Olanzapine

ADAGIO® 5 mg film-coated tablets, 10 mg film-coated tablets

Instruction manual

For medical use of the drug

Adagio

(adagio)

Structure:

Active ingredient: 1 tablet contains olanzapine 5 mg or 10 mg;

excipients: lactose, monohydrate; magnesium stearate; microcrystalline cellulose; corn starch;

film coating: hydroxypropyl methylcellulose; hydroxypropyl cellulose; polyethylene glycol; titanium dioxide (E171).

Dosage form.

Film-coated tablets.

Basic physical and chemical properties:

5 mg film-coated tablets: white, round, biconvex, film-coated tablets. Engraving "ARC" on one side, "OLA" over "5" on the other.

10 mg film-coated tablets: white, round, biconvex, film-coated tablets. The engraving is “ARC” on one side, “OLA” over “10” on the other.

Pharmacotherapeutic group.

Antipsychotic drugs. code atx n05a h03.

Pharmacological properties.

Pharmacodynamics

Olanzapine is an antipsychotic, anti-manic drug that stabilizes mood. It has a wide range of pharmacological effects, due to the effect on various receptors. Binding to 5 HT Serotonin Receptors Revealed_{2A / 2C}5 NT₃5 NT₆dopamine receptors D₁, D₂, D₃, D₄, D₅muscarinic receptors M₁ - M₅, adrenergic receptor α₁ and histamine H₁-receptor. In studies of the behavior of animals that were administered olanzapine, antagonism of olanzapine was revealed both to serotonin 5HT receptors and to dopamine and cholinergic. Olanzapine has a higher level of binding to serotonin 5HT receptors₂than with dopamine D receptors₂, in both in vitro and in vivo models. Electrophysiological studies have shown that olanzapine selectively reduces the excitability of mesolimbic (A10) dopaminergic neurons, with a slight effect on striatal (A9) pathways associated with motor function. Olanzapine inhibits the conditioned avoidance reflex, which indicates its antipsychotic activity when taken in doses lower than the doses that cause catalepsy, which is a sign of side motor effects. Unlike some other antipsychotic drugs, olanzapine enhances the response to irritants during the anxiolytic test.

With a single dose of 10 mg of olanzapine by volunteers during positron emission tomography (PET), it was found that olanzapine had a higher level of binding to 5 NT receptors_2Athan with dopamine D receptors₂. In addition, as a result of the analysis of images obtained during studies of patients with schizophrenia using single photon emission computed tomography (SPECT), it was found that patients sensitive to olanzapine had a lower level of binding to striatal D₂receptors than other antipsychotic and risperid-sensitive patients, which is comparable to that of clozapine-sensitive patients.

Clinical efficacy.

In the treatment of schizophrenia patients with positive and negative symptoms of olanzapine, statistically reliable data were obtained regarding the improvement of both negative and positive symptoms.

In patients with manic or mixed episodes of bipolar disorder, olanzapine has been shown to be highly effective in reducing manic symptoms.

Children.

The experience of use for adolescents (aged 13 to 17 years) is limited.

Pharmacokinetics

Absorption.

The drug is well absorbed after oral administration, C_max in blood plasma is reached after 5 - 8 hours. Eating does not affect the absorption of olanzapine.

Distribution.

The level of binding of olanzapine to plasma proteins is approximately 93% at a concentration ranging from 7 ng / ml to 1000 ng / ml. Olanzapine binds predominantly to albumin and α₁-acid glycoprotein.

Biotransformation.

Olanzapine is metabolized in the liver by conjugation and oxidation. The main circulating metabolite is 10-N-glucuronide, which does not cross the blood-brain barrier. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the formation of metabolites of N-desmethyl and 2-hydroxymethyl, which exhibit significantly lower pharmacological activity in vivo than olanzapine in animal studies. The predominant pharmacological activity is due to primary olanzapine.

Breeding.

After oral administration, the average half-life of olanzapine in volunteers varied depending on age and gender.

In healthy elderly volunteers (65 years and older), compared with younger volunteers, the average half-life was longer (51.8 compared to 33.8 hours), plasma clearance was reduced (17.5 compared to 18.2 l / h). The pharmacokinetic fluctuations observed in elderly volunteers were within the range of younger volunteers. In 44 patients with schizophrenia at the age of 65, a dosage of 5 to 20 mg / day was not associated with any characteristic profile of adverse events.

