Salveo ODT

5 mg Orodispersible tablet: Yellow, round, biconvex, tablet.
10 mg Orodispersible tablet: Yellow, round, flat, tablet.

Antipsychotic.
Pharmacology: Pharmacodynamics: Olanzapine is an atypical antipsychotic agent that shows a broad pharmacologic profile across a number of receptor systems.
Olanzapine binds with high affinity to the following receptors: serotonin 5HT_2A/2C, 5HT₆, dopamine D_1-4, histamine H₁, and adrenergic α₁, receptors. Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT₃, and muscarinic M_1-5. It binds weakly to GABA_A, benzodiazepine and β-adrenergic receptors.
Antagonism at receptors other than dopamine and 5HT₂, may explain some of olanzapine's other therapeutic and side effects. Olanzapine's antagonism of muscarinic M_1-5 receptors may explain its anticholinergic-like effects; antagonism of histamine H₁ receptors may explain somnolence, and antagonism of adrenergic α₁ receptors may explain orthostatic hypotension observed with this drug.
Pharmacokinetics: Olanzapine is well absorbed after oral administration, Peak plasma concentrations of film-coated and orodispersible olanzapine tablets are reached in approximately six and five hours, respectively. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Olanzapine displays linear kinetics over the clinical dose range of 1 to 20 mg. Food does not affect the rate or extent of olanzapine absorption.
The half-life of olanzapine ranges from 21 to 54 hours. Administration of olanzapine once daily leads to steady-state concentrations in about one week that are approximately twice the concentrations after single doses. Plasma concentration, half-life and clearance of olanzapine may vary between individuals on the basis of smoking status, gender and age.
Olanzapine is extensively distributed throughout the body. Its volume of distribution is approximately 1,000 L. The drug is highly protein-bound (93%) over the concentration range of 7 to 1,110 ng/mL, binding primarily to albumin and α₁-acid glycoprotein. Olanzapine and its glucuronide metabolite have been shown to cross the placenta in humans. It is also distributed into milk.
Olanzapine is metabolized in the liver primarily by direct glucuronidation and cytochrome P450 (CYP)-mediated oxidation. It is highly metabolized, with 7% of the dose recovered in the urine as unchanged drug. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. The major circulating metabolite is the 10-N-glucuronide, which is pharmacologically inactive and does not pass the blood brain barrier. Cytochrome P450 CYP 1A2 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.
Olanzapine's mean terminal elimination half-life is 33 hours (21 to 54 hours) and the mean olanzapine plasma clearance is 26 L/hr (12 to 47 L/hr).
Special Populations: Renal Impairment: Olanzapine is highly metabolized before excretion and only 7% of the drug is excreted unchanged. The pharmacokinetic characteristics of olanzapine were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based on the degree of renal impairment is not required. The effect of renal impairment on metabolite elimination has not been studied.
Hepatic Impairment: While the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, a study of the effect of impaired liver function in subjects with clinical significant (Child-Pugh Classification A and B) cirrhosis showed little effect on the pharmacokinetics of olanzapine.
Elderly: In a study involving 24 healthy subjects, the mean elimination half-life of olanzapine was about 1.5 times greater in elderly (≥65 years old) than in nonelderly subjects (<65 years old). Caution should be exercised in dosing the elderly, particularly if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity.
Adolescents (13 to 17 years old): Since most adolescents have a lower average body weight, administration of olanzapine in this population resulted to higher average drug exposure compared to adults.
Gender: Olanzapine's clearance is approximately 30% lower in women compared to men. However, there are no apparent differences between men and women in terms of efficacy and safety. Dosage modifications based on gender is not needed.
Smoking: Clearance of olanzapine is about 40% higher in smokers than in nonsmokers. However, dosage modifications are not recommended.
Combined Effects: The combined effects of age, smoking and gender could lead to substantial pharmacokinetic differences in populations. Example, the clearance in young smoking males may be three times higher than that in elderly nonsmoking females. Dosing adjustment may be necessary in patients who exhibit a combination of factors that may result in slower metabolism of olanzapine.

Schizophrenia: Acute and maintenance treatment of schizophrenia and related psychoses in adults and adolescents (13 to 17 years old).
Bipolar I Disorder (Manic or Mixed Episodes): As monotherapy for the acute and maintenance treatment of manic or mixed episodes associated with Bipolar I Disorder in adults and adolescents (13 to 17 years old).
Adjunct to valproate or lithium in the treatment of manic or mixed episodes associated with Bipolar I Disorder in adults.
For preventing recurrence of manic, mixed or depressive episodes in Bipolar I Disorder.
In combination with fluoxetine: Acute treatment of depressive episodes associated with Bipolar I Disorder in adults and children (10 to 17 years old): Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.
Acute treatment of treatment-resistant depression in adults (major depressive disorder in patients who do not respond to two separate trials of different antidepressants of adequate dose and duration in the current episode): Olanzapine monotherapy is not indicated for the treatment of treatment-resistant depression.

