Olanzapine

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

Stability. A suspension of olanzapine 1 mg/mL, made by crushing olanzapine tablets and suspending the powder in a syrup-based mixture containing carboxymethylcellulose preserved with methyl hydroxybenzoate and propyl hydroxybenzoate (Guy’s Hospital paediatric base formula), was considered to be stable for 2 weeks when stored in a refrigerator.

Adverse Effects, Treatment, and Precautions

Although olanzapine may share some of the adverse effects seen with the classical antipsychotics (see Chlorpromazine), the incidence and severity of such effects may vary.

The most frequent adverse effects with olanzapine are

somnolence and weight gain hyperprolactinaemia is also common, but usually asymptomatic.

Increased appetite, dizziness, fatigue, elevated plasma glucose, triglyceride, and liver enzyme values, eosinophilia, oedema, orthostatic hypotension, and mild transient antimuscarinic effects such as constipation and dry mouth are also relatively common.

More severe abnormalities of glucose homoeostasis are uncommon severe hyperglycaemia, or exacerbation of pre-existing diabetes, sometimes leading to ketoacidosis, coma, or death, has occurred. Clinical monitoring for hyperglycaemia has been recommended, especially in patients with or at risk of developing diabetes. Clinical monitoring of plasma lipids and weight have also been recommended.

Olanzapine is associated with a low incidence of ex-trapyramidal effects, including tardive dyskinesia, although these effects may be more likely at high doses and in the elderly the risk of tardive dyskinesia also increases with long-term use. Neuroleptic malignant syndrome has been reported rarely.

Patients receiving olanzapine intramuscularly should be closely observed for 2 to 4 hours for hypotension, bradyarrhythmia, and hypoventilation. Olanzapine should not be given intramuscularly to patients with a history of cardiovascular disease or following heart surgery caution is recommended when giving olanzapine by mouth to such patients and to those with cere-brovascular disease or conditions predisposing to hypotension. It is recommended that blood pressure is periodically assessed in elderly patients.

The antimuscarinic effects of olanzapine contra-indicate its use in patients with angle-closure glaucoma caution is also advised in those with conditions such as benign prostatic hyperplasia or paralytic ileus. Olanzapine is also not recommended in Parkinson’s disease since its use has commonly been associated with an increase in parkinsonian symptoms and hallucinations. It should be used with caution in patients with hepatic impairment, or a history of blood dyscrasias, bone marrow depression, or myeloproliferative disease. Seizures are rare with olanzapine but it should be used with care in those with a history of seizures or with conditions that lower the seizure threshold.

Olanzapine may affectthe performance of skilled tasks such as driving.

Withdrawal symptoms, including sweating, tremor, anxiety, and nausea and vomiting, have occurred rarely when olanzapine has been stopped abruptly a gradual dose reduction may be appropriate when stopping olanzapine.

Breast feeding.

From a study of the distribution of olanzapine into breast milk in 7 breast feeding women taking a median dose of 7.5 mg daily, it was estimated that the weight-adjusted median dose ingested by the breast-fed infants was 1.02% of the maternal dose. Olanzapine was not detected in the plasma of the 6 infants from whom a sample was taken no adverse effects were observed in all 7 infants. However, UK licensed product information states that at steady state the estimated mean exposure of breast-fed infants of mothers taking olanzapine would be 1.8% of the maternal dose and recommends that patients should not breast feed if they are taking olanzapine.

Dementia.

For details of a possibly increased risk of mortality in elderly patients with dementia given olanzapine and other atypical antipsychotics, see under Risperidone.

Effects on the blood.

A review has described 11 reports of olanzapine-associated haematotoxicity that included 3 cases of agranulocytosis, 6 of neutropenia, and 2 of leucopenia. In most cases, the haematotoxicity developed within the first month of treatment and patients recovered after olanzapine withdrawal. There was a history of clozapine-associated haematotoxicity in 5 patients. It was suggested that white blood cell counts should be monitored periodically during olanzapine treatment. Olanzapine has also apparently delayed recovery of granulocyte counts in patients with clozapine-induced granulocytopenia who were switched to olanzapine before blood counts had returned to the normal range.

