepatitis
(including hepatocellular, cholestatic or mixed liver injury) has been diagnosed, olanzapine treatment
should be discontinued.
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
6
myeloproliferative disease. Neutropenia has been reported commonly when olanzapine and valproate
are used concomitantly (see section 4.8).
Discontinuation of treatment
Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported
rarely ( ≥ 0.01 % and < 0.1 %) when olanzapine is stopped abruptly.
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. However, caution should be exercised when
olanzapine is prescribed with medicines known to increase QTc interval, especially in the elderly, in
patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia
or hypomagnesaemia.
Thromboembolism
Temporal association of olanzapine treatment and venous thromboembolism has been reported
uncommonly (≥ 0.1% and < 1%). 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 venous thromboembolism all possible
risk factors of VTE e.g. immobilisation of patients, should be identified and preventive measures
undertaken.
General CNS activity
Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination
with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism,
olanzapine may antagonize the effects of direct and indirect dopamine agonists.
Seizures
Olanzapine should be used cautiously in patients who have a history of seizures or are subject to
factors which may lower the seizure threshold. Seizures have been reported to occur uncommonly in
patients when treated with olanzapine. In most of these cases, a history of seizures or risk factors for
seizures were reported.
Tardive Dyskinesia
In comparator studies of one year or less duration, olanzapine was associated with a statistically
significant lower incidence of treatment emergent dyskinesia. However the risk of tardive dyskinesia
increases with long term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in
a patient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms
can temporally deteriorate or even arise after discontinuation of treatment.
Postural hypotension
Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. It is
recommended that blood pressure is measured periodically in patients over 65 years.
Sudden cardiac death
In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported in
patients with olanzapine. In a retrospective observational cohort study, the risk of presumed sudden
cardiac death in patients treated with olanzapine was approximately twice the risk in patients not using
antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical
antipsychotics included in a pooled analysis.
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Paediatric population
Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients
aged 13-17 years showed various adverse reactions, including weight gain, changes in metabolic
parameters and increases in prolactin levels(see sections 4.8 and 5.1).
Aspartame
This medicine contains up to 1.6 mg aspartame in each tablet.
Aspartame is a source of phenylalanine. It may be harmful for people who have phenylketonuria
(PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it
properly.
Sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate
This medicine contains sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate,
which may cause allergic reactions (possibly delayed)
Sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially
‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.
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.
Induction of CYP1A2
The metabolism of olanzapine may be induced by smoking and carbamazepine, which may lead to
reduced olanzapine concentrations. Only slight to moderate increase in olanzapine clearance has been
observed. The clinical consequences are likely to be limited, but clinical monitoring is recommended
and an increase of olanzapine dose may be considered if necessary (see section 4.2).
Inhibition of CYP1A2
Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism of
olanzapine. The mean increase in olanzapine Cmax following fluvoxamine was 54 % in female nonsmokers and 77 % in male smokers. The mean increase in olanzapine AUC was 52 % and 108 %
respectively. A lower starting dose of olanzapine should be considered in patients who are using
fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin. A decrease in the dose of
olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated.
Decreased bioavailability
Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60 % and should be taken at
least 2 hours before or after olanzapine.
Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have
not been found to significantly affect the pharmacokinetics of olanzapine.
Potential for olanzapine to affect other medicinal products
Olanzapine may antagonise the effects of direct and indirect dopamine agonists.
Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2, 2D6, 2C9, 2C19, 3A4).
Thus no particular interaction is expected as verified through in vivo studies where no inhibition of
metabolism of the following active substances was found: tricyclic antidepressant (representing mostly
CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19).
8
Olanzapine showed no interaction when co-administered with lithium or biperiden.
Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is
required after the introduction of concomitant olanzapine.
General CNS activity
Caution should be exercised in patients who consume alcohol or receive medicinal products that can
cause central nervous system depression.
The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with
Parkinson's disease and dementia is not recommended (see section 4.4).
QTc interval
Caution should be used if olanzapine is being administered concomitantly with medicinal products
known to increase QTc interval (see section 4.4).
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate and well-controlled studies in pregnant women. Patients should be advised to
notify their physician if they become pregnant or intend to become pregnant during treatment with
olanzapine. Nevertheless, because human experience is limited, olanzapine should be used in
pregnancy only if the potential benefit justifies the potential risk to the foetus.
New born 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 agitation, hypertonia,
hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns
should be monitored carefully.
Breast-feeding
In a study in breast-feeding, healthy women, olanzapine was excreted in breast milk. Mean infant
exposure (mg/kg) at steady state was estimated to be 1.8 % of the maternal olanzapine dose (mg/kg).
Patients should be advised not to breast feed an infant if they are taking olanzapine.
Fertility
Effects on fertility are unknown (see section 5.3 for preclinical information).
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. Because
olanzapine may cause somnolence and dizziness, patients should be cautioned about operating
machinery, including motor vehicles.
4.8 Undesirable effects
Summary of the safety profile
Adults
The most frequently (seen in ≥ 1% of patients ) reported adverse reactions associated with the use of
olanzapine in clinical trials were somnolence, weight gain, eosinophilia, elevated prolactin,
cholesterol, glucose and triglyceride levels (see section 4.4), glucosuria, increased appetite, dizziness,
akathisia, parkinsonism, leukopenia, neutropenia (see section 4.4), dyskinesia, orthostatic hypotension,
anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases (see section
4.4), rash, asthenia, fatigue, pyrexia, arthralgia, increased alkaline phosphatase, high gamma
glutamyltransferase, high uric acid, high creatine phosphokinase and oedema.