Olanzapine alone or in combination with fluoxetine is administered once a day, with or without food.
Schizophrenia: See Tables 1 and 2.

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Long-term treatment options in adult patients with schizophrenia with remitting first episodes or multiple episodes include either indefinite maintenance therapy or gradual discontinuation of the antipsychotic agent with close follow-up and a plan to reinstitute treatment if symptoms recur.
Discontinuance of antipsychotic therapy should be considered only after a period of at least one year of symptom remission or optimal response while receiving the antipsychotic agent. In patients who have had multiple previous psychotic episodes or two psychotic episodes within five years, indefinite maintenance antipsychotic treatment is recommended.
Bipolar I Disorder (Manic or Mixed Episodes): See Table 3.

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Olanzapine in Combination with Fluoxetine: See Tables 4 and 5.

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For orodispersible tablets: Olanzapine can be taken without regard to meals. Olanzapine orodispersible tablets should be placed in the mouth, where it will be rapidly dispersed in saliva and can be easily swallowed. Removal of the intact orodispersible tablet from the mouth is difficult. The orodispersible tablet is fragille, thus it should be taken immediately upon opening the blister. Alternatively, it may be dispersed in a full glass of water or other appropriate beverages (orange juice, apple juice, milk, or coffee) immediately before administration.
Olanzapine orodispersible tablet is bioequivalent and has similar rate and extent of absorption with olanzapine coated tablets. 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 Population: Elderly (65 years and older): Recommended Olanzapine Starting Dose: 5 mg/day.
When necessary, increase in dose should be done with caution in these patients.
Patients with Hepatic and/or Renal Impairment: In case of moderate hepatic insufficiency (e.g., cirrhosis, Child-Pugh class A or B), the recommended starting dose should be 5 mg/day.
Further dose adjustments, when indicated, should be conservative in these patients.
Smokers: The starting dose and dose range of olanzapine need not be routinely altered for non-smokers relative to smokers.
Consideration should be given to decreasing the starting dose, when more than one factor is present which might result in slower metabolism (e.g., female gender, geriatric age, non-smoking status). Dose escalation, when indicated, should be conservative in these patients.
Debilitated patients, patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, non-smoking status), or those patients who may be pharmacodynamically sensitive to olanzapine: Recommended Olanzapine Starting Dose for Schizophrenia: 5 mg; when indicated, dose escalation should be performed with caution in these patients.
Recommended Olanzapine in Combination with Fluoxetine Starting Dose: Olanzapine 2.5 to 5 mg with fluoxetine 20 mg.
Dose modification may be necessary in patients who exhibit a combination of factors that may slow metabolism.
When indicated, dose escalation should be done with caution in these patients.
For children and elderly patients: Olanzapine and fluoxetine in combination have not been systematically studied in patients over 65 years old or in patients below 18 years old.
Or, as prescribed by a physician.

Very common symptoms reported for olanzapine overdose include tachycardia, agitation/aggressiveness, dysarthria, various extrapyramidal symptoms and reduced level of consciousness ranging from sedation to coma. Other significant symptoms of overdose include delirium, convulsion, possible NMS, respiratory depression/arrest, aspiration, hypertension or hypotension, cardiac arrhythmias (e.g., supraventricular tachycardia), and cardiopulmonary arrest. Fatal outcomes have been reported for acute overdoses as low as 450 mg of olanzapine administered orally. However, survival has also been reported following acute overdose of 2,000 mg.
Induction of emesis is not recommended. Standard procedures for the management of overdose may be given. The possibility of multiple drug involvement should also be considered.
During acute overdose, airway should be established and maintained. Adequate oxygenation and ventilation, which may include intubation, should also be ensured. The use of activated charcoal for overdose should be considered because concomitant use of activated charcoal was shown to reduce the oral bioavailability of olanzapine by 50% to 60%. In patients who are not fully conscious or who have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected. Olanzapine is not substantially removed by hemodialysis.
There is no specific antidote to olanzapine overdosage. Thus, symptomatic treatment and monitoring of vital organ function should be done according to clinical presentation, including treatment of hypotension and circulatory collapse, and support of respiratory function. Appropriate measures such as Trendelenburg's position, intravenous fluids and/or sympathomimetic agents (e.g., norepinephrine, phenylephrine) should be given to treat hypotension and circulatory collapse. Epinephrine, dopamine or other sympathomimetic agents with beta-agonist activity should not be used since beta stimulation may worsen hypotension in the setting of α-blockade induced by olanzapine, Tachycardia associated with olanzapine overdose does not usually require specific therapy. Cardiovascular monitoring should be considered to detect possible atrial and ventricular arrhythmias and conduction disturbances. Sodium bicarbonate may be helpful in the presence of QRS interval prolongation. Benzodiazepines followed by barbiturates may be used in the initial treatment of seizures after olanzapine overdosage, if necessary. Acute extrapyramidal reactions should be treated with anticholinergic drugs (e.g., diphenhydramine, benztropine).
Toxic effects from intoxication with atypical antipsychotics are usually resolved within 12 to 48 hours following acute overdosage, although it has taken up to six days in some cases. Close medical supervision and monitoring should continue until the patient recovers.