There have been case reports of thrombocytopenia associated with olanzapine treatment. In one report, the patient improved on stopping olanzapine but subsequently had a similar episode associated with benzatropine therapy. In another report, an elderly patient with pre-existing idiopathic thrombocytopenic purpura died from bleeding complications due to thrombocytopenia associated with olanzapine treatment the patient’s plasma concentration of olanzapine was reported to be 10 times the usual mean therapeutic value.

Effects on body temperature.

Olanzapine has been associated with occasional reports of hypothermia. In one report body temperature fell as low as 33.4° over several days in a woman receiving olanzapine for bipolar disorder. The patient, who also had subclinical hypothyroidism, was asymptomatic, and body temperature returned to normal once olanzapine was stopped it was unclear whether the endocrine abnormalities had contributed to the condition.

Effects on body-weight.

The increased risk of weight gain with some atypical antipsychotics is discussed under Adverse Effects of Clozapine.

Effects on carbohydrate metabolism.

The increased risk of glucose intolerance and diabetes mellitus with some atypical antipsychotics, and recommendations on monitoring, are discussed under Adverse Effects of Clozapine. Further references for such effects associated with olanzapine use are given below in some cases the outcome was fatal.

Effects on the cardiovascular system.

Two of 3 elderly patients who developed venous thromboembolism shortly after starting treatment with olanzapine also had symptoms of pulmonary embolism. There have been 2 further isolated cases’ of pulmonary embolism associated with olanzapine therapy it had been reported in a 28-year-old man and in a 22-year-old man after 10 weeks and after 6 months of olanzapine therapy, respectively. Both patients recovered and were switched to another atypical antipsychotic.

Effects on lipid metabolism.

The increased risk of hyperlip-idaemia with some atypical antipsychotics is discussed under Adverse Effects of Chlorpromazine. See also Effects on Carbohydrate Metabolism under Adverse Effects of Clozapine.

Effects on the liver.

A report of acute hepatocellular cholestatic jaundice that developed in a 78-year-old woman 13 days after starting treatment with olanzapine.

Effects on the nervous system.

A 31-year-old woman with a complicated medical history suffered three generalised tonic-clonic seizures after 13 days of therapy with olanzapine. She recovered after treatment with phenytoin. Another patient with Huntington’s disease also suffered a severe generalised tonic-clonic seizure following treatment with olanzapine 30 mg daily for 1 month. Olanzapine was continued but carbamazepine was added there was no recurrence of the seizure.

Effects on the pancreas.

There have been isolated reports of pancreatitis associated with olanzapine. See also under Clozapine.

Effects on sexual function.

Priapism has been reported in 2 patients receiving olanzapine.

Extrapyramidal disorders.

There have been isolated reports of tardive dyskinesia associated with olanzapine treatment. However, the incidence of extrapyramidal effects is generally lower with atypical than classical antipsychotics.

Mania.

Although olanzapine is used in the treatment of bipolar disorder, it has been associated with reports of mania in both schizophrenic and bipolar patients. A report sponsored by the manufacturers noted that no association was seen in pooled data from 2 placebo-controlled studies involving 254 bipolar patients.

Neuroleptic malignant syndrome.

Cases of neuroleptic malignant syndrome have been associated with olanzapine therapy.

Overdosage.

A 2/ -year-old boy was found sleeping and difficult to arouse after taking one or two 7.5-mg olanzapine tablets. His reported symptoms included agitation, aggressive behaviour, miosis, hypersalivation, tachycardia, and ataxia he recovered after 24 hours. Symptoms suggestive of diabetes insipidus, together with mild CNS depression, have also been reported, in an adolescent who took 75 mg of olanzapine with a small quantity of prazepam. The polyuria responded to desmopressin. A review identified 29 fatalities associated with olanzapine overdose, but evidence of a direct causative relationship was limited.

Parkinsonism.