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Tabulated list of adverse reactions
The following table lists the adverse reactions and laboratory investigations observed from spontaneous
reporting and in clinical trials. Within each frequency grouping, adverse reactions are presented in order
of decreasing seriousness. The frequency terms listed are defined as follows: Very common (≥ 1/10),
common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very
rare (< 1/10,000), not known (cannot be estimated from the data available).
Very
common
Common Uncommon Rare Not known
Blood and the lymphatic system disorders
Eosinophilia
Leukopenia10
Neutropenia10
Thrombocytopenia11
Immune system disorders
Hypersensitivity11
Metabolism and nutrition disorders
Weight gain1 Elevated
cholesterol levels2,3
Elevated glucose
levels4
Elevated
triglyceride levels2,5
Glucosuria
Increased appetite
Development or
exacerbation of
diabetes occasionally
associated with
ketoacidosis or coma,
including some fatal
cases (see section
4.4) 11
Hypothermia12
Nervous system disorders
Somnolence Dizziness
Akathisia6
Parkinsonism6
Dyskinesia6
Seizures where in
most cases a history
of seizures or risk
factors for seizures
were reported11
Dystonia (including
oculogyration) 11
Tardive dyskinesia11
Amnesia 9
Dysarthria
Stuttering11
Restless Legs
Syndrome11
Neuroleptic malignant
syndrome (see section
4.4)12
Discontinuation
symptoms7, 12
Cardiac disorders
Bradycardia
QTc prolongation (see
section 4.4)
Ventricular
tachycardia/fibrillation,
sudden death (see
section 4.4)11
Vascular disorders
Orthostatic
hypotension10
Thromboembolism
(including pulmonary
embolism and deep
vein thrombosis) (see
section 4.4)
10
Respiratory, thoracic and mediastinal disorders
Epistaxis9
Gastrointestinal disorders
Mild, transient
anticholinergic
effects including
constipation and
dry mouth
Abdominal
distension9
Salivary
hypersecretion11
Pancreatitis11
Hepatobiliary disorders
Transient,
asymptomatic
elevations of
hepatic
aminotransferases
(ALT, AST),
especially in early
treatment (see
section 4.4)
Hepatitis (including
hepatocellular,
cholestatic or mixed
liver injury)11
Skin and subcutaneous tissue disorders
Rash Photosensitivity
reaction
Alopecia
Drug
Reaction
with
Eosinophilia
and
Systemic
Symptoms
(DRESS)
Musculoskeletal and connective tissue disorders
Arthralgia9 Rhabdomyolysis11
Renal and urinary disorders
Urinary incontinence,
urinary retention
Urinary hesitation11
Pregnancy, puerperium and perinatal conditions
Drug
withdrawal
syndrome
neonatal (see
section 4.6)
Reproductive system and breast disorders
Erectile dysfunction
in males
Decreased libido in
males and females
Amenorrhea
Breast enlargement
Galactorrhea in
females
Gynaecomastia/breast
enlargement in males
Priapism12
General disorders and administration site conditions
Asthenia
Fatigue
Oedema
Pyrexia10
11
Investigations
Elevated
plasma
prolactin
levels8
Increased alkaline
phosphatase10
High creatine
phosphokinase11
High Gamma
Glutamyltransferase
10
High uric acid 10
Increased total
bilirubin
1 Clinically significant weight gain was observed across all baseline Body Mass Index (BMI)
categories. Following short term treatment (median duration 47 days), weight gain ≥ 7% of baseline
body weight was very common (22.2 %), ≥ 15 % was common (4.2 %) and ≥ 25 % was uncommon
(0.8 %). Patients gaining ≥ 7 %, ≥ 15 % and ≥ 25 % of their baseline body weight with long-term
exposure (at least 48 weeks) were very common (64.4 %, 31.7 % and 12.3 % respectively).
2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were
greater in patients without evidence of lipid dysregulation at baseline.
3 Observed for fasting normal levels at baseline (< 5.17 mmol/l) which increased to high
(≥ 6.2 mmol/l). Changes in total fasting cholesterol levels from borderline at baseline (≥ 5.17 -
< 6.2 mmol/l) to high (≥ 6.2 mmol/l) were very common.
4 Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (≥ 7 mmol/l).
Changes in fasting glucose from borderline at baseline (≥ 5.56 - < 7 mmol/l) to high (≥ 7 mmol/l) were
very common.
5 Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high
(≥ 2.26 mmol/l). Changes in fasting triglycerides from borderline at baseline (≥ 1.69 mmol/l -
< 2.26 mmol/l) to high (≥ 2.26 mmol/l) were very common.
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 of Parkinsonism, akathisia and dystonia compared with titrated doses of
haloperidol. In the absence of detailed information on the pre-existing history of individual acute and
tardive extrapyramidal movement disorders, it cannot be concluded at present that olanzapine produces
less tardive dyskinesia and/or other tardive extrapyramidal syndromes.
7 Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and vomiting have been
reported when olanzapine is stopped abruptly.
8 In clinical trials of up to 12 weeks, plasma prolactin concentrations exceeded the upper limit of
normal range in approximately 30% of olanzapine treated patients with normal baseline prolactin
value. In the majority of these patients the elevations were generally mild, and remained below two
times the upper limit of normal range.
9 Adverse event identified from clinical trials in the Olanzapine Integrated Database.
10 As assessed by measured values from clinical trials in the Olanzapine Integrated Database.
11 Adverse event identified from spontaneous post-marketing reporting with frequency determined
utilising the Olanzapine Integrated Database.