Hypersensitivity to olanzapine or to any component in the product.
Patients with known risk of narrow-angle glaucoma.

Increased mortality in elderly patients with dementia-related psychosis: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo-group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristics of the patients is not clear. Olanzapine is not approved for the treatment of patients with dementia-related psychosis.

General: 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.
When using olanzapine in combination with fluoxetine, lithium, or valproate, also refer to their individual product literature for additional information.
Neuroleptic Malignant Syndrome: There have been reports of neuroleptic malignant syndrome (NMS), a potentially fatal symptom complex, in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If unexplained high fever occurred in a patient taking antipsychotics without additional clinical manifestations of NMS, all antipsychotic drugs, including olanzapine, should be discontinued.
NMS has been reported in patients using olanzapine as monotherapy or in combination with other drugs, including antipsychotic agents, antidepressants, lithium, or valproate. About two-thirds of olanzapine-treated patients diagnosed with NMS also experience extrapyramidal reactions. Atypical symptoms of NMS (e.g., absence or decreased rigidity, presenting as fever of unknown origin) and less serious manifestations of NMS have been reported in patients treated with olanzapine or other atypical antipsychotic agents.
The diagnosis of patients with NMS is complicated. In arriving at a diagnosis, serious medical illnesses (e.g., pneumonia, systemic infections, etc.), and untreated or other inadequately treated extrapyramidal signs and symptoms (EPS) must be identified and excluded. The clinical features of NMS and serotonin syndrome may overlap, suggesting that these two syndromes may share certain underlying pathophysiologic mechanisms. Other conditions that should be considered in differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS includes the immediate discontinuation of antipsychotics and other drugs that are considered as not essential to concomitant treatment; intensive symptomatic treatment and medical monitoring; and treatment of any concurrent serious medical problems for which specific treatments are available. Although dantrolene, bromocriptine, amantadine, and benzodiazepines have been utilized in some patients, there is no specific pharmacological treatment regimen for NMS.
If antipsychotic treatment after recovery from NMS is required, the potential reintroduction of treatment after several weeks should be carefully considered. The dosage used in the reintroduction of antipsychotic treatment should be gradually increased, and an antipsychotic agent other than the agent assumed to have induced NMS should be chosen. The tolerability of oral olanzapine should also be established before initiating treatment with extended-release intramuscular (IM) olanzapine pamoate.
Weight Gain: Significant weight gain was observed in all baseline body mass index categories of patients treated with olanzapine. With similar exposure, both the magnitude of weight gain and the proportion of patients who had clinically important weight gain were greater in olanzapine-treated adolescent patients compared with adult patients. The magnitude of weight gain and the proportion of adolescent patients who had clinically significant weight gain were higher with long-term exposure (i.e., at least 24 weeks) compared with short-term exposure. Potential consequences of weight gain should be considered before starting olanzapine. As with all antipsychotics, patients receiving olanzapine should conduct regular weight monitoring.
Falls: Falls which may lead to fracture or other injuries may be caused by olanzapine-induced somnolence, postural hypotension, and motor and sensory instability. Complete fall risk assessments should be performed in patients with diseases, conditions, or medications that could exacerbate these effects during initiation of antipsychotic treatment and regularly for patients on long-term antipsychotic therapy.
Body Temperature Regulation: Caution should be exercised and appropriate care is advised when giving olanzapine to patients experiencing conditions that may contribute to an elevation in core body temperature (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration), since the use of antipsychotic agents are associated with the disruption of the body's ability to reduce core body temperature. Patients should be informed on the appropriate precautions to avoid overheating and dehydration. Patients should also be instructed to contact their physician immediately if they become severely ill and have some or all of the symptoms of dehydration (e.g., sweating too much or not at all, dry mouth, feeling very hot or thirsty, unable to produce urine).
Potential for Cognitive and Motor Impairment: Somnolence or sedation is one of the most commonly reported adverse effects of olanzapine. It is dose-related and usually appears to be relatively moderate in severity than with other antipsychotic agents. Marked somnolence associated with antipsychotics is observed during early therapy, and tolerance to the sedation effect develops in some patients upon continued treatment with antipsychotics. Although sedation may have therapeutic benefits in some patients, persistent daytime drowsiness and increased sleep time can be bothersome and may require a lower dosage or evening administration of the drug. Sedation-related adverse events (i.e., hypersomnia, lethargy, somnolence) occurred more frequently in adolescents than in adults.