Worsening of motor function has been reported in patients with parkinsonism after use of olanzapine.

Pregnancy.

The manufacturer has reviewed both prospective and retrospective cases of pregnancies that have been exposed to olanzapine treatment. Of the 37 prospective pregnancies, there were 14 therapeutic abortions (with no reported abnormality in the fetus), 3 spontaneous abortions (again with no reported abnormality in the fetus), and 1 still-birth.

The remaining 19 pregnancies included 16 normal births without complications and 1 premature birth the 2 other births were complicated by post-term deliveries. Eleven retrospective cases were also identified and included 2 cases of major malformation (dysplastic kidney and Down’s syndrome), 1 case of fetal death following an overdose by the mother, and 1 case each of neonatal convulsion and sudden infant death. For comments on the use of some atypical antipsychotics, including olanzapine, during pregnancy, see under Precautions of Clozapine.

Speech disorders.

Although olanzapine may be used in the treatment of stuttering, it has also been associated with reports of the development of the disorder, see under Uses and Administration, below.

Interactions

The central effects of other CNS depressants, including alcohol, may be enhanced by olanzapine. Olanzapine may antagonise the effects of dopaminergics. Neutro-penia may be more common when olanzapine is given with valproate. Use with valproate or lithium has also been associated with an increased incidence of tremor, dry mouth, increased appetite, and weight gain.There is a theoretical risk of QT prolongation when olanzapine is given with other drugs that are known to cause this effect.

Drugs that induce hypotension, bradycardia, or respiratory depression should be used with caution in patients given intramuscular olanzapine. Parenteral benzodiazepine treatment should be given at least 1 hour after intramuscular olanzapine as it is recommended that they are not given together.

The metabolism of olanzapine is mediated to some extentby the cytochrome P450 isoenzyme CYP1A2. Use with drugs that inhibit, induce, or act as a substrate to this isoenzyme may affect plasma concentrations of olanzapine and a dose adjustment of olanzapine may be required. The CYP1A2 inhibitor fluvoxamine significantly inhibits the metabolism of olanzapine. The clearance of olanzapine is increased by tobacco smoking and carbamazepine.

Valproate.

In a study of 4 patients, valproate reduced plasma concentrations of olanzapine by 32.3 to 78.8% (mean 53.6%).

Pharmacokinetics

Olanzapine is well absorbed from the gastrointestinal tract after oral doses but undergoes considerable first-pass metabolism. Peak plasma concentrations are achieved about 5 to 8 hours after oral doses and about 15 to 45 minutes after an intramuscular dose. Olanzapine is about 93% bound to plasma proteins. It is extensively metabolised in the liver, primarily by direct glu-curonidation and by oxidation mediated through the cytochrome P450 isoenzymes CYP1A2, and, to a lesser extent, CYP2D6.

The 2 major metabolites 10-N-glucuronide and 4′-N-desmethyl olanzapine appear to be inactive. About 57% of a dose is excreted in the urine, mainly as metabolites, and about 30% appears in the faeces. The mean plasma elimination half-life has been variously reported to be about 30 to 3 8 hours half-lives tend to be longer in female than in male patients. Olanzapine is distributed into breast milk.

Uses and Administration

Olanzapine is a thienobenzodiazepine atypical antipsy-chotic. It has affinity for serotonin, muscarinic, histamine (H1), and adrenergic (α1) receptors as well as various dopamine receptors.

Olanzapine is used for the management of schizophrenia and for tiie treatment of moderate to severe mania associated with bipolar disorder. In the UK, the usual initial oral dose for schizophrenia is 10 mg daily as a single dose thereafter dosage adjustments may be made according to response at intervals of not less than 24 hours to within the range of 5 to 20 mg daily. In tiie USA, tiie starting dose is 5 to 10 mg daily and it is recommended that dosage adjustments beyond 10 mg daily are made at intervals of not less than 1 week tiie daily dosage should be adjusted in steps of 5 mg. However, it is recommended that doses above 10 mg daily should be given only after clinical reassessment.