In women, compared with men, the average half-life was longer (36.7 compared to 32.3 hours), plasma clearance was reduced (18.9 compared to 27.3 l / h). However, olanzapine (5–20 mg) showed a comparable safety profile in both women (N = 467) and men (N = 869).

Patients with renal failure.

In patients with renal failure (creatinine clearance, compared with healthy volunteers, there was no significant difference in mean half-life (37.7 compared to 32.4 hours) or plasma clearance (21.2 compared to 25.0 l / h) Studies have shown that approximately 57% of radioactive-labeled olanzapine is present in the urine, mainly as metabolites.

Patients who smoke.

In smokers with mild hepatic impairment, the mean elimination half-life was longer (39.3 h), and plasma clearance was reduced (18.0 l / h) compared with non-smokers without liver dysfunction (48.8 h) and 14.1 l / h, respectively).

In non-smokers compared with smokers (men and women), the average elimination half-life was long (38.6 compared to 30.4 hours), and plasma clearance was reduced (18.6 compared to 27.7 l / h).

Plasma clearance of olanzapine is lower in elderly patients compared to younger patients, in women compared to men, and in non-smokers compared to smokers. Nevertheless, the significance of the influence of factors such as age, gender, and smoking on plasma olanzapine clearance and half-life is small compared with differences between individuals.

Children.

The pharmacokinetics of olanzapine in adolescents and adults is similar.

Clinical characteristics.

Indications.

Olanzapine is indicated for the treatment of schizophrenia.

Olanzapine is effective in maintaining the clinical effect achieved with long-term therapy in patients who have responded to initial therapy.

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

Olanzapine is indicated for the prevention of repeated attacks in patients with bipolar disorders who have received a positive response in the treatment of olanzapine mania.

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the drug; known risk of angle-closure glaucoma.

Interaction with other drugs and other types of interactions.

Children.

Studies of interactions with other drugs were conducted only with the participation of adults.

Substances affecting olanzapine.

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

Inductors CYP1A2.

Smoking or using carbamazepine increases the metabolism of olanzapine, which can lead to a decrease in the concentration of olanzapine. A mild or moderate increase in clearance of olanzapine was observed. Clinical findings are limited, but clinical monitoring and, if necessary, an increase in the dose of olanzapine are recommended.

CYP1A2 Inhibitors.

Fluoxamine, a specific inhibitor of CYP1A2, significantly reduces the metabolism of olanzapine. This leads to an average increase in C_max after taking fluoxamine, 54% in women who do not smoke, and 77% in men who smoke. The average AUC growth of olanzapine is 52% and 108%, respectively. For patients who use fluoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin, it is necessary to prescribe reduced doses of olanzapine. Consideration should be given to reducing the dose of olanzapine if treatment with a CYP1A2 inhibitor is initiated.

Decreased bioavailability.

Activated carbon reduced the oral bioavailability of olanzapine by 50-60% - it should be used at least 2 hours before administration or 2 hours after administration of olanzapine.

Fluoxetine (a CYP2D6 inhibitor), a single dose of antacids containing aluminum and magnesium, or cimetidine did not significantly affect the pharmacokinetics of olanzapine.

The potential ability of olanzapine to influence other drugs.

Olanzapine may antagonize the effects of direct and indirect dopamine agonists.

Olanzapine did not suppress major CYP450 isoenzymes (e.g. 1A2, 2D6, 2C9, 2C19, 3A4) in vitro. Thus, no particular interactions are expected, which is confirmed in in vivo studies where there was no inhibition of olanzapine metabolism when using such active substances: tricyclic antidepressants (mainly represented by the isoenzyme CYP2D6), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam ( CYP3A4, 2C19).

No interaction of olanzapine was observed when used with lithium or biperiden.

Therapeutic monitoring of valproate levels in blood plasma did not reveal the need for dose adjustment of valproate with concomitant administration with olanzapine.

Total activity against the central nervous system.

With caution, olanzapine should be used in patients who take ethanol or drugs that can cause depression of the central nervous system (CNS).

The simultaneous use of olanzapine with antiparkinsonian drugs in patients with Parkinsons disease and dementia is not recommended.