12 Adverse event identified from spontaneous post-marketing reporting with frequency estimated at the
upper limit of the 95% confidence interval utilising the Olanzapine Integrated Database.
12
Long-term exposure (at least 48 weeks)
The proportion of patients who had adverse, clinically significant changes in weight gain, glucose,
total/LDL/HDL cholesterol or triglycerides increased over time. In adult patients who completed 9-12
months of therapy, the rate of increase in mean blood glucose slowed after approximately 6 months.
Additional information on special populations
In clinical trials in elderly patients with dementia, olanzapine treatment was associated with a higher
incidence of death and cerebrovascular adverse reactions compared to placebo (see section 4.4). Very
common adverse reactions associated with the use of olanzapine in this patient group were abnormal
gait and falls. Pneumonia, increased body temperature, lethargy, erythema, visual hallucinations and
urinary incontinence were observed commonly.
In clinical trials in patients with drug-induced (dopamine agonist) psychosis associated with
Parkinson’s disease, worsening of Parkinsonian symptomatology and hallucinations were reported
very commonly and more frequently than with placebo.
In one clinical trial in patients with bipolar mania, valproate combination therapy with olanzapine
resulted in an incidence of neutropenia of 4.1%; a potential contributing factor could be high plasma
valproate levels. Olanzapine administered with lithium or valproate resulted in increased levels
(≥ 10%) of tremor, dry mouth, increased appetite, and weight gain. Speech disorder was also reported
commonly. During treatment with olanzapine in combination with lithium or divalproex, an increase
of ≥ 7% from baseline body weight occurred in 17.4% of patients during acute treatment (up to 6
weeks). Long-term olanzapine treatment (up to 12 months) for recurrence prevention in patients with
bipolar disorder was associated with an increase of ≥ 7% from baseline body weight in 39.9% of
patients.
Paediatric population
Olanzapine is not indicated for the treatment of children and adolescent patients below 18 years.
Although no clinical studies designed to compare adolescents to adults have been conducted, data
from the adolescent trials were compared to those of the adult trials.
The following table summarises the adverse reactions reported with a greater frequency in adolescent
patients (aged 13-17 years) than in adult patients or adverse reactions only identified during short-term
clinical trials in adolescent patients. Clinically significant weight gain (≥ 7%) appears to occur more
frequently in the adolescent population compared to adults with comparable exposures. The magnitude
of weight gain and the proportion of adolescent patients who had clinically significant weight gain
were greater with long-term exposure (at least 24 weeks) than with short-term exposure.
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The frequency terms listed are defined as follows: Very common (≥ 1/10), common (≥ 1/100 to
< 1/10).
Metabolism and nutrition disorders
Very common: Weight gain13, elevated triglyceride levels14, increased appetite.
Common: Elevated cholesterol levels15
Nervous system disorders
Very common: Sedation (including: hypersomnia, lethargy, somnolence).
Gastrointestinal disorders
Common: Dry mouth
Hepatobiliary disorders
Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4).
Investigations
Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16.
13 Following short term treatment (median duration 22 days), weight gain ≥ 7% of baseline body
weight (kg) was very common (40.6 %), ≥ 15% of baseline body weight was common (7.1 %) and ≥
13
25 % was common (2.5 %). With long-term exposure (at least 24 weeks), 89.4 % gained ≥ 7 %, 55.3
% gained ≥ 15 % and 29.1 % gained ≥ 25% of their baseline body weight.
14 Observed for fasting normal levels at baseline (< 1.016 mmol/l) which increased to high
(≥ 1.467 mmol/l) and changes in fasting triglycerides from borderline at baseline (≥ 1.016 mmol/l -
< 1.467 mmol/l) to high (≥ 1.467 mmol/l).
15Changes in total fasting cholesterol levels from normal at baseline (< 4.39 mmol/l) to high
(≥ 5.17 mmol/l) were observed commonly. Changes in total fasting cholesterol levels from borderline
at baseline (≥ 4.39 - < 5.17 mmol/l) to high (≥ 5.17 mmol/l) were very common.
16 Elevated plasma prolactin levels were reported in 47.4% of adolescent patients.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via the national reporting system listed
in Appendix V.
4.9 Overdose
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.
Other medically significant sequelae of overdose include delirium, convulsion, coma, possible
neuroleptic malignant syndrome, respiratory depression, aspiration, hypertension or hypotension,
cardiac arrhythmias (< 2 % of overdose cases) and cardiopulmonary arrest. Fatal outcomes have been
reported for acute overdoses as low as 450 mg but survival has also been reported following acute
overdose of approximately 2 g of oral olanzapine.
Management
There is no specific antidote for olanzapine. Induction of emesis is not recommended. Standard
procedures for management of overdose may be indicated (i.e. gastric lavage, administration of
activated charcoal). The concomitant administration of activated charcoal was shown to reduce the
oral bioavailability of olanzapine by 50 to 60 %.
Symptomatic treatment and monitoring of vital organ function should be instituted according to
clinical presentation, including treatment of hypotension and circulatory collapse and support of
respiratory function. Do not use epinephrine, dopamine, or other sympathomimetic agents with betaagonist activity since beta stimulation may worsen hypotension. Cardiovascular monitoring is
necessary to detect possible arrhythmias. Close medical supervision and monitoring should continue
until the patient recovers.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: psycholeptics, diazepines, oxazepines, thiazepines and oxepines, ATC
code N05A H03.
