Composition, form of production and packaging
The tablets covered with a film shell from white color, round, biconcave, with engraving "OL5" on one of the sides; on the cross-section - the core of yellow color.
1 tab.
olanzapine 5 mg
Auxiliary substances: lactose monohydrate - 75.2 mg, giprolose - 3 mg, crospovidone type A - 5 mg, salted 50 (microcrystalline cellulose 98% - 3.92 mg, silicon dioxide colloid 2% - 0.08 mg), salted 90 (microcrystalline cellulose 98% 9.8 mg, silicon dioxide colloid 2% - 0.2 mg), magnesium stearate - 0.5 mg.
The composition of the film shell: opedrai II white Y-22-7719 (titanium dioxide (E171) 1.5 mg, polydextrose 1.2 mg, hypromellose 3cP 0.9 mg, hypromellose 6cP 0.7715 mg, hypromellose 50 cp 0.1285 mg, triacetin 0.3750 mg , macrogol 8000 - 0.1250 mg).
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (5) - packs of cardboard.
Tablets covered with a film shell from white, round, biconcave, engraved "OL10" on one side; on the cross-section - the core of yellow color.
1 tab.
olanzapine 10 mg
Auxiliary substances: lactose monohydrate 145 mg, giprolose 6 mg, crospovidone type A 10 mg, salting 50 (microcrystalline cellulose 98% - 7.84 mg, colloidal silicon dioxide 2% 0.16 mg), salting 90 (microcrystalline cellulose 98% 19.6 mg, silicon dioxide colloid 2% - 0.4 mg), magnesium stearate - 1 mg.
The composition of the film shell: opadrai II white Y-22-7719 (titanium dioxide (E171) -3 mg, polydextrose 2.4 mg, hypromellose 3cR 1.8 mg, hypromellose 6cP 1.543 mg, hypromellose 50 cP 0.2570 mg, triacetin 0.75 mg , macrogol 8000 - 0.25 mg).
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (5) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
PHARMACHOLOGIC EFFECT
Olanzapine is an antipsychotic drug (neuroleptic) with a broad pharmacological spectrum of influence on a number of receptor systems. Antipsychotic action is due to antagonism with respect to 5HT2 A / 2C - ; 5HT 3 -, 5HT 6 -serotonin receptors, D1-, D2-, D3-, D4-, D5-dopamine receptors, m-cholinoblocking effects - blockade of M 1-5 muscarinic cholinergic receptors; also has an affinity for alpha 1- adreno-and H 1 -histamine receptors. In vivo and in vitro, olanzapine has a more pronounced affinity and activity for 5HT 2 -serotonin receptors compared to D2-dopamine receptors.
Olanzapine selectively decreases the excitability of mesolimbic (A10) dopaminergic neurons, has an insignificant effect on the striatal (A9) nerve pathways involved in the regulation of motor functions. Olanzapine reduces the conditioned protective reflex (a test characterizing antipsychotic activity) at lower doses than the doses causing catalepsy (a disorder reflecting the effect on motor function). Unlike other antipsychotics, olanzapine enhances the anti-anxiety effect during the "anxiolytic" test.
Olanzapine reduces the delta rhythm (1-4 Hz) in the anterior parts of the frontal-central regions of the brain (F3,4, C3,4), diffusely enhances the theta range (4-8 Hz) in the same fronto-central and parietal-central regions, and also enhances the alpha-rhythm (8-13 Hz) in the occipital and parietal cortical areas. The increment of the alpha rhythm indicates the normalization of the EEG structure under the influence of olanzapine, which gives a global inhibitory effect in almost all parts of the brain, with the exception of the frontal regions.
Eliminates productive symptoms of psychosis (delirium, hallucinations, thinking disorders, hostility, suspiciousness), reduces negative symptoms (emotional and social autism, introvert, poor speech). Dulls the acuteness of emotional experiences, weakens aggressiveness and impulsiveness of behavioral reactions, forms tolerance to the surrounding reality and reduces initiative. It stops the stimulation and corrects behavioral and mental disorders in patients with mental disorders.