QTc interval.

Caution is advised to prescribe olanzapine with other drugs to patients at risk of an increase in the QTc interval.

CYP2D6 inhibitors. Fluoxetine (60 mg per dose or 60 mg daily for 8 days) leads to an increase in the maximum concentration of olanzapine by an average of 16% and a decrease in clearance of olanzapine by an average of 16%. The significance of the influence of these factors is small compared with the differences between individuals, therefore dose changes are usually not recommended.

Antihypertensive agents. Olanzapine, due to its potential ability to lower blood pressure, may enhance the effects of certain antihypertensive agents.

Levodopa and dopamine agonists. Olanzapine may be antagonistic to the effects of levodopa and dopamine agonists.

Imipramine. Single doses of olanzapine do not affect the pharmacokinetics of imipramine or its active metabolite desipramine.

Features of the application.

During treatment with antipsychotics, an improvement in a patient’s clinical condition may take from several days to several weeks. during this period, careful monitoring of the patients condition is necessary.

Psychosis associated with dementia and / or behavior disorders.

Olanzapine is not intended for the treatment of psychoses associated with dementia and / or behavioral disorders, and is also not recommended for use in these patients due to an increase in mortality and risk of cerebrovascular cases.

In placebo-controlled clinical trials (lasting 6 to 12 weeks) with elderly patients (average age 78 years) suffering from psychosis associated with dementia and / or impaired behavior, the number of fatal cases was 2 times higher in patients taking olanzapine compared with placebo (3.5% versus 1.5%, respectively). High mortality was not associated with the magnitude of the used doses of olanzapine (average daily dose was 4.4 mg) or with the duration of treatment. Risk factors for increasing mortality include age over 65, dysphagia, anxiety, malnutrition and dehydration, pulmonary conditions (pneumonia with or without aspiration), and the simultaneous use of benzodiazepines. However, mortality was higher with olanzapine therapy than with placebo, regardless of risk factors.

During clinical trials, cases of cerebrovascular adverse reactions (stroke, transient ischemic stroke), including fatal outcomes, were observed. The number of cerebrovascular adverse reactions was 3 times higher in patients taking olanzapine compared with placebo (1.3% versus 0.4%, respectively). All patients who took olanzapine or placebo and who had cerebrovascular adverse reactions had risk factors. Over 75 years of age and a vascular / mixed type of dementia have been identified as risk factors for cerebrovascular adverse reactions with olanzapine therapy. The efficacy of olanzapine has not been established in the course of these studies.

Parkinsons disease. The use of olanzapine in the treatment of psychoses associated with dopamine agonists is not recommended. The simultaneous use of olanzapine and antiparkinsonian drugs is not recommended for patients with Parkinsons disease and dementia. In clinical trials, symptoms of Parkinsons disease and hallucinations often worsened, more often than with placebo; in treating psychotic symptoms, olanzapine therapy was not more effective than placebo. From the very beginning of these studies, patients were required to continuously use the lowest effective dose of antiparkinsonian drugs (dopamine agonists), as well as the use of the same antiparkinsonian drugs and doses throughout the study. Olanzapine therapy was started with a dose of 2.5 mg / day, which was increased by titration to a maximum of 15 mg / day.

Neuroleptic malignant syndrome.

Neuroleptic malignant syndrome (NSA) is a potentially fatal symptom complex described in connection with antipsychotic drugs. Rarely reported cases of NSA associated with the use of olanzapine. The clinical manifestations of NSA are hyperpyrexia, muscle stiffness, loss of consciousness, and symptoms of cardiac instability (irregular heartbeat or changes in blood pressure, tachycardia, increased sweating, and cardiac arrhythmia). Additional signs include elevated levels of creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The clinical manifestation of NSA or the presence of hyperthermia without the clinical manifestation of NSA requires immediate withdrawal of all antipsychotic drugs, including olanzapine.

Hyperglycemia and diabetes.

Infrequently reported hyperglycemia and / or the development of diabetes mellitus or a worsening of the course of existing diabetes mellitus associated with ketoacidosis or diabetic coma, as well as fatal cases.Sometimes a previous increase in body weight has been reported, which could be a risk factor.