Cardiac and Vascular Effects: Orthostatic Hypotension: Patients receiving oral olanzapine therapy are reported to develop orthostatic hypotension associated with dizziness, tachycardia or bradycardia, and/or syncope, particularly during the initial dosage titration period. Patient should be cautioned about the risk of orthostatic hypotension if olanzapine was concomitantly used with drugs that may potentiate its hypotensive and bradycardic effect, or those that may cause respiratory or central nervous system depression (e.g., diazepam, alcohol) (See Interactions). The risk of orthostatic hypotension and syncope may be minimized by initiating therapy with a dose of 5 mg orally once a day. If hypotension occurs, a more gradual titration to the target dose should be considered.
Patients should be instructed to change positions carefully to help avoid orthostatic hypotension, and to lie down once they feel dizzy or faint until they feel better. They should also be advised to consult their physicians if they experience dizziness, fast or slow heartbeat, fainting, or other signs and symptoms associated with orthostatic hypotension.
Sudden Cardiac Death: It has been demonstrated in a retrospective observational study that patients treated with typical or atypical antipsychotics had a similar dose-related increase of presumed sudden cardiac death compared to non-users of antipsychotics, but with almost twice the risk than that for non-users. The risk of sudden cardiac death of patients taking olanzapine was comparable to the risk of atypical antipsychotics included in a pooled analysis. However, postmarketing reports demonstrated that events of sudden cardiac death associated with olanzapine have been reported very rarely.
Cerebrovascular Effects: Cerebrovascular adverse events (CVAEs) such as stroke and transient ischemic attack (TIA), including mortalities, were reported in elderly patients with dementia-related psychosis taking olanzapine. Age greater than 75 years, history of previous CVAES or TIA, hypertension, cigarette smoking, and vascular/mixed type dementia were the risk factors for olanzapine-related CVAES. Olanzapine is not approved for the treatment of patients with dementia-related psychosis.
Patients or caregivers should be instructed to report immediately any signs and symptoms of potential CVAES, such as sudden weakness or numbness in the face, arms, or legs; and speech or vision problems.
QT interval: There are rare reports of clinically significant QTc prolongations in patients treated with olanzapine. However, as with other antipsychotics, caution should be exercised when olanzapine is prescribed with drugs and/or conditions known to increase QTc interval (e.g., in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalemia or hypomagnesemia).
Venous thromboembolism: Association of intake of antipsychotics with cases of venous thromboembolism (VTE), including fatal pulmonary embolism, has been rarely reported. However, a causal relationship between the occurrence of VTE and the use of olanzapine has not been established.
Since most patients with schizophrenia present the acquired risk factors for VTE (e.g., immobilization of patients), all potential risk factors for VTE should be identified before prescribing olanzapine, and preventive measures should be performed. Very rare cases of VTE have been reported in olanzapine-treated patients during the post-marketing period.
Endocrine and Metabolic Effects: Hyperglycemia and Diabetes Mellitus: There have been rare reports of severe hyperglycemia and/or exacerbation of diabetes (sometimes associated with ketoacidosis, hyperosmolar coma, or death) in patients receiving certain atypical antipsychotic agents including olanzapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia, and the increasing incidence of diabetes mellitus in the general population. A prior body weight increase has been reported, which may be a predisposing factor in some patients. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics.
Physicians should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100 to 126 mg/dL; nonfasting 140 to 200 mg/dL). Patients starting olanzapine therapy should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Likewise, patients who develop symptoms of hyperglycemia (e.g., polydipsia, polyuria, polyphagia, and weakness) during treatment with atypical antipsychotics should undergo fasting blood glucose testing. Patients with diabetes mellitus or with risk factors for diabetes melitus (e.g., obesity, family history of diabetes) should be monitored regularly for worsening of glucose control. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. In some cases, hyperglycemia was resolved when the atypical antipsychotic was discontinued or with continuance of both antipsychotic drug and initiation of antidiabetic treatment. However, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.