PHARMACOKINETICS
After ingestion olanzapine is well absorbed from the digestive tract. Eating food does not affect the bioavailability of olanzapine. Bioavailability decreases by 40% due to the effect of "first passage" through the liver. C max in blood plasma is achieved after 5-8 hours. The equilibrium concentration is achieved after 1 week of daily intake and twice the plasma concentration after a single dose. Plasma concentration in the dose range from 1-20 mg varies linearly and is proportional to the dose.
At a plasma concentration of 7 to 1000 ng / ml, binding to plasma proteins, mainly albumin and alpha-1-acid glycoprotein, is about 93%.
Passes through the histohematological barriers, including the blood-brain barrier. The volume of distribution is about 1000 liters.
Olanzapine is metabolized in the liver by conjugation and oxidation. The main circulating metabolite is 10-N-glucuronide, which does not theoretically penetrate the blood-brain barrier. Isozymes CYP1A2 and CYP2D6 cytochrome P450 are involved in the formation of N-desmethyl and 2-hydroxymethylmetabolites of olanzapine.The main pharmacological activity of the drug is due to the starting substance - olanzapine. Metabolites have significantly less pharmacological activity in vivo than olanzapine. The activity of the cytochrome P450 CYP2D6 isoenzyme does not affect the rate of metabolism of olanzapine. About 57% of the oral dose of olanzapine is excreted in the urine, mainly in the form of metabolites.
T 1/2 and the clearance of olanzapine (KO) vary depending on sex, age, the presence of a predilection for smoking. In young healthy volunteers (mixed population) T1/2 is, on the average, 33 h (21-54 h), and the average value of total plasmatic KO is 26 l / h (12-47 l / h). In healthy elderly volunteers (age 65 years and older), T 1/2 isextended to 51.8 hours, KO drops to 17.7 l / h. In women compared with men, T 1/2 olanzapine is higher (36.7 h versus 32.3 h), and KO is lower (18.9 ml vs. 27.3 l / h). For non-smokers, men and women compared with those who smoke T 1/2 increase (38.6 hours vs. 30.4 hours), while KO decreases (18.6 l / h versus 27.7 l / h).However, the degree of changes in T 1/2 and total plasma KO, depending on sex, age, smoking addiction, is significantly inferior to the degree of individual differences in these parameters.
There were no significant differences between the mean values ​​of T 1/2 and KO in patients with severe renal dysfunction, compared to those with normal renal function.
In smokers with minor hepatic impairment, T 1/2 is higher (48.8 h) and KO is lower (14.1 l / h) than for non-smokers without liver disorders (T 1/2 - 39.3 h, KO - 18 l / h ).
In people over 65 years, T 1/2 olanzapine may be significantly prolonged, so the average daily dose of olanzapine should be lower than usual. In studies involving individuals from European, Japanese and Chinese populations, no differences in the pharmacokinetics of olanzapine related to race were established.
INDICATIONS
- schizophrenia: treatment of exacerbations, sustained and prolonged anti-relapse therapy;
- bipolar affective disorder: treatment of acute manic or mixed episodes;
- to prevent relapse in patients with bipolar affective disorder, in which olanzapine was effective in treating the manic phase.
DOSING MODE
Inside, regardless of food intake.
In schizophrenia, the recommended initial dose is 10 mg once a day.
For the treatment of an acute manic episode with bipolar affective disorder, the recommended initial dose is 15 mg once a day (when used as monotherapy) or 10 mg once a day (with combination with lithium or valproic acid).
To prevent recurrence of bipolar affective disorder, the recommended initial dose is 10 mg once a day.
In the treatment of schizophrenia, an acute manic episode with bipolar affective disorder and to prevent recurrence of bipolar affective disorders, olanzapine doses are individually selected depending on the clinical status of the patient and vary in the range of 5-20 mg once a day. An increase in the dose above the standard dose (15 mg once a day) is recommended only after an appropriate clinical examination of the patient. Increase the dose should be gradual, with intervals of at least 24 hours.
A reduction in the initial dose is recommended in patients with a combination of factors (female, elderly, non-smokers), which can help slow the metabolism of olanzapine.
For elderly patients , as well as for renal failure of severe or insufficient liver function of moderate severity, the drug is used in an initial dose of 5 mg once a day.