It is recommended to conduct appropriate clinical monitoring of the condition of patients with diabetes mellitus and patients with risk factors for diabetes mellitus, in particular, to measure the level of glucose in the blood at the beginning of treatment, after 12 weeks, and also annually thereafter. Patients receiving antipsychotic medication, including Adagio, should be monitored for symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness). In patients with diabetes mellitus and patients with risk factors for developing diabetes, it is necessary to regularly check the level of glucose control. Body weight should be monitored, for example: at the beginning of treatment, after 4 weeks, after 8 weeks and after 12 weeks, as well as once a quarter thereafter.

Anticholinergic activity. In the course of clinical studies, a low incidence of anticholinergic events was revealed. However, due to the limited clinical experience with olanzapine, patients with concomitant diseases should be careful when prescribing the drug to patients with prostate hypertrophy, paralytic intestinal obstruction, or similar conditions.

Indicators of liver function. When olanzapine was used, a transient asymptomatic increase in the level of hepatic transaminases of alanine aminotransferase (AlAT) and aspartate aminotransferase (AsAT) was often observed, especially at the beginning of treatment. Adagio is prescribed with caution to patients with elevated levels of AlAT and / or AsAT, symptoms of impaired liver function, conditions associated with liver failure, as well as patients taking potentially hepatotoxic drugs. If hepatitis is detected (including hepatocellular, cholestatic, or mixed liver damage), olanzapine must be discontinued.

Neutropenia Olanzapine should be prescribed with caution at a low level of leukocytes and / or neutrophils for any reason, patients receiving treatment with drugs that can cause neutropenia, patients with a history of drug suppression / toxic damage to the bone marrow, patients with bone marrow depression caused by concomitant diseases, radiation or chemotherapy, and patients with hypereosinophilia and myeloproliferative disease. Neutropenia is a frequent side effect with the combined use of valproate and olanzapine.

Discontinuation of therapy. With a sharp cessation of therapy, acute symptoms were rarely reported (≥ 0.01% and 0.1%), in particular, excessive sweating, insomnia, tremor, irritability, nausea, or vomiting.

QT interval. In clinical studies, olanzapine did not cause prolonged prolongation of the absolute QT and QTc intervals. However, as with other antipsychotics, olanzapine should be used in combination with drugs that can cause QT prolongation, caution, especially in elderly patients, patients with congenital QT prolongation syndrome, congestive heart failure, heart hypertrophy, hypokalemia, or hypomagnesemia.

Thromboembolism. Cases of development of venous thromboembolism (≥ 0.1% -

 

General effect on the central nervous system. Given the predominant effect of olanzapine on the central nervous system, additional precautions must be taken when taking olanzapine with other centrally acting drugs, including alcohol.

Epileptic seizures. Olanzapine should be used with caution in patients with a history of epileptic seizures and in patients sensitive to factors that reduce the threshold of seizures. Cases of epileptic seizures during treatment with olanzapine have been infrequently reported.In most of these cases, patients had a history of epileptic seizures or the risk of their occurrence was increased.

Tardive dyskinesia. In clinical trials of one year or less, when taking olanzapine, a statistically significantly lower incidence of treatment-related dyskinesia was observed. Due to the growing risk of developing tardive dyskinesia with prolonged use of antipsychotic drugs, a consistent dose reduction or complete withdrawal of the drug is necessary if the patient has symptoms of tardive dyskinesia. Over time, these symptoms may worsen or even appear after discontinuation of treatment.

Orthostatic hypotension. Cases of orthostatic hypotension have been reported infrequently in elderly patients during clinical trials. As with other antipsychotics, the use of olanzapine is recommended to periodically measure blood pressure in patients over the age of 65.

Sudden cardiac death. Post-marketing reports reported cases of sudden cardiac death. According to a retrospective observational cohort study, the risk of sudden cardiac death in patients treated with olanzapine was almost doubled compared with patients who did not use antipsychotics. The risk with olanzapine is consistent with that associated with the use of atypical antipsychotic drugs that were included in the combined analysis.

Lactose. Tablets contain lactose, so they can not be prescribed to patients with hereditary lactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome.

Dopaminergic antagonism. In vitro olanzapine antagonizes dopamine and theoretically can counteract the effects of levodopa and dopamine agonists, as well as other antipsychotic drugs.