Pharmacodynamic effects
Olanzapine is an antipsychotic, antimanic and mood stabilising agent that demonstrates a broad
pharmacologic profile across a number of receptor systems.
14
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; α1
adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT,
dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine
demonstrated a greater in vitro affinity for serotonin 5HT2 than dopamine D2 receptors and greater 5
HT2 than D2 activity in vivo models. Electrophysiological studies demonstrated that olanzapine
selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on
the striatal (A9) pathways involved in motor function. Olanzapine reduced a conditioned avoidance
response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an effect
indicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increases
responding in an “anxiolytic” test.
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. In addition, a Single
Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed
that olanzapine-responsive patients had lower striatal D2 occupancy than some other antipsychoticand risperidone-responsive patients, while being comparable to clozapine-responsive patients.
Clinical efficacy
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.
In a multinational, 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).
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. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the
proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a
co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition
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.
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. Olanzapine also
showed a statistically significant advantage over placebo in terms of preventing either recurrence into
mania or recurrence into depression.
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).
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.
Paediatric population
Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term studies in
schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than
200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to
15
20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared
with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and
prolactin (see sections 4.4 and 4.8) were 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). Information on long term
safety is primarily limited to open-label, uncontrolled data.
5.2 Pharmacokinetic properties
Olanzapine orodispersible tablet is bioequivalent to olanzapine coated tablets, with a similar rate and
extent of absorption. Olanzapine orodispersible tablets may be used as an alternative to olanzapine
coated tablets.
Absorption
Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5 to
8 hours. The absorption is not affected by food. Absolute oral bioavailability relative to intravenous
administration has not been determined.
Distribution
The plasma protein binding of olanzapine was about 93 % over the concentration range of about 7 to
about 1000 ng/ml. Olanzapine is bound predominantly to albumin and α1-acid-glycoprotein.
Biotransformation
Olanzapine is metabolized in the liver by conjugative and oxidative pathways. The major circulating
metabolite is the 10-N-glucuronide, which does not pass the blood brain barrier. Cytochromes P450-
CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl
metabolites, both exhibited significantly less in vivo pharmacological activity than olanzapine in
animal studies. The predominant pharmacologic activity is from the parent olanzapine.
Elimination
After oral administration, the mean terminal elimination half-life of olanzapine in healthy subjects
varied on the basis of age and gender.
In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination half-life was
prolonged (51.8 versus 33.8 hr) and the clearance was reduced (17.5 versus 18.2 l/hr). The
pharmacokinetic variability observed in the elderly is within the range for the non-elderly. In 44
patients with schizophrenia > 65 years of age, dosing from 5 to 20 mg/day was not associated with any
distinguishing profile of adverse events.
In female versus male subjects the mean elimination half life was somewhat prolonged (36.7 versus
32.3 hrs) and the clearance was reduced (18.9 versus 27.3 l/hr). However, olanzapine (5-20 mg)
demonstrated a comparable safety profile in female (n=467) as in male patients (n=869).
Renal impairment
In renally impaired patients (creatinine clearance < 10 ml/min) versus healthy subjects, there was no
significant difference in mean elimination half-life (37.7 versus 32.4 hr) or clearance (21.2 versus
25.0 l/hr). A mass balance study showed that approximately 57 % of radiolabelled olanzapine
appeared in urine, principally as metabolites.
Hepatic impairment
A small study of the effect of impaired liver function in 6 subjects with clinically significant (Childs
Pugh Classification A (n = 5) and B (n = 1)) cirrhosis revealed little effect on the pharmacokinetics of
orally administered olanzapine (2.5 – 7.5 mg single dose): Subjects with mild to moderate hepatic
dysfunction had slightly increased systemic clearance and faster elimination half-time compared to
subjects with no hepatic dysfunction (n = 3). There were more smokers among subjects with cirrhosis
(4/6; 67 %) than among subjects with no hepatic dysfunction (0/3; 0 %).
16
Smoking
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. However, the magnitude of the impact of age, gender, or smoking
on olanzapine clearance and half-life is small in comparison to the overall variability between
individuals.
In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the
pharmacokinetic parameters among the three populations.
Paediatric population
Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between
adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27%
higher in adolescents. Demographic differences between the adolescents and adults include a lower
average body weight and fewer adolescents were smokers. Such factors possibly contribute to the
higher average exposure observed in adolescents.
5.3 Preclinical safety data
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. The median lethal doses
were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to
100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate,
labored respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in
prostration and, at higher doses, semi-consciousness.
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. Tolerance
developed to the CNS depression. Growth parameters were decreased at high doses. 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.
Haematologic toxicity: Effects on haematology parameters were found in each species, including
dose-related reductions in circulating leukocytes in mice and non-specific reductions of circulating
leukocytes in rats; however, no evidence of bone marrow cytotoxicity was found. Reversible
neutropenia, thrombocytopenia, or anaemia developed in a few dogs treated with 8 or 10 mg/kg/day
(total olanzapine exposure [area under the curve] is 12- to 15-fold greater than that of a man given a
12-mg dose). In cytopenic dogs, there were no adverse effects on progenitor and proliferating cells in
the bone marrow.
Reproductive toxicity
Olanzapine had no teratogenic effects. Sedation affected mating performance of male rats. 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). In the offspring
of rats given olanzapine, delays in foetal development and transient decreases in offspring activity
levels were seen.
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.
Carcinogenicity
Based on the results of studies in mice and rats, it was concluded that olanzapine is not carcinogenic.