SIDE EFFECT
The frequency of side effects is classified according to the recommendations of the World Health Organization: very often - not less than 10%: often - not less than 1%, but less than 10%; infrequently - not less than 0.1%, but less than 1%: rarely - not less than 0.01%, but less than 0.1%: very rarely - not less than 0.01%, including single messages.
On the part of the blood and lymphatic system: often - eosinophilia; rarely - leukopenia; very rarely - thrombocytopenia, neutropenia.
From the side of metabolism: very often - an increase in body weight; often - increased appetite; unknown frequency - development or exacerbation of diabetes mellitus, diabetic ketoacidosis, diabetic coma, including fatal.
From the nervous system: very often - drowsiness; often - dizziness, akathisia, parkinsonism, dyskinesia, gait disorders (in patients with Alzheimer's dementia); rarely - extrapyramidal disorders (mainly when high doses are used); very rarely - sweating, insomnia, tremor, anxiety, nausea; unknown frequency - malignant neuroleptic syndrome (CNS), dystonia (including oculogic crisis), tardive dyskinesia.
From the cardiovascular system: often - orthostatic hypotension; infrequent bradycardia, prolongation of the QT interval; unknown frequency - ventricular tachycardia / ventricular fibrillation; sudden death, thromboembolism of the pulmonary artery, deep vein thrombosis.
From the side of the digestive system: often - dryness of the oral mucosa, constipation (m-cholinoblock effect); very rarely - hepatitis (including hepatocellular, cholestatic or mixed), pancreatitis.
From the skin and subcutaneous tissues: infrequently - the reaction of photosensitization; rarely - skin rash; very rarely - alopecia.
From the side of the musculoskeletal system: very rarely - rhabdomyolysis.
From the genitourinary system: infrequently - incontinence; very rarely - priapism, delay urination.
Laboratory indicators: very often - an increase in the concentration of prolactin in the blood plasma *; often - an increase in the concentration of glucose, cholesterol and triglycerides in the blood plasma, glucosuria, a transient increase in the activity of hepatic enzymes (aspartate aminotransferase (ACT) and alanine aminotransferase (ALT)); infrequently-increased activity of creatine phosphokinase (CK); very rarely - an increase in the activity of alkaline phosphatase and a concentration of total bilirubin.
* Increase in the concentration of prolactin in the blood plasma - poorly expressed, having a transient nature (the mean value of maximum concentrations of prolactin did not reach the upper limit of the norm and was statistically significantly different from placebo). Clinical manifestations of hyperprolactinaemia, possibly associated with taking olanzapine (ie, amenorrhea, galactorrhea, breast enlargement in women, gynecomastia in men) were rare. Sexual dysfunction, possibly associated with the use of olanzapine (erectile dysfunction in men, decreased libido in men and women) was observed frequently. In most patients the normalization of prolactin concentration was observed without the abolition of olanzapine.
Other: often - asthenia, fatigue, peripheral edema; unknown frequency - hypothermia, withdrawal syndrome (increased sweating, insomnia, tremor, anxiety, nausea, vomiting).
Special patient groups
In elderly patients with psychosis associated with dementia: very often - cerebrovascular disorders (stroke, transient ischemic attacks), including fatal, violation of gait and fall; often - incontinence of urine and pneumonia.
In patients with drug-induced psychosis (dopamine receptor agonist) for the treatment of Parkinson's disease: very often - increased symptoms of parkinsonism and hallucinations.
In patients with bipolar mania who take olanzapine in combination with lithium or valproic acid: very often - weight gain, dryness of the oral mucosa, increased appetite, tremor; often - speech disorder.
CONTRAINDICATIONS
- Closed-angle glaucoma in history;
- the period of breastfeeding;
- age under 18 years (effectiveness and safety not established);
- lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;
- Hypersensitivity to olanzapine and other components of the drug.
Carefully:
Renal failure; liver failure; in patients receiving treatment with potentially hepatotoxic drugs; benign prostatic hyperplasia; neutropenia; myelosuppression (including due to concomitant diseases, chemo- and radiation therapy); myeloproliferative diseases; hypereosinophilic syndrome; conditions predisposing to the development of arterial hypotension (dehydration, hypovolemia, antihypertensive drugs); cardiovascular diseases (myocardial infarction, ischemic heart disease, heart failure, intracardiac conduction disturbance, etc.); epileptic seizures in the anamnesis; elderly patients (over 65 years of age), including those with dementia associated with psychosis and / or behavioral disorders; paralytic ileus and similar conditions; pneumonia; simultaneous use with medicinal products of central action, benzodiazepines, ethanol.