Glucose. In clinical studies (up to 52 weeks), olanzapine caused large changes in glucose levels compared with placebo. The difference in changes in values ​​between olanzapine and placebo was greater in patients with a history of history of glucose dysregulation (including patients with diabetes mellitus or patients with manifestations of hyperglycemia). These patients showed a significant increase in HbA1c compared with the placebo group.

The percentage of patients in whom the glucose level has changed from normal or extreme to high has been constantly increasing.

In the analyzes of patients who underwent 9-12-month therapy with olanzapine, elevated blood glucose levels decreased after 6 months.

Changes in lipid levels. Undesirable changes in lipid levels can be observed in patients who are treated with olanzapine. Changes in lipid levels should be treated appropriately in patients with dyslipidemia and in patients with risk factors for impaired lipid metabolism. In patients receiving treatment with antipsychotic drugs, including Adagio, it is necessary to regularly monitor the level of lipids in the blood, for example: at the beginning of treatment, after 12 weeks, and also every 5 years thereafter.

In clinical trials lasting more than 12 weeks, patients taking olanzapine showed an increase in total cholesterol, low density lipoproteins, and triglycerides compared with the placebo group.

A significant increase in the level of lipids (total cholesterol, low density lipoproteins, triglycerides) was observed more often in patients without a history of lipid metabolism.

There were no statistically significant differences in the increase in high density lipoproteins between patients who took olanzapine and patients who took placebo.

The quantitative ratio of patients who have changed the level of total cholesterol, low density lipoproteins or triglycerides from normal or extreme to high or have changed the level of high density lipoproteins from normal or extreme to low was large during long-term studies (at least 48 weeks) compared with that in short-term studies. In patients who underwent 12-month therapy, total cholesterol did not increase after 4 to 6 months.

Suicide. Suicidal tendency is characteristic of both patients with schizophrenia and patients with type I bipolar disorder, and therefore it is necessary to carefully monitor patients who are at high risk of suicide and receive olanzapine therapy. In order to reduce the possibility of an overdose, olanzapine in tablets should be prescribed in small quantities sufficient to ensure the proper therapeutic effect.

Body mass. Before starting olanzapine therapy, the potential consequences of increasing the patients body weight should be considered. Patients receiving olanzapine treatment should undergo regular body weight monitoring.

Monotherapy with olanzapine in adults. During 13 placebo-controlled clinical trials, it was found that patients receiving olanzapine therapy showed an average weight gain of 2.6 kg compared with an average weight loss of 0.3 kg in the placebo group with a median of 6 weeks 22.2% of patients who received olanzapine therapy had an increase in body weight of at least 7% of the mass at the beginning of treatment compared with 3% of the placebo group with a median of 8 weeks; 4.2% of patients had an increase in body weight of at least 15% by weight at the beginning of treatment compared with 0.3% of patients in the placebo group with a median of 12 weeks. A clinically significant increase in body weight was observed in all categories of patients by BMI (body mass index). Discontinuation of therapy due to weight gain was required for 0.2% of patients receiving olanzapine treatment, compared with 0% of patients in the placebo group.

During long-term clinical trials (at least 48 weeks), the average increase in body weight in patients was 5.6 kg (with median use of 573 days; N = 2021). The number of patients who showed an increase in body weight of at least 7%, 15% or 25% of the initial weight, with long-term use of olanzapine was 64%, 32% and 12%, respectively. Discontinuation of therapy due to weight gain was required for 0.4% of patients treated with olanzapine for at least 48 weeks.

Dysphagia. Violation of esophageal motility and shortness of breath have been associated with the use of antipsychotic drugs. Aspiration pneumonia has been a common cause of morbidity and mortality in patients with Alzheimers disease. Olanzapine is not approved for the treatment of patients with Alzheimers disease.

Regulation of body temperature. Violation of the bodys ability to lower its temperature was observed in connection with antipsychotics. It is recommended to take this fact into account when prescribing olanzapine to patients under conditions that may lead to an increase in body temperature, such as increased training, exposure to extreme temperatures, the simultaneous use of anticholinergic drugs or a state of dehydration.

