Olanzapine

May alter cardiac conduction; life-threatening arrhythmias have occurred with therapeutic doses of antipsychotics.

May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems (including narrow-angle glaucoma). Relative to other neuroleptics, olanzapine has a moderate potency of cholinergic blockade (Richelson 1999).

Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low WBC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count 3.

An increased incidence of cerebrovascular effects (eg, transient ischemic attack, stroke), including fatalities, has been reported in placebo-controlled trials of olanzapine for the unapproved use in elderly patients with dementia-related psychosis.

May cause CNS depression, which impair physical and mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving). May be moderate to highly sedating in comparison with other antipsychotics (APA [Lehman 2004]); dose-related effects have been observed.

Dose-related increases in cholesterol and triglycerides have been noted. Use with caution in patients with preexisting abnormal lipid profile.

Antipsychotic use has been associated with esophageal dysmotility and aspiration; use with caution in patients at risk of pneumonia (ie, Alzheimer disease).

May cause extrapyramidal symptoms (EPS), including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics; frequencies reported are similar to placebo). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Lehman 2004]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.

May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability. Complete fall risk assessments at baseline and periodically during treatment in patients with diseases or on medications that may also increase fall risk.

Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. Olanzapine may have a greater association with hyperglycemia than other atypical antipsychotics. Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control. Patients with risk factors for diabetes (eg, obesity or family history) should have a baseline fasting blood sugar (FBS) and periodic assessment of glucose regulation.

May cause dose-related increases in prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown. Clinical manifestations of increased prolactin levels included menstrual-, sexual- and breast-related events.

Use may be associated with NMS; monitor for mental status changes, fever, muscle rigidity, and/or autonomic instability.

May cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use that may predispose to hypotension/bradycardia).

The possibility of a suicide attempt is inherent in psychotic illness or bipolar disorder; use with caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.

Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.

Significant weight gain (>7% of baseline weight) has been observed with antipsychotic therapy; incidence varies with product. Dose-related changes have been observed with olanzapine. Monitor waist circumference and BMI. Disease-related concerns:

Use with caution in patients with severe cardiac disease, hemodynamic instability, prior myocardial infarction, ischemic heart disease, or hypercholesterolemia.

Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared with placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in patients with Lewy body dementia or Parkinson disease dementia due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and association with irreversible cognitive decompensation or death. (APA [Reus 2016]). Olanzapine is not approved for the treatment of dementia-related psychosis.

Use with caution in patients with hepatic disease or impairment; may increase transaminases (primarily ALT).

Use with caution in patients with Parkinson disease; antipsychotic may aggravate motor disturbances (APA [Lehman 2004]; APA [Reus 2016]).

Use with caution in patients with renal disease.

Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications that may lower seizure threshold. Elderly patients may be at increased risk of seizures because of an increased prevalence of predisposing factors. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Use in patients ≥13 years of age may result in increased weight gain and sedation, as well as greater increases in LDL cholesterol, total cholesterol, triglycerides, prolactin, and liver transaminase levels when compared with adults. Adolescent patients should be maintained on the lowest dose necessary.

Olanzapine levels may be lower in patients who smoke. Smokers may require a daily dose 30% higher than nonsmokers in order to obtain an equivalent olanzapine concentration (Tsuda 2014); however, the manufacturer does not routinely recommend dosage adjustments. Dosage form-specific concerns:

There are two Zyprexa formulations for intramuscular injection: Zyprexa Relprevv is an extended-release formulation and Zyprexa IntraMuscular is short-acting. Extended-release IM injection (Zyprexa Relprevv): Postinjection delirium/sedation syndrome: [US Boxed Warning]: Sedation (including coma) and delirium (including agitation, anxiety, confusion, disorientation) have been observed following use of Zyprexa Relprevv; events associated with an inadvertent rapid rise in serum concentrations; administer at a registered health care facility where patients should be continuously monitored (≥3 hours) for symptoms of olanzapine overdose; symptom development highest in first hour but may occur within or after 3 hours; risk of syndrome is cumulative with each injection; recovery expected by 72 hours. Upon determining alert status, patient should be escorted to their destination and not drive or operate heavy machinery for the remainder of the day. Unexplained deaths: Two unexplained deaths in patients who received Zyprexa Relprevv have been reported. The patients died 3 to 4 days after receiving an appropriate dose of the drug. Both patients were found to have high blood concentrations of olanzapine postmortem. It is unclear if these deaths were the result of postinjection delirium sedation syndrome (PDSS) (FDA Safety Communication 2013). Restricted distribution program: Zyprexa Relprevv is only available under a restricted distribution program. Only prescribers, health care faciliti

Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling. Other warnings/precautions:

When discontinuing antipsychotic therapy, the American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid physical withdrawal symptoms, including anorexia, anxiety, diaphoresis, diarrhea, dizziness, dyskinesia, headache, myalgia, nausea, paresthesia, restlessness, tremulousness, and vomiting (APA [Lehman 2004]; CPA [Addington 2005]; Lambert 2007; WFSBP [Hasan 2012]). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anti-cholinergic or dopaminergic antipsychotics (Cerovecki 2013). Additional factors such as duration of antipsychotic exposure, the indication for use, medication half-life, and risk for relapse should be considered. In schizophrenia, there is no reliable indicator to differentiate the minority who will not from the majority who will relapse with drug discontinuation. However, studies in which the medication of well-stabilized patients were discontinued indicate that 75% of patients relapse within 6 to 24 months. Indefinite maintenance antipsychotic medication is generally recommended, and especially for patients who have had multiple prior episodes or 2 episodes within 5 years (APA [Lehman 2004]).

IV administration has only been studied in emergency department settings, where patients can be closely monitored for respiratory depression (ie, pulse oximetry) (Chan 2013; Cole 2017; Martel 2015; Taylor 2017).