Olanzapine

Registered South African indications:

• Psychotic disorders
• Bipolar disorder
• Mania

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Known risk of narrow angle glaucoma
• Children <18 years

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Known risk of narrow angle glaucoma

Cautions

South African manufacturer recommendations

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
  - Elevated alanine transferase (ALT) and/or aspartate transferase (AST)
  - Signs and symptoms of hepatic impairment
  - Pre-existing conditions associated with limited hepatic functional reserve
  - Hepatitis (including hepatocellular, cholestatic or mixed liver injury)
  - Coadministration with potentially hepatotoxic agents
• Elderly
• Smokers
• Dementia-related psychosis
  - ≥65 years
  - Dysphagia
  - Sedation
  - Malnutrition
  - Dehydration
  - Pulmonary conditions (e.g., pneumonia, with or without aspiration)
  - Coadministration with benzodiazepines
• Risk factors for cerebrovascular adverse events (CVAE)
  - Elderly patients with dementia
  - History of previous CVAE or transient ischemic attack
  - Hypertension
  - Cigarette smoking
• History of seizures
• Factors that may lower the seizure threshold
• Risk factors for seizures
• Parkinson's disease
  - Dopamine agonist associated psychosis
• Unstable medical conditions (inj)
  - Acute myocardial infarction
  - Unstable angina pectoris
  - Severe hypotension
  - Bradycardia
  - Sick sinus syndrome
  - Following heart surgery
  - Unstable heart disease
• Serious cardiovascular disease (inj)
• Risk factors for lipid alterations
• Congenital long QT syndrome
• Congestive heart failure
• Cardiac hypertrophy
• Hypokalaemia
• Hypomagnesaemia
• Risk factors for venous thromboembolism
  - Immobilised patients
• Risk factors for orthostatic hypotension
• Low leukocyte and/or neutrophil counts
• History of drug-induced bone marrow depression or toxicity
• Bone marrow depression caused by concomitant illness, radiation therapy or chemotherapy
• Hypereosinophilic conditions
• Myeloproliferative disease
• Diabetes mellitus or risk factors thereof
  - Obesity
  - Family history of diabetes
• Abrupt withdrawal
• Prostatic hypertrophy
• Paralytic ileus and related conditions
• Long term exposure (>48 weeks)
• Risk for aspiration pneumonia
• Simultaneous administration with parenteral benzodiazepines (inj)
• Concurrent medical conditions and/or coadminstration with medications having a temporal association with CVAE 
• Coadministration with other agents having haemodynamic properties similar to those of olanzapine including other antipsychotics (oral and/or intramuscular) and benzodiazepines (inj)
• Coadministration with valproate (inj)
• Coadministration with agents known to prolong QTc interval (inj)
• Coadministration with other centrally acting medicines and alcohol
• Galactose intolerance (inj)
• Total lactase deficiency (inj)
• Glucose-galactose malabsorption (inj)
• Phenylketonuria
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
  - Elevated alanine transferase (ALT) and/or aspartate transferase(AST)
  - Signs and symptoms of hepatic impairment
  - Pre-existing conditions associated with limited hepatic functional reserve
  - Hepatitis (including hepatocellular, cholestatic or mixed liver injury)
  - Coadministration with potentially hepatotoxic agents
• Elderly
• Smokers
• Dementia-related psychosis and/or behavioural disturbances and risk factors thereof
  - >65 years
  - Dysphagia
  - Sedation
  - Malnutrition
  - Dehydration
  - Pulmonary conditions (e.g., pneumonia, with or without aspiration)
  - Coadministration with benzodiazepines
• Risk factors for cerebrovascular adverse events
  - Age >75 years and vascular/mixed type dementia
• Parkinson's disease
  - Dopamine agonist associated psychosis
• Factors that may lower the seizure threshold
• Risk factors for seizures
• History of seizures
• Risk factors for orthostatic hypotension
• Congenital long QT syndrome
• Congestive heart failure
• Cardiac hypertrophy
• Hypokalaemia
• Hypomagnesaemia
• Risk factors for venous thromboembolism
  - Immobilised patients
• Diabetes mellitus or risk factors thereof
• Dyslipidemic patients
• Risk factors for the development of lipid disorders
• Prostatic hypertrophy
• Paralytic ileus and related conditions
• Low leukocyte and/or neutrophil counts
• History of drug-induced bone marrow depression or toxicity
• Bone marrow depression caused by concomitant illness, radiation therapy or chemotherapy
• Hypereosinophilic conditions
• Myeloproliferative disease
• Abrupt withdrawal
• Long term exposure (>48 weeks)
• Coadministration with medicines known to cause neutropenia
• Coadministration with medicines known to prolong QTc interval
• Coadministration with other centrally acting medicines and alcohol
• Phenylketonuria (dsp)
• Galactose intolerance (tab)
• Total lactase deficiency (tab)
• Glucose-galactose malabsorption (tab)
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: tab, dsp, inj