Use for patients who have concomitant diseases. The clinical experience with olanzapine in patients with certain diseases is limited. Olanzapine enhances in vitro affinity for muscarinic receptors. During pre-marketing clinical studies of olanzapine, its use was associated with constipation, a feeling of dry mouth, tachycardia and other side effects that may be associated with cholinergic antagonism.Such adverse reactions infrequently led to discontinuation of olanzapine therapy, but olanzapine should be used with caution in patients with clinically significant prostate hypertrophy, narrow-angle glaucoma, a history of paralytic bowel obstruction, or with related conditions caused by cholinergic antagonism, which may worsen in the presence of olanzapine. In 5 placebo-controlled studies of olanzapine in elderly patients with psychosis associated with dementia (n = 1184), the following adverse reactions were observed associated with therapy, with a frequency of occurrence of at least 2% and a significantly higher incidence compared with placebo patients: falling, drowsiness, peripheral edema, gait disturbance, urinary incontinence, lethargy, weight gain, asthenia, pyrexia, pneumonia, a feeling of dry mouth and visual hallucinations. The incidence of discontinuation of therapy due to adverse events was higher in the olanzapine group compared with placebo (13% compared to 7%, respectively). Older patients with dementia-related psychosis who receive olanzapine have a higher death rate compared to the placebo group. Olanzapine is not indicated for the treatment of elderly patients with psychosis associated with dementia. Olanzapine has not been used in a sufficient number of patients with recent myocardial infarction or unstable heart disease.

Patients with the above diagnoses were excluded from pre-marketing clinical trials. Caution is advised when using olanzapine to treat patients with heart disease due to the risk of orthostatic hypotension.

Laboratory research. It is recommended that fasting glucose and the lipid profile be monitored at the beginning of treatment and periodically during treatment.

Hyperprolactinemia Like other drugs with the properties of antagonists of dopamine D2 receptors, olanzapine increases prolactin levels in the blood, and this increase persists with prolonged use. Hyperprolactinemia can suppress the hypothalamic hormone GnRH, resulting in a decrease in the secretion of pituitary gonadotropin. This, in turn, can inhibit reproductive function by disrupting gonadal spermatogenesis in both men and women. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving drugs that increase prolactin levels. Prolonged hyperprolactinemia associated with hypogonadism can lead to a decrease in bone density in both men and women.

Additional research / laboratory data. Considering that in some animal studies, neutropenia associated with taking other psychotropic components and leukopenia associated with taking olanzapine (see “Toxicological studies on animals” below) were observed, hematological parameters were evaluated with particular care in pre-marketing studies of olanzapine . There was no evidence of a clinically significant neutropenia associated with olanzapine treatment in the pre-marketing database of olanzapine.

Post-marketing reports.

Reports of adverse reactions after olanzapine entered the market, which included neutropenia, were associated in time with its administration, but did not necessarily have a causal relationship.

Toxicological studies in animals.

During studies of olanzapine in animals, the main hematological results were reverse peripheral cytopenia in individual dogs at a dosage of 10 mg / kg (17 times more than the maximum recommended daily oral dose for humans when calculating the dose in mg / m² body surface), dose-dependent decrease in the number of lymphocytes and neutrophils in mice and lymphopenia in rats.Several dogs who received doses of 10 mg / kg developed reverse neutropenia and / or reverse hemolytic anemia between the 1st and 10th month of treatment. A dose-dependent decrease in the number of lymphocytes and neutrophils was observed in mice treated with a dose of 10 mg / kg (equal to twice the maximum recommended daily oral dose for humans when calculating the dose in mg / m² body surface) during studies lasting 3 months. Nonspecific lymphopenia, in accordance with a decrease in body weight gain, was observed in rats receiving a dose of 22.5 mg / kg (11 times the maximum recommended daily oral dose for humans when calculating the dose in mg / m² body surface) for 3 months or 16 mg / kg (8 times the maximum recommended daily oral dose for humans when calculating the dose in mg / m² body surface) for 6 or 12 months. There was no evidence of bone marrow cytotoxicity in any of the species studied. Bone marrow cells were normocellular or hypercellular, suggesting that the decrease in the number of circulating blood cells was probably due to peripheral (not related to bone marrow) factors.

Use during pregnancy or lactation.

Adequate and well-controlled studies are lacking.