Hyperprolactinemia: As with other drugs that antagonize dopamine D₂ and/or serotonin 5-HT₂ receptors, olanzapine increases prolactin levels and a modest elevation persists during chronic administration. Hyperprolactinemia may suppress hypothalamic gonadotropin-releasing hormone (GnRH), leading to decreased pituitary gonadotropin secretion and repressed reproductive function through the impairment of gonadal steroidogenesis in both male and female patients. In usual dosages, olanzapine produces transient increases in serum prolactin levels in humans. Elevations in prolactin levels associated with olanzapine are usually mild, and may decline with continued treatment. Prolactin-elevating drugs have been associated with disorders such as galactorrhea, amenorrhea, gynecomastia, and impotence. Chronic hyperprolactinemia related to hypogonadism may result to reduced bone density. A higher incidence of increased prolactin levels have been observed in adolescents than in adults.
When prescribing olanzapine, there is the possibility of secondary amenorrhea and hypoestrogenism arising from treatment. Premenopausal women should be questioned on menstrual irregularities and those who experience secondary amenorrhea for longer than six months duration while taking olanzapine, should be appropriately investigated and offered appropriate therapy. Reduction of olanzapine dosages or switching to a more prolactin-sparing antipsychotic agents (e.g., aripiprazole, clozapine, quetiapine, ziprasidone) or use of dopamine receptor agonists (e.g., bromocriptine) may be helpful in patients who developed elevated prolactin concentration during antipsychotic therapy. Estrogen replacement therapy may also be considered in hypoestrogenic female patients.
About one-third of human breast cancers are prolactin-dependent in vitro. If olanzapine is considered in a patients previously diagnosed with breast cancer, physicians should only recommend olanzapine in these patients if the benefits outweigh the potential risks.
Dyslipidemia: Olanzapine-treated patients had a greater mean increase in fasting total cholesterol, LDL-cholesterol, and triglycerides. Mean increases in fasting lipid values (total cholesterol, LDL-cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline. Increases in serum concentrations of total cholesterol, triglycerides, and LDL-cholesterol are greater in adolescent patients compared to adults. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using olanzapine, is recommended.
Hematologic Effects: Leukopenia, neutropenia, and agranulocytosis: Events of leukopenia/neutropenia temporally related to antipsychotic agents, including olanzapine, have been reported. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy. Discontinuation of olanzapine should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1,000/mm³) should discontinue olanzapine and have their WBC monitored until recovery.
Hepatic Effects: Transient, asymptomatic elevations of hepatic aminotransferases, alanine transferase (ALT), aspartate transferase (AST), and y-glutamyltransferase (GGT) have been commonly reported, particularly in early treatment. Jaundice, cholestatic or mixed liver injury have been reported, but rarely, in postmarketing studies. Caution should be exercised and follow-up should be conducted in patients with elevated ALT and/or AST; signs and symptoms of hepatic impairment; pre-existing conditions associated with limited hepatic functional reserve; and who are being treated with potentially hepatotoxic medicines. Dose reduction should be considered if elevation of ALT and/or AST occurred during treatment with olanzapine. Olanzapine treatment should be discontinued in cases where hepatitis (including hepatocelular, cholestatic or mixed liver injury) has been diagnosed.
Nervous System Effects: Tardive Dyskinesia: Tardive dyskinesia is a syndrome of potentially irreversible, involuntary, dyskinetic movement. Although tardive dyskinesia occurs more frequently among the elderly, particularly in elderly women, patients of any age can also be affected. Tardive dyskinesia has been associated with the use of antipsychotic agents. Although comparator studies of one year or less in duration showed that olanzapine was associated with a statistically significant lower incidence of treatment-emergent dyskinesia, the difference of antipsychotics in their potential to cause tardive dyskinesia is not known.
The risk of developing tardive dyskinesia and the possibility that it will become irreversible increase with the duration of treatment and the total cumulative dose of the antipsychotic drug. However in rare cases, the syndrome can develop after relatively short periods of treatment at low doses. Tardive dyskinesia may remit partially or completely, if treatment with antipsychotics is withdrawn. The antipsychotic drug itself may suppress the signs and symptoms of tardive dyskinesia, and may possibly mask the underlying process.
Olanzapine should be prescribed in a manner that most likely reduces the risk of tardive dyskinesia. Chronic use of olanzapine should be reserved for patients who suffer from a chronic illness that is known to benefit from antipsychotic agents and to those whom equally effective but potentially less harmful alternative treatments are unavailable or inappropriate. The lowest effective dose and the shortest duration of treatment producing a satisfactory clinical response should be given in patients who do not require chronic treatment.
If signs or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction or drug discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.
