Salveo ODT Special Precautions

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.