For the treatment of acute mixed or manic episodes in bipolar disorder, a recommended initial oral dose is 10 or 15 mg daily as monotherapy or 10 mg if given as part of combination therapy the daily dosage may be adjusted in steps of 5 mg if necessary, at intervals of not less than 24 hours to a dose of between 5 and 20 mg daily. If a response is achieved, therapy may continue at tiie same dosage to prevent recurrence.

For prevention of recurrence in patients whose manic episodes have responded previously to olanzapine, the recommended starting dose is 10 mg daily. For the rapid control of agitation and disturbed behaviour in patients with schizophrenia or mania, olanzapine may be given intramuscularly in an initial dose of 5 to 10 mg followed by 5 to 10 mg as required after 2 hours. Notmore than 3 injections should be given in any 24-hour period and the maximum daily dose, including olanzapine given orally, should not exceed 20 mg. Injections may be given for up to a maximum of 3 days but transfer to oral therapy should be started as soon as possible.

The metabolism of olanzapine might be slower in female, elderly, or non-smoking patients if more than one of these factors is present, a lower initial dose (e.g. 5 mg daily if given orally) and a more gradual dose escalation should be considered. The intramuscular dose should be reduced by half in the elderly. See below for doses in patients with hepatic or renal impairment.

Administration in hepatic or renal impairment.

A starting dose of 5 mg daily of olanzapine orally or by intramuscular injection may be necessary for patients with renal or hepatic impairment for patients with moderate hepatic insufficiency, the starting dose should only be increased with caution.

Bipolar disorder.

Olanzapine is of benefit for the treatment of mania, with or without psychosis, in patients with bipolar disorder, and the use of atypical antipsychotics in the management of such patients is increasing. However, there have been individual case reports of olanzapine-induced mania. There is also increasing interest in the use of olanzapine for the depressive phase of bipolar disorder, and for other forms of resistant depression. In some countries olanzapine is available as a fixed-dose combination with fluoxetine for use in the former condition. References.

Nausea and vomiting.

For mention of the use of olanzapine as a second-line drug to control nausea and vomiting in palliative care.

Parkinsonism.

Olanzapine is associated with a relatively low incidence of extrapyramidal disorders and has been studied for use in the treatment of psychosis in patients with Parkinson’s disease (see Disturbed Behaviour). However, there have been a number of reports of adverse effects including exacerbation of the movement disorder (see Parkinsonism, under Precautions, above).

Psychiatric disorders.

The main treatment for post-traumatic stress disorder is psychotherapy but adjunctive olanzapine may be used in patients refractory to psychotherapy and/or drug treatment with antidepressants. Olanzapine has also been tried for the control of aggression in children with autism and conduct disorder (see Disturbed Behaviour).

Schizophrenia.

Studies suggest that olanzapine is as effective as haloperidol against positive symptoms of schizophrenia and more effective against negative symptoms in the short-term and possibly in the long-term, although a systematic review considered the evidence equivocal. Quality of life has also been judged to be greater in patients treated with olanzapine. In comparative studies, extrapyramidal adverse effects have been less frequent with olanzapine than haloperidol and fewer patients have discontinued treatment with olanzapine.

There are relatively few published comparisons with other atypical antipsychotics, but one systematic review concluded that there was little to differentiate between olanzapine and risperidone apart from their adverse effects risperidone was particularly associated with movement disorders and sexual dysfunction while olanzapine induced rapid weight gain. Another study has suggested that olanzapine is not inferior to clozapine. Olanzapine’s efficacy in the treatment of patients with refractory schizophrenia remains to be determined a small, randomised study found it to be no more effective than haloperidol.

Stuttering.

Although olanzapine may be of benefit in the treatment of stuttering, it has been associated with reports of stuttering in 6 adult patients with schizophrenia or depression.

Tourette’s syndrome.

When drug treatment is required for tics and behavioural disturbances in Tourette’s syndrome (see Tics) haloperidol or pimozide are commonly used but atypical antipsychotics, including olanzapine, are increasingly being tried.

Preparations

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