17
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Gelatin
Mannitol (E421)
Aspartame (E951)
Sodium methyl parahydroxybenzoate (E219)
Sodium propyl parahydroxybenzoate (E217)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in the original package in order to protect from light and moisture.
6.5 Nature and contents of container
Aluminium blister strips in cartons of 28, 35, 56, 70 or 98 orodispersible tablets per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
CHEPLAPHARM Registration GmbH, Weiler Straße 5e, 79540 Lörrach, Germany.
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/99/125/001
EU/1/99/125/002
EU/1/99/125/003
EU/1/99/125/004
EU/1/99/125/005
EU/1/99/125/006
EU/1/99/125/007
EU/1/99/125/008
EU/1/99/125/009
EU/1/99/125/010
EU/1/99/125/011
EU/1/99/125/012
EU/1/99/125/013
EU/1/99/125/014
18
EU/1/99/125/015
EU/1/99/125/016
EU/1/99/125/017
EU/1/99/125/018
EU/1/99/125/019
EU/1/99/125/020
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 3 February 2000
Date of latest renewal: 12 September 2006
10. DATE OF REVISION OF THE TEXT
{MM/YYYY}
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
19
ANNEX II
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING
AUTHORISATION
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
20
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
Name and address of the manufacturer responsible for batch release
Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain
Fidelio Healthcare Limburg GmbH, Mundipharmastraße 2, 65549 Limburg an der Lahn, Germany.
CHEPLAPHARM Registration GmbH, Weiler Straße 5e, 79540 Lörrach, Germany.
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
Medicinal product subject to medical prescription.
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING
AUTHORISATION
• Periodic safety update reports (PSURs)
The requirements for submission of PSURs for this medicinal product are set
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC and any subsequent updates published on the European medicines web-portal.
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
• Risk management plan (RMP)
The marketing authorization holder (MAH) shall perform the required pharmacovigilance activities
and interventions detailed in the agreed RMP presented in Module 1.8.2. of the marketing
authorisation and any agreed subsequent updates of the RMP.
An updated RMP should be submitted:
• At the request of the European Medicines Agency
• Whenever the risk management system is modified, especially as the result of new information
being received that may lead to a significant change to the benefit/risk profile or as the result of
an important (pharmacovigilance or risk minimisation) milestone being reached
21
ANNEX III
LABELLING AND PACKAGE LEAFLET
22
A. LABELLING
23
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON OF ZYPREXA VELOTAB 5 mg ORODISPERSIBLE TABLETS
1. NAME OF THE MEDICINAL PRODUCT
ZYPREXA VELOTAB5 mg orodispersible tablets
olanzapine
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each orodispersible tablet contains 5 mg olanzapine.
3. LIST OF EXCIPIENTS
Other ingredients: gelatin, mannitol (E421), aspartame (E951), sodium methyl parahydroxybenzoate
(E219), sodium propyl parahydroxybenzoate (E217).
4. PHARMACEUTICAL FORM AND CONTENTS
28 orodispersible tablets
35 orodispersible tablets
56 orodispersible tablets
70 orodispersible tablets
98 orodispersible tablets
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use
1. Separate one blister cell from the strip.
2. Carefully peel off the backing.
3. Gently push the tablet out.
4. Put the tablet in your mouth.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
24
8. EXPIRY DATE
EXP
9. SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light and moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
CHEPLAPHARM Registration GmbH, Weiler Straße 5e, 79540 Lörrach, Germany.
12. MARKETING AUTHORISATION NUMBER (S)
EU/1/99/125/001 28 orodispersible tablets
EU/1/99/125/009 35 orodispersible tablets
EU/1/99/125/005 56 orodispersible tablets
EU/1/99/125/013 70 orodispersible tablets
EU/1/99/125/017 98 orodispersible tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
zyprexa velotab 5 mg
17. UNIQUE IDENTIFIER – 2D BARCODE
2D barcode carrying the unique identifier included.
25
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA
PC
SN
NN
26
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
ZYPREXA VELOTAB 5 mg ORODISPERSIBLE TABLETS: BLISTER FOIL LABEL
1. NAME OF THE MEDICINAL PRODUCT
ZYPREXA VELOTAB 5 mg orodispersible tablets
olanzapine
2. NAME OF THE MARKETING AUTHORISATION HOLDER
CHEPLAPHARM
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
27
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON OF ZYPREXA VELOTAB 10 mg ORODISPERSIBLE TABLETS
1. NAME OF THE MEDICINAL PRODUCT
ZYPREXA VELOTAB10 mg orodispersible tablets
olanzapine
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each orodispersible tablet contains 10 mg olanzapine.
3. LIST OF EXCIPIENTS
Other ingredients: gelatin, mannitol (E421), aspartame (E951), sodium methyl parahydroxybenzoate
(E219), sodium propyl parahydroxybenzoate (E217).
4. PHARMACEUTICAL FORM AND CONTENTS
28 orodispersible tablets
35 orodispersible tablets
56 orodispersible tablets
70 orodispersible tablets
98 orodispersible tablets
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use
1. Separate one blister cell from the strip.
2. Carefully peel off the backing.
3. Gently push the tablet out.
4. Put the tablet in your mouth.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
28
8. EXPIRY DATE
EXP
9. SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light and moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
CHEPLAPHARM Registration GmbH, Weiler Straße 5e, 79540 Lörrach, Germany.