PREGNANCY AND LACTATION
Women should be informed of the need to inform the doctor about the onset or planned pregnancy during therapy with Olanzapine-Teva.
Due to limited experience with olanzapine during pregnancy, Olanzapine Teva should be used to treat pregnant women only if the potential benefit of therapy for the mother exceeds the potential risk to the fetus.
Olanzapine is excreted in breast milk. If you need to use Olanzapine-Teva, breastfeeding should be discontinued.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution should be used for kidney failure
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution should be used for liver failure
APPLICATION FOR CHILDREN
Contraindicated appointment to patients under the age of 18 years (efficacy and safety not established).
APPLICATION IN ELDERLY PATIENTS
Use with caution in elderly patients (over 65 years of age), including with dementia associated with psychosis and / or behavioral disorders.
In people over 65 years, T 1/2 olanzapine may be significantly prolonged, so the average daily dose of olanzapine should be lower than usual.
SPECIAL INSTRUCTIONS
Malignant neuroleptic syndrome. With the use of any antipsychotics, including olanzapine, the development of NSA is possible, the clinical manifestations of which include a significant increase in body temperature, rigidity of the muscles, changes in mental status, and autonomic disorders (tachycardia, unstable pulse or blood pressure, cardiac arrhythmia, increased sweating). Additional signs may include an increase in serum CK, myoglobinuria (a symptom of rhabdomyolysis), and acute renal failure. Clinical manifestations of malignant neuroleptic syndrome or a significant increase in body temperature without other symptoms of this syndrome require the withdrawal of all neuroleptics, including olanzapine.
Parkinson's disease. The use of Olanzapine-Teva is not recommended for the treatment of psychosis in Parkinson's disease caused by the use of dopamine receptor agonists, due to the fact that the symptoms of parkinsonism and hallucinations may increase. The effectiveness of olanzapine in the treatment of psychotic symptoms in this case does not exceed the use of placebo.
Psychoses associated with dementia, and / or behavioral disorders. Olanzapine-Teva is not recommended for use in elderly patients with psychosis associated with dementia and / or behavioral disorders due to the increased risk of developing cerebrovascular disorders (stroke, transient ischemic attacks) in this group of patients and death. It was found that high mortality was not associated with a dose of olanzapine or duration of treatment with olanzapine. Risk factors that could predispose to an increase in the mortality of patients in this population were age over 65 years, dysphagia, sedation, malnutrition, dehydration, lung disease (pneumonia with or without aspiration) or simultaneous use of benzodiazepines. Additionally, all patients who had cerebrovascular disorders, both in the olanzapine group and in the placebo group, suffered from vascular dementia or mixed-type dementia. The effectiveness of olanzapine in this group of patients has not been determined.
Hyperglycemia and / or development or exacerbation of diabetes mellitus. In some cases, with the use of olanzapine may develop hyperglycemia, diabetes mellitus, exacerbation of pre-existing diabetes, diabetic ketoacidosis and diabetic coma, including fatal. As reported, an increase in the patient's body weight may be a predisposing factor for the development of these side effects. It is necessary during application of the preparation of olanzapine-Teva in patients with diabetes or diabetes risk factors caution and control the display of signs of hyperglycemia (polydipsia, polyuria, increased appetite, fatigue) as well as regular monitoring of the patient's body and the plasma glucose concentration blood.
Changing concentrations of lipids. Changes in lipid concentrations in the blood plasma in the treatment of drug-Olanzapine Teva is necessary to control in patients with dyslipidaemia and in patients with risk factors for disorders of lipid metabolism.
M-anticholinergic effect.Olanzapine may be associated with adverse reactions associated with the expression of m-anticholinergic effect. Clinical experience with olanzapine in patients with concomitant diseases is limited, so caution is advised when the use of olanzapine in patients with clinically significant benign prostatic hypertrophy, paralytic ileus, angle-closure glaucoma, and other similar states.