Seizures: Seizures have been reported to occur rarely in patients treated with olanzapine, most of which were reported to occur in patients with history of seizures or have risk factors for seizures. Olanzapine should be used cautiously in patients who have a history of seizures or with conditions that potentially lower the seizure threshold (e.g., Alzheimer's dementia). Conditions that lower the seizure threshold may be more common in patients 65 years of age and older.
Suicide: The possibility of a suicide attempt is inherent in schizophrenia and in bipolar disorder. Close supervision and appropriate clinical management of high-risk patients should accompany drug therapy.
Prescriptions for olanzapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Akathisia: The use of olanzapine is associated with akathisia. It may be manifested with different symptoms and subjective complaints of restlessness, an overwhelming urge to move, and either distress or motor phenomena, such as pacing, swinging of the legs while seated, rocking from foot to foot, or both. Patients treated with olanzapine should be monitored for signs and symptoms of akathisia. When left untreated, akathisia may result to poor compliance and an increased risk of relapse.
Gastrointestinal and Respiratory Effects: Dysphagia: Esophageal dysmotility, dysphagia, and aspiration have been associated with antipsychotic use. Olanzapine and other antipsychotic agents should be used cautiously in patients at risk for aspiration pneumonia. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease. Olanzapine is not approved for the treatment of patients with Alzheimer's disease.
Antiemetic Effect: Olanzapine may have an antiemetic effect due to its dopamine antagonist effects. Olanzapine-induced antiemesis may mask signs of toxicity caused by overdosage of other drugs, or may mask symptoms of diseases such as brain tumors or intestinal obstruction.
Use in Patients with Concomitant Illness: Olanzapine has demonstrated anticholinergic effects in vitro such as constipation, dryness of the mouth, and tachycardia, Since clinical experience with olanzapine in patients with concomitant illness is limited, caution is advised when prescribing in patients with prostatic hypertrophy, narrow-angle glaucoma, or a history of paralytic ileus or related conditions.
There are no clinical studies on the use of olanzapine in patients with a recent history of myocardial infarction or unstable heart disease. Caution should be observed in cardiac patients because of the risk of orthostatic hypotension with olanzapine.
Use in Patients with Parkinson's Disease: Olanzapine may worsen the symptomatology and may cause hallucinations in patients with Parkinson's disease. Thus, the use of olanzapine in the treatment of psychosis associated with Parkinson's disease is not recommended.
Effects on Skin and Subcutaneous Tissue: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with the use of olanzapine and may be fatal. DRESS may present with the following symptoms: cutaneous reaction (e.g., rash or exfoliative dermatitis), eosinophillia, fever, and/or lymphadenopathy with systemic complications (e.g., hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis). Treatment with olanzapine should be immediately discontinued if DRESS is suspected.
Effects on the Urogenital System: Priapism: There have been rare reports of priapism associated with antipsychotic use, such as olanzapine. As with other psychotropic drugs, priapism did not appear to be dependent on the dose and duration of the treatment. The most likely explanation for this adverse reaction is a relative decrease in sympathetic tone.
Urinary retention: Several serious cases of urinary retention (some of which required catheterization) have been reported in olanzapine-treated patients. Olanzapine should be used with caution in patients with a history or diagnosis of urinary retention; those receiving anticholinergic drugs that can affect voiding; and those with other risk factors for urinary retention (e.g., benign prostatic hyperplasia).
Effects on Ability to Drive and Use Machines: Olanzapine may cause somnolence and dizziness. Since olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that olanzapine therapy does not affect them adversely.
Lactose: This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use in Children: When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential for weight gain and dyslipidemia in adolescents compared to adults. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in this population.
The safety and efficacy of olanzapine in children <13 years old have not been established.
Use in the Elderly: Olanzapine is not indicated for the treatment of patients with dementia-related psychosis. Moreover, olanzapine may worsen Parkinsonian symptoms and hallucinations. The presence of factors that may reduce the pharmacokinetic clearance or increase the pharmacodynamics response to olanzapine should be considered (see Precautions), which may lead to initiation of treatment with a lower starting dose.
Olanzapine treatment resulted with a higher incidence of death and cerebrovascular adverse reactions in elderly patients with dementia compared to placebo. Adverse reactions commonly reported with olanzapine treatment in elderly patients were gait abnormality, falls, pneumonia, increased body temperature, lethargy, erythema, visual hallucinations, and urinary incontinence. Exercise caution with the use of olanzapine in the elderly patient, recognizing the more frequent hepatic, renal, central nervous system, and cardiovascular dysfunctions, and more frequent use of concomitant medication in this population.