12. MARKETING AUTHORISATION NUMBER (S)
EU/1/99/125/002 28 orodispersible tablets
EU/1/99/125/010 35 orodispersible tablets
EU/1/99/125/006 56 orodispersible tablets
EU/1/99/125/014 70 orodispersible tablets
EU/1/99/125/018 98 orodispersible tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
zyprexa velotab 10 mg
17. UNIQUE IDENTIFIER – 2D BARCODE
2D barcode carrying the unique identifier included.
29
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA
PC
SN
NN
30
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
ZYPREXA VELOTAB 10 mg ORODISPERSIBLE TABLETS: BLISTER FOIL LABEL
1. NAME OF THE MEDICINAL PRODUCT
ZYPREXA VELOTAB 10 mg orodispersible tablets
olanzapine
2. NAME OF THE MARKETING AUTHORISATION HOLDER
CHEPLAPHARM
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
31
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON OF ZYPREXA VELOTAB 15 mg ORODISPERSIBLE TABLETS
1. NAME OF THE MEDICINAL PRODUCT
ZYPREXA VELOTAB15 mg orodispersible tablets
olanzapine
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each orodispersible tablet contains 15 mg olanzapine.
3. LIST OF EXCIPIENTS
Other ingredients: gelatin, mannitol (E421), aspartame (E951), sodium methyl parahydroxybenzoate
(E219), sodium propyl parahydroxybenzoate (E217).
4. PHARMACEUTICAL FORM AND CONTENTS
28 orodispersible tablets
35 orodispersible tablets
56 orodispersible tablets
70 orodispersible tablets
98 orodispersible tablets
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use
1. Separate one blister cell from the strip.
2. Carefully peel off the backing.
3. Gently push the tablet out.
4. Put the tablet in your mouth.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
32
8. EXPIRY DATE
EXP
9. SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light and moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
CHEPLAPHARM Registration GmbH, Weiler Straße 5e, 79540 Lörrach, Germany.
12. MARKETING AUTHORISATION NUMBER (S)
EU/1/99/125/003 28 orodispersible tablets
EU/1/99/125/011 35 orodispersible tablets
EU/1/99/125/007 56 orodispersible tablets
EU/1/99/125/015 70 orodispersible tablets
EU/1/99/125/019 98 orodispersible tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
zyprexa velotab 15 mg
17. UNIQUE IDENTIFIER – 2D BARCODE
2D barcode carrying the unique identifier included.
33
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA
PC
SN
NN
34
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
ZYPREXA VELOTAB 15 mg ORODISPERSIBLE TABLETS: BLISTER FOIL LABEL
1. NAME OF THE MEDICINAL PRODUCT
ZYPREXA VELOTAB 15 mg orodispersible tablets
olanzapine
2. NAME OF THE MARKETING AUTHORISATION HOLDER
CHEPLAPHARM
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
35
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON OF ZYPREXA VELOTAB 20 mg ORODISPERSIBLE TABLETS
1. NAME OF THE MEDICINAL PRODUCT
ZYPREXA VELOTAB20 mg orodispersible tablets
olanzapine
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each orodispersible tablet contains 20 mg olanzapine.
3. LIST OF EXCIPIENTS
Other ingredients: gelatin, mannitol (E421), aspartame (E951), sodium methyl parahydroxybenzoate
(E219), sodium propyl parahydroxybenzoate (E217).
4. PHARMACEUTICAL FORM AND CONTENTS
28 orodispersible tablets
35 orodispersible tablets
56 orodispersible tablets
70 orodispersible tablets
98 orodispersible tablets
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use
1. Separate one blister cell from the strip.
2. Carefully peel off the backing.
3. Gently push the tablet out.
4. Put the tablet in your mouth.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
36
8. EXPIRY DATE
EXP
9. SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light and moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
CHEPLAPHARM Registration GmbH, Weiler Straße 5e, 79540 Lörrach, Germany.
12. MARKETING AUTHORISATION NUMBER (S)
EU/1/99/125/004 28 orodispersible tablets
EU/1/99/125/012 35 orodispersible tablets
EU/1/99/125/008 56 orodispersible tablets
EU/1/99/125/016 70 orodispersible tablets
EU/1/99/125/020 98 orodispersible tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
zyprexa velotab 20 mg
17. UNIQUE IDENTIFIER – 2D BARCODE
2D barcode carrying the unique identifier included.
37
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA
PC
SN
NN
38
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
ZYPREXA VELOTAB 20 mg ORODISPERSIBLE TABLETS: BLISTER FOIL LABEL
1. NAME OF THE MEDICINAL PRODUCT
ZYPREXA VELOTAB 20 mg orodispersible tablets
olanzapine
2. NAME OF THE MARKETING AUTHORISATION HOLDER
CHEPLAPHARM
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
39
B. PACKAGE LEAFLET
40
Package leaflet: Information for the user
ZYPREXA VELOTAB 5 mg orodispersible tablets
ZYPREXA VELOTAB 10 mg orodispersible tablets
ZYPREXA VELOTAB 15 mg orodispersible tablets
ZYPREXA VELOTAB 20 mg orodispersible tablets
olanzapine
Read all of this leaflet carefully before you start taking this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,
even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.
What is in this leaflet
1. What ZYPREXA VELOTAB is and what it is used for
2. What you need to know before you take ZYPREXA VELOTAB
3. How to take ZYPREXA VELOTAB
4. Possible side effects
5. How to store ZYPREXA VELOTAB
6. Contents of the pack and other information
1. What ZYPREXA VELOTAB is and what it is used for
ZYPREXA VELOTAB contains the active substance olanzapine. ZYPREXA VELOTAB 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 sensing things which are not
there, mistaken beliefs, unusual suspiciousness, and becoming withdrawn. People with this
disease may also feel depressed, anxious or tense.