Liver function.Transient asymptomatic increase in the activity of "liver" transaminases (ALT and ACT) most frequently mentioned at the beginning of treatment with olanzapine. Care should be taken in patients with initially increased ALT activity and / or ACT, in patients with liver failure, liver reserve limited functionality or patients treated with potentially hepatotoxic drugs. In the case of the hepatitis (including hepatocellular, cholestatic or mixed aetiology) preparation of olanzapine-Teva should be canceled.
neutropenia. Care should be taken in patients with low numbers of leukocytes and / or neutrophil associated with any reasons, including the reception of drugs which cause neutropenia, bone marrow depression caused by concomitant diseases, radio- or chemotherapy history and hypereosinophilia or myeloproliferative disease. Neutropenia usually occurs while olanzapine and valproic acid. Use of olanzapine in patients with clozapine-agranulocytosis dependent neutropenia or a history of recurrent not accompanied by such disorder.
withdrawal. In sharp discontinuation of olanzapine-Teva drug in some cases, may develop a condition accompanied by acute symptoms arising: sweating, insomnia, tremor, anxiety, nausea, and vomiting.
QT interval elongation.During clinical studies in patients taking olanzapine, compared with patients in the placebo group, there was a clinically significant elongation of QTc interval (QT interval corrected by Fridericia; elongation QTcF interval not less than 500 ms in patients with baseline QTcF less than 500 ms), which is not associated with any side effects of the cardiovascular system. However, as with the reception of other antipsychotics, caution should be exercised while the use of drugs that prolong the QT interval, especially in the elderly, patients with congenital syndrome elongate interval QT, in congestive heart failure while taking the drug olanzapine-Teva, myocardial hypertrophy, hypokalaemia or hypomagnesemia.During treatment with olanzapine should be periodic monitoring of electrocardiograms.
Thromboembolism. Reported individual cases of VTE with olanzapine. The causal relationship between VTE and olanzapine has not been established. However, since patients with schizophrenia, along with acquired risk factors for VTE, can make all the other possible risk factors for VTE such as prolonged immobilization, it is necessary to identify these risk factors and take preventive measures for VTE.
Convulsions. Olanzapine Teva drug, should be used with caution in patients who have a history of convulsions indication or risk factors that may contribute to the lowering of the threshold for seizure activity.
Tardive Dyskinesia.In a comparative study of olanzapine less than 1 year was significantly less often accompanied by the development of dyskinesia, requiring medical treatment than treatment with haloperidol. However the risk of tardive dyskinesia increases with longer use of olanzapine. If signs or symptoms of tardive dyskinesia should consider lowering the dose of the drug Olanzapine Teva, or its abolition. The symptoms of tardive dyskinesia can worsen temporarily, or even occur after discontinuation of the drug.
Orthostatic hypotension.Because olanzapine adrenoceptor blocking action may cause orthostatic hypotension accompanied by dizziness, palpitations, fainting during primary selection dose. Most often orthostatic hypotension occurs in elderly patients, and the use of other antipsychotics. The development of these effects can be minimized by a fractional dose titration and the start of treatment with the lowest dose. In applying the drug Olanzapine Teva, should monitor blood pressure, especially in patients older than 65 years. In the event of severe patients orthostatic hypotension it is necessary to warn them so they do not get up abruptly and without assistance.
Sudden death.Clinical experience with all antipsychotics, including olanzapine showed similar dose-dependent, two-fold increased risk of sudden death compared with the cases of sudden death in patients who did not apply the neuroleptics.
Effect on the central nervous system (CNS). Given the nature of the drug on the CNS, should be used with caution olanzapine in combination with other drugs and central action ethanol.
Under conditions in vitro olanzapine exhibits antagonism of dopamine receptors, and, like other neuroleptics, can theoretically suppress the action of levodopa and dopamine receptor agonists.
Impact on the ability to drive vehicles and manage mechanisms
Caution should be exercised when using the drug Olanzapine Teva, due to the potential for adverse reactions that may adversely affect the ability to drive vehicles and the performance of potentially hazardous activities that require high concentration and psychomotor speed reactions.