Pregnancy: Pregnancy Category C.
There are no adequate and well-controlled trials with olanzapine in pregnant women. Seven pregnancies were observed during clinical trials with olanzapine, including two resulting in normal births, one resulting in neonatal death due to a cardiovascular defect, three therapeutic abortions, and one spontaneous abortion.
Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms after delivery. There have been reports of agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity. In some cases, symptoms have been self-limited, while neonates have required intensive care unit support and prolonged hospitalization in other cases. Newborns exposed to antipsychotic drugs should be carefully monitored.
Patients should notify their physician if they become pregnant or intend to become pregnant during treatment with olanzapine, Olanzapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: In a study of breastfeeding, healthy women, olanzapine was excreted in breast milk. Mean infant exposure at steady-state was estimated to be 1.8% of the maternal olanzapine dose. Patients should be advised not to breastfeed an infant if they are taking olanzapine.

The most commonly reported adverse reactions associated with olanzapine were somnolence, weight gain, eosinophilia, elevated prolactin, cholesterol, glucose and triglyceride levels; glucosuria, increased appetite, dizziness, akathisia, parkinsonism, leukopenia, neutropenia, dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases, rash, asthenia, fatigue, pyrexia, arthralgia, increased alkaline phosphatase, high gamma glutamyltransferase, high uric acid, high creatine phosphokinase and edema.
Infections and infestations: Nasopharyngitis, sinusitis.
Blood and lymphatic system disorders: Agranulocytosis, ecchymosis, granulocytopenia, thrombocytopenia, thrombocytopenic purpura.
Immune system disorders: Allergic reaction, anaphylactoid reaction, angioedema, drug reaction with eosinophilia and systemic symptoms (DRESS).
Endocrine disorders: Goiter.
Metabolism and nutrition disorders: Anorexia, diabetes aggravated, diabetic coma, diabetic ketoacidosis, dyslipidemia, eruptive xanthoma, gout, hyperosmolar coma, hypokalemia, hypernatremia, hyponatremia, hypoproteinemia, ketosis, peripheral edema, water intoxication.
Psychiatric disorders: Abnormal dreams, abnormal thinking, alcohol misuse, antisocial reaction, apathy, anxiety, confusion, delusions, depersonalization, depression, drug dependence, emotional lability, euphoria, hallucinations, hostility, insomnia, manic reaction, neurosis, obsessive-compulsive symptoms, paranoid reaction, personality disorder, phobia, restlessness, sedation, schizophrenic reaction, sleep apnea, somatization, somnolence, stimulant misuse, suicide attempt, tobacco misuse.
Nervous system disorders: Agitation, akinesia, altered mental status, amnesia, anticholinergic effects, ataxia, autonomic instability, choreoathetosis, circumoral paresthesia, cogwheel rigidity, CNS stimulation, coma, convulsion, dysarthria, dystonia, encephalopathy, extrapyramidal symptoms, facial paralysis, headache, hyperkinesia, hypersomnia, hypesthesia, hypokinesia, incoordination, lethargy, movement disorder, myasthenia, myoclonus, nervousness, neuralgia, neuroleptic malignant syndrome, neuropathy, nystagmus, oculogyric crisis, opisthotonos, paralysis, paresthesia, restless legs syndrome, seizures, speech disorder, stupor, stuttering, subarachnoid hemorrhage, tardive dyskinesia, torticollis, tremor, twitching, vertigo, worsening of parkinsonism.
Eye disorders: Abnormality of accommodation, abnormal vision, amblyopia, blepharitis, cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, eye disorder, eye hemorrhage, eye inflammation, eye pain, glaucoma, keratoconjunctivitis, macular hypopigmentation, lenticular pigmentation (pigment deposits in the eye lens), miosis, ocular muscle abnormality, mydriasis.
Ear and labyrinth disorders: Deafness, ear pain, tinnitus.
Cardiac disorders: Arrhythmia, bradycardia, cardiac arrest, chest pain, QT prolongation, sinus pause, tachycardia, torsade de pointes, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia.
Vascular disorders: Cerebrovascular accident, deep vein thrombosis, hypertension, hypotension, syncope, vasodilatation, venous thromboembolism.
Respiratory, thoracic, and mediastinal disorders: Apnea, aspiration pneumonia, asthma, atelectasis, cough increased, dyspnea, epistaxis, hemoptysis, hiccup, hyperventilation, hypoxia, laryngitis, lung edema, pharyngitis, pneumonia, pulmonary embolism (some are fatal), respiratory failure, respiratory tract infection, rhinitis, stridor, voice alteration.
Gastrointestinal disorders: Abdominal distention, abdominal pain, aphthous stomatitis, constipation, buccoglossal syndrome, diarrhea, dry mouth, dyspepsia, dysphagia, enteritis, esophageal dysmotility, eructation, esophageal ulcer, esophagitis, fecal impaction, fecal incontinence, flatulence, gastritis, gingivitis, glossitis, ileus, intestinal obstruction, melena, mouth ulceration, nausea, oral moniliasis, pancreatitis, periodontal abscess, rectal hemorrhage, salivation increased, stomatitis, taste perversion, tongue discoloration, tongue edema, tooth caries, vomiting.
Hepatic and hepatobiliary disorder: Bilirubinemia, hepatitis, jaundice, liver failure, liver fatty deposit, liver impairment, liver injury (cholestatic, hepatocellular, mixed).
Skin and subcutaneous tissue disorders: Acne, alopecia, contact dermatitis, dry skin, eczema, erythema, fungal dermatitis, hirsutism, hyperpigmentation, photosensitivity reaction, pruritus, rash (maculopapular, pustular, urticaria, vesicobullous), seborrhea, skin discoloration, skin ulcer, sweating, urticaria.
Musculoskeletal and connective tissue disorders: Back pain, bone pain, bursitis, hypertonia, joint disorder, joint pain, leg cramps, muscle rigidity, musculoskeletal stiffness, myalgia, myopathy, neck rigidity, osteoarthritis, osteoporosis, pain in extremities, rheumatoid arthritis.
Renal and urinary disorders: Acute renal failure, albuminuria, cystitis, dysuria, hematuria, myoglobinuria, oliguria, polyuria, urinary frequency, urinary hesitation, urinary incontinence, urinary retention, urinary tract infection, urinary urgency, urination impaired, uterine fibroids enlarged.
Pregnancy, puerperium and perinatal conditions: Unintended pregnancy.
Reproductive system and breast disorders: Amenorrhea, breast enlargement, breast pain, dysmenorrhea, ejaculation abnormal, erectile dysfunction, galactorrhea, gynecomastia, hypomenorrhea, impotence, lactation disorder, libido decreased, libido increased, loss of libido, mastitis, menorrhagia, menstrual disorder, menstruation decreased, menstruation increased, metrorrhagia, orgasm abnormal, pelvic pain, priapism, vaginal hemorrhage, vaginitis.
General disorders and administration site conditions: Chills, diaphoresis, face edema, fever, gait abnormality, hangover effect, hypothermia, lethargy, neonatal drug withdrawal syndrome, pain, sudden death, thirst.
Injury, poisoning, and procedural complications: Accidental injury, falls, intentional injury.
Investigations: Decreased albumin, decreased hematocrit, decreased hemoglobin, decreased high-density lipoprotein, decreased total bilirubin, increased HbA1c concentration, increased low-density lipoprotein, QTc prolonged.