• Moderate to severe manic episodes, a condition with symptoms of excitement or euphoria.
ZYPREXA VELOTAB has been shown to prevent recurrence of these symptoms in patients with
bipolar disorder whose manic episode has responded to olanzapine treatment.
2. What you need to know before you take ZYPREXA VELOTAB
Do not take ZYPREXA VELOTAB
• If you are allergic (hypersensitive) to olanzapine or any of the other ingredients of this medicine
(listed in section 6). An allergic reaction may be recognised as a rash, itching, a swollen face,
swollen lips or shortness of breath. If this has happened to you, tell your doctor.
• If you have been previously diagnosed with eye problems such as certain kinds of glaucoma
(increased pressure in the eye).
Warnings and precautions
Talk to your doctor or pharmacist before you take ZYPREXA VELOTAB
• The use of ZYPREXA VELOTAB in elderly patients with dementia is not recommended as it may
have serious side effects.
• Medicines of this type may cause unusual movements mainly of the face or tongue. If this happens
after you have been given ZYPREXA VELOTAB tell your doctor.
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• Very rarely, medicines of this type cause a combination of fever, faster breathing, sweating,
muscle stiffness and drowsiness or sleepiness. If this happens, contact your doctor at once.
• Weight gain has been seen in patients taking ZYPREXA VELOTAB. You and your doctor should
check your weight regularly. Consider referral to a dietician or help with a diet plan if necessary.
• High blood sugar and high levels of fat (triglycerides and cholesterol) have been seen in patients
taking ZYPREXA VELOTAB. Your doctor should do blood tests to check blood sugar and certain
fat levels before you start taking ZYPREXA VELOTAB and regularly during treatment.
• Tell the doctor if you or someone else in your family has a history of blood clots, as medicines like
these have been associated with the formation of blood clots.
If you suffer from any of the following illnesses tell your doctor as soon as possible:
• Stroke or “mini” stroke (temporary symptoms of stroke)
• Parkinson’s disease
• Prostate problems
• A blocked intestine (Paralytic ileus)
• Liver or kidney disease
• Blood disorders
• Heart disease
• Diabetes
• Seizures
• If you know that you may have salt depletion as a result of prolonged severe diarrhoea and vomiting
(being sick) or usage of diuretics (water tablets)
If you suffer from dementia, you or your carer/relative should tell your doctor if you have ever had a
stroke or “mini” stroke.
As a routine precaution, if you are over 65 years your blood pressure may be monitored by your
doctor.
Children and adolescents
ZYPREXA VELOTAB is not for patients who are under 18 years.
Other medicines and ZYPREXA VELOTAB
Only take other medicines while you are on ZYPREXA VELOTAB if your doctor tells you that you
can. You might feel drowsy if ZYPREXA VELOTAB is taken in combination with antidepressants or
medicines taken for anxiety or to help you sleep (tranquillisers).
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:
• medicines for Parkinson’s disease.
• carbamazepine (an anti-epileptic and mood stabiliser), fluvoxamine (an antidepressant) or
ciprofloxacin (an antibiotic) - it may be necessary to change your ZYPREXA VELOTAB dose.
ZYPREXA VELOTAB with alcohol
Do not drink any alcohol if you have been given ZYPREXA VELOTAB as together with alcohol it
may make you feel drowsy.
Pregnancy and breast-feeding
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 be given this medicine when breast-feeding, as small amounts of ZYPREXA
VELOTAB can pass into breast milk.
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The following symptoms may occur in newborn babies, of mothers that have used ZYPREXA
VELOTAB in the last trimester (last three months of their pregnancy): shaking, muscle stiffness
and/or weakness, sleepiness, agitation, breathing problems, and difficulty in feeding. If your baby
develops any of these symptoms you may need to contact your doctor.
Driving and using machines
There is a risk of feeling drowsy when you are given ZYPREXA VELOTAB. If this happens do not
drive or operate any tools or machines. Tell your doctor.
ZYPREXA VELOTAB contains aspartame, sodium methyl parahydroxybenzoate and sodium
propyl parahydroxybenzoate
This medicine contains up to 1.6 mg aspartame in each tablet.
Aspartame is a source of phenylalanine. It may be harmful if you have phenylketonuria (PKU), a rare
genetic disorder in which phenylalanine builds up because the body cannot remove it properly.
This medicine contains sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate,
which may cause allergic reactions (possibly delayed). An allergic reaction may be recognised as a
rash, itching or shortness of breath. This may occur immediately or some time after you take
ZYPREXA VELOTAB.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially
‘sodium-free’.
3. How to take ZYPREXA VELOTAB
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist
if you are not sure.
Your doctor will tell you how many ZYPREXA VELOTAB tablets to take and how long you should
continue to take them. The daily dose of ZYPREXA VELOTAB is between 5 mg and 20 mg. Consult
your doctor if your symptoms return but do not stop taking ZYPREXA VELOTAB unless your doctor
tells you to.
You should take your ZYPREXA VELOTAB tablets once a day following the advice of your doctor.
Try to take your tablets at the same time each day. It does not matter whether you take them with or
without food. ZYPREXA VELOTAB orodispersible tablets are for oral use.
ZYPREXA VELOTAB tablets break easily, so you should handle the tablets carefully. Do not handle
the tablets with wet hands as the tablets may break up.
1. Hold the blister strip at the edges and separate one blister cell from the rest of the strip by gently
tearing along the perforations around it.