OVERDOSE
Symptoms: tachycardia, agitation / aggression, dysarthria, various extrapyramidal disorders and impaired consciousness different severity (from sedation to coma), delirium, seizures, CSN, respiratory depression, aspiration, hypertension or hypotension, ventricular tachycardia (less than 2% overdose), cardiac arrest and breathing. The minimum dose for acute lethal overdose was 450 mg, the maximum dose overdose with a favorable outcome (survival) - 1500 mg.
Treatment: there is no specific antidote. Artificially induce vomiting is not recommended. Showing detoxification standard techniques (i.e., gastric lavage, administration of activated charcoal). Simultaneous treatment with activated charcoal reduces the bioavailability of olanzapine, taken orally, by 50-60%. Symptomatic treatment according to clinical status and control functions of the vital organs, including the correction of hypotension, circulatory collapse and support of respiratory function. You should not use epinephrine, dopamine and other sympathomimetic, which are agonists of the beta-adrenergic receptors, as the latter stimulation may worsen hypotension.
DRUG INTERACTION
The metabolism of olanzapine can vary under the effect of inhibitors or inducers of cytochrome P450 isoenzymes, exhibiting a specific activity against isozyme CYP1A2. CO increases in smoking patients and patients receiving carbamazepine (due to the increased activity of the isoenzyme CYP1A2). Known potential inhibitors can reduce the CYP1A2 isoenzyme DA. Olanzapine is not a potential inhibitor of isozyme CYP1A2, so the pharmacokinetics of olanzapine drugs such as theophylline, are metabolized mainly involving isoenzyme CYP1A2, is not changed.
Fluvoxamine, a specific inhibitor of isoenzyme CYP1A2, significantly alters the pharmacokinetics of olanzapine, increasing its the C max54% in non-smoking women and 77% in male smokers with increasing values of the area under the concentration-time curve by 52% and 108%, respectively. It should reduce the dosage of olanzapine in patients taking fluvoxamine or other inhibitors isoenzyme CYP1A2, such as ciprofloxacin.
A single dose of olanzapine therapy following medications: imipramine or its metabolite desipramine (isoenzymes CYP2D6, CYP3A4, CYP1A2), warfarin (isoenzyme CYP2C19), theophylline (isoenzyme CYP1A2) or diazepam (isozymes CYP3A4, CYP2C19) - was not accompanied by the suppression of their metabolism. There were no signs of drug interactions as olanzapine simultaneously with lithium or biperidenom.
Olanzapine has an extremely small potential to inhibit the activity of these isoenzymes of cytochrome P 450 : CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. A single dose of aluminium- and magnesium-containing antacid or cimetidine does not affect olanzapine oral bioavailability. Simultaneous reception of activated charcoal reduces the bioavailability of olanzapine by 50-60%.
Fluoxetine (60 mg or 60 mg once daily for 8 days) causes an increase in C max olanzapine on average 16% decrease in CO and an average of 16%. The degree of influence of fluoxetine significantly inferior expression of individual differences in pharmacokinetic parameters, however generally not recommended to change the dose of olanzapine when used in combination with fluoxetine.
In in vitro studies using human liver microsomes, it was shown that olanzapine significantly suppresses the formation of glucuronide valproic acid (major route of metabolism of valproic acid). Valproic acid is also significantly affect the metabolism of olanzapine. Therefore, clinically significant pharmacokinetic interaction between valproic acid and olanzapine unlikely.
On the background of stable concentrations of ethanol pharmacokinetics of olanzapine changes were noted. However, reception of ethanol with olanzapine may be associated with increased pharmacological effects of olanzapine, such as sedation.
Caution must be exercised when olanzapine in patients who consume alcohol or taking medications that can cause central nervous system depression.
The simultaneous use of olanzapine with antiparkinsonian drugs in patients with dementia in Parkinson's disease patients is not recommended.
As with other antipsychotic drugs olanzapine Caution should be exercised while the use of drugs which prolong the interval QT.
TERMS OF RELEASE FROM PHARMACY
On prescription.
TERMS AND CONDITIONS OF STORAGE
Store at a temperature of no higher than 25 В° C in a dark place. Keep out of the reach of children. Shelf life - 2 years. Do not take after the expiry date stated on the package.