Alcohol: Coadministration of ethanol with olanzapine may potentiate the orthostatic hypotension, and have an additive effect in sedation observed with olanzapine administered alone.
Antihypertensive drugs: Since olanzapine may induce hypotension, olanzapine may enhance the effects of antihypertensive agents.
Antiparkinsonian drugs: The concomitant use of olanzapine with anti-Parkinsonian drugs is not recommended in patients with Parkinson's disease and dementia (see Precautions).
Charcoal: One gram of activated charcoal reduced the C_max and AUC of orally administered olanzapine by 50% to 60%. Charcoal should be taken two hours prior to or after dosing with olanzapine.
Since the C_max of olanzapine is attained six hours after dosing, charcoal may be used as treatment for olanzapine overdose.
CNS Acting Drugs: Given that olanzapine has primarily CNS effects, it should be used with caution when taken in combination with other centrally acting drugs, including alcohol.
CYP1A2 Inducers: CYP1A2 inducers only slightly to moderately increase the olanzapine clearance. Although clinical consequences of the interaction between olanzapine and CYP1A2 inducers are likely to be limited, clinical monitoring and increasing the olanzapine dose may be considered, if necessary.
Smoking: Concomitant smoking may induce the metabolism of olanzapine, resulting to a 33% decrease in clearance of olanzapine. Moreover, the terminal elimination half-life of non-smokers was 21% longer than those of smokers.
Carbamazepine: The administration of carbamazepine 200 mg twice a day increases the clearance of olanzapine by approximately 50%. Higher doses of carbamazepine, a potent CYP1A2 inducer, may further increase the olanzapine clearance.
Omeprazole and Rifampicin: These CYP inducers may increase the clearance of olanzapine.
CYP1A2 Inhibitors: Fluvoxamine: Fluvoxamine significantly inhibits the metabolism of olanzapine, thereby decreasing the clearance of olanzapine and increasing the mean C_max of olanzapine in female nonsmokers and male smokers by 54% and 77%, respectively. The mean lower doses of olanzapine should be considered in concomitant use with fluvoxamine.
CYP2A6 Inhibitors: Fluoxetine 60 mg administered either as a single dose or daily for eight days slightly increases the C_max and decrease the clearance of olanzapine (~16%). Since the impact of this interaction is small compared to the overall interindividual variability, dose modification is not routinely recommended.
Diazepam: The coadministration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine administered alone.
Drug metabolizing enzymes: In vitro studies in human liver microsomes demonstrated that olanzapine has little potential to inhibit CYP1A2, CYP2C1, CYP2C19, CYP2D6, and CYP3A4. The maximum inhibition of CYP450 system by olanzapine would be <0.7%. The use of olanzapine is unlikely to produce clinically important interactions with drugs metabolized by these enzymes. However, the possibility that olanzapine may alter the metabolism of other drugs, or that other drugs may affect the metabolism of olanzapine, should be considered.
Drugs affecting QT interval: Olanzapine should be used in caution with drugs known to affect the QT interval (see Precautions).
Drugs causing electrolyte imbalance: Olanzapine should be used in caution with drugs known to cause electrolyte imbalance (see Precautions).
Drugs causing CNS depression: Olanzapine should be used in caution in patients who consume alcohol or other drugs that can cause CNS depression or those that induce hypotension, bradycardia, or respiratory depression.
Levodopa and Dopamine Agonists: Olanzapine may antagonize the effects of levodopa and dopamine agonists.
Valproate: In vitro studies using human liver microsomes demonstrated that olanzapine and valproate have little effect on the major metabolic pathways of each drug, which are oxidative metabolism and glucuronidation, respectively. Moreover, daily concomitant use of olanzapine 10 mg for two weeks in vivo did not alter the steady state plasma concentration of valproate. However, neutropenia, and the incidence of tremor, dry mouth, increased appetite, and weight gain may be more frequent in patients concomitantly taking olanzapine and valproate. Dosage adjustment of valproate during concomitant use of olanzapine is not required.

Store at temperatures not exceeding 30°C.

Antipsychotics

N05AH03 - olanzapine ; Belongs to the class of diazepines, oxazepines and thiazepines antipsychotics

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