2. Carefully peel off the backing.
3. Gently push the tablet out.
4. Put the tablet in your mouth. It will dissolve directly in your mouth, so that it can be easily
swallowed.
You can also place the tablet in a full glass or cup of water, orange juice, apple juice, milk or coffee,
and stir. With some drinks, the mixture may change colour and possibly become cloudy. Drink it
straight away.
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If you take more ZYPREXA VELOTAB than you should
Patients who have taken more ZYPREXA VELOTAB than they should have experienced the
following symptoms: rapid beating of the heart, agitation/aggressiveness, problems with speech,
unusual movements (especially of the face or tongue) and reduced level of consciousness. Other
symptoms may be: acute confusion, seizures (epilepsy), coma, a combination of fever, faster
breathing, sweating, muscle stiffness and drowsiness or sleepiness, slowing of the breathing rate,
aspiration, high blood pressure or low blood pressure, abnormal rhythms of the heart. Contact your
doctor or hospital straight away if you experience any of the above symptoms. Show the doctor your
pack of tablets.
If you forget to take ZYPREXA VELOTAB
Take your tablets as soon as you remember. Do not take two doses in one day.
If you stop taking ZYPREXA VELOTAB
Do not stop taking your tablets just because you feel better. It is important that you carry on taking
ZYPREXA VELOTAB for as long as your doctor tells you.
If you suddenly stop taking ZYPREXA VELOTAB, symptoms such as sweating, unable to sleep,
tremor, anxiety or nausea and vomiting might occur. Your doctor may suggest you to reduce the dose
gradually before stopping treatment.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Tell your doctor immediately if you have:
• unusual movement (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 legs (symptoms include swelling, pain, and redness in the leg), which may travel
through blood vessels to the lungs causing chest pain and difficulty in breathing. If you notice any
of these symptoms seek medical advice immediately;
• a combination of fever, faster breathing, sweating, muscle stiffness and drowsiness 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 people) include weight gain; sleepiness; and
increases in 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. This will
usually pass on its own but if it does not, 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 early in treatment, temporary increases in liver enzymes ; increases in the level
of sugars in the blood and urine; increases in levels of uric acid and creatine phosphokinase in the blood;
feeling more hungry; 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 dysfunctions 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 (e.g. swelling in the
mouth and throat, itching, rash); diabetes or the worsening of diabetes, occasionally associated with
ketoacidosis (ketones in the blood and urine) or coma; seizures, usually associated with a history of
seizures (epilepsy); muscle stiffness or spasms ( including eye movements); restless legs syndrome;
problems with speech; stuttering; slow heart rate; sensitivity to sunlight; bleeding from the nose;
abdominal distension; drooling; memory loss or forgetfulness; urinary incontinence; lack of ability to
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urinate; hair loss; absence or decrease in menstrual periods; and changes in breasts in males and females
such as an abnormal production of breast milk or abnormal growth.
Rare side effects (may affect up to 1 in 1000 people) include lowering of normal body temperature;
abnormal rhythms of the heart; sudden unexplained death; inflammation of the pancreas causing severe
stomach pain, fever and sickness; liver disease appearing as yellowing of the skin and white parts of the
eyes; muscle disease presenting as unexplained aches and pains; and prolonged and/or painful erection.
Very rare side effects include serious allergic reactions such as Drug Reaction with Eosinophilia and
Systemic Symptoms (DRESS). DRESS appears initially as flu-like symptoms with a rash on the face
and then with an extended rash, high temperature, enlarged lymph nodes, increased levels of liver
enzymes seen on blood tests and an increase in a type of white blood cells (eosinophilia).
While taking olanzapine, 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 and have trouble walking. Some fatal cases have been reported in this particular group of patients.
In patients with Parkinson's disease ZYPREXA VELOTAB may worsen the 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.
5. How to store ZYPREXA VELOTAB
Keep this medicine out of sight and reach of children.
Do not use this medicine after the expiry date, which is stated on the carton.
ZYPREXA VELOTAB should be stored in its original pack in order to protect from light and
moisture.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to
throw away medicines you no longer use. These measures will help to protect the environment.
6. Contents of the pack and other information
What ZYPREXA VELOTAB contains
• The active substance is olanzapine. Each ZYPREXA VELOTAB orodispersible tablet contains
either 5 mg, 10 mg, 15 mg or 20 mg of the active substance. The exact amount is shown on your
ZYPREXA VELOTAB pack.
• The other ingredients are
- gelatin, mannitol (E421), aspartame (E951), sodium methyl parahydroxybenzoate (E219) and
sodium propyl parahydroxybenzoate (E217).
What ZYPREXA VELOTAB looks like and contents of the pack
ZYPREXA VELOTAB 5 mg, 10 mg, 15 mg and 20 mg are yellow orodispersible tablets.
Orodispersible tablet is the technical name for a tablet which dissolves directly in your mouth, so that
it can be easily swallowed.
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ZYPREXA VELOTAB is available in packs containing 28, 35, 56, 70 or 98 tablets. Not all pack sizes
may be marketed.
Marketing Authorisation Holder
CHEPLAPHARM Registration GmbH, Weiler Straße 5e, 79540 Lörrach, Germany.
Manufacturer
Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain.
Fidelio Healthcare Limburg GmbH, Mundipharmastraße 2, 65549 Limburg an der Lahn, Germany.
CHEPLAPHARM Registration GmbH, Weiler Straße 5e, 79540 Lörrach, Germany.
This leaflet was last revised in {month XXXX}