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Management of the manifestations of psychotic disorders

• Oral (tab, dsp): Initial: 5-10mg, dly; Target dose: 10mg, dly within several days; Max: 20mg/24hrs

Schizophrenia and related psychoses
- Control of agitation and disturbed behaviour when oral therapy is not appropriate

• IM: Initial: 10mg; 2nd dose: Up to 10mg after 2hrs, if needed; 3rd dose: Up to 10mg after 4hrs (after 2nd dose), if needed: Max 30mg/24hrs 

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Oral: In order to evaluate efficacy and guard against side effects, dosage increases should not be considered before one week, since steady state for olanzapine would not be achieved for approximately one week

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Oral: The dose range is from 5-20mg per day. Increasing the dose over the routine daily dose of 10mg is advised only after appropriate clinical assessment

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The efficacy of olanzapine IM has not been established in patients with agitation and disturbed behaviours related to conditions other than schizophrenia or manic episode

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Acute mania - moderate to severe

• Oral (tab, dsp): Initial: 10mg, dly; Titrate at intervals of ≥24hrs within dose range of 5-20mg/day, if required; Max: 20mg/24hrs

- In bipolar I disorder when oral therapy is not appropriate

• IM: Initial: 10mg; 2nd dose: Up to 10mg after 2hrs, if needed; 3rd dose: Up to 10mg after 4hrs (after 2nd dose), if needed: Max 30mg/24hrs 

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IM (above indications): The safety of total daily doses greater than 30mg has not been evaluated in clinical trials

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IM (above indications): Treatment with olanzapine for injection should be discontinued and oral olanzapine in a range of 5-20mg/day should be initiated as soon as clinically appropriate

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Prevention of recurrence of manic or depressive episodes of bipolar disorder

• Oral (tab, dsp): Initial: 10mg, dly; Titrate at intervals of ≥24hrs within dose range of 5-20mg/day, if required after appropriate clinical assessment; Max: 20mg/24hrs

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Oral: For patients who have been receiving olanzapine for treatment of manic episode, continue therapy for preventing recurrence at the same dose

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Oral: The safety of doses above 20mg/day has not been evaluated in clinical trials

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Gradual tapering of the dose should be considered when discontinuing olanzapine

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International manufacturer recommendations

Schizophrenia
-  Treatment and maintenance of clinical improvement during continuation therapy in patients who have shown an initial treatment response

• Oral (tab, dsp): Initial: 10mg, dly

Manic episode - moderate to severe

• Monotherapy: Oral (tab, dsp): Initial: 15mg, dly
• Combination therapy: Oral (tab, dsp): Initial: 10mg, dly

Prevention of recurrence in bipolar disorder

• Oral (tab, dsp): Initial: 10mg, dly

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During treatment for schizophrenia, manic episode, and recurrence prevention in bipolar disorder, daily dosage may subsequently be adjusted on the basis of individual clinical status within the range 5-20mg/day

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An increase to a dose greater than the recommended starting dose is advised only after appropriate clinical reassessment and should generally occur at intervals of not less than 24hrs

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For patients who have been receiving olanzapine for treatment of manic episode, continue therapy for preventing recurrence at the same dose

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If a new manic, mixed, or depressive episode occurs, olanzapine treatment should be continued (with dose optimization as needed), with supplementary therapy to treat mood symptoms, as clinically indicated

Not established for use in children below 18 years

Pregnancy

South African manufacturer recommendations

• Caution; not recommended
• Safety of olanzapine during pregnancy has not been established
• There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with olanzapine
• Newborn infants exposed to antipsychotics (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery
• There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully

International manufacturer recommendations

• Caution; not recommended
• There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with olanzapine
• Nevertheless, because human experience is limited, olanzapine should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus
• Newborn infants exposed to antipsychotics (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery
• There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully

Breastfeeding

South African manufacturer recommendations

• Caution; not recommended 
• Safety of olanzapine during breastfeeding has not been established
• In a study in breastfeeding, healthy women, olanzapine was excreted in breast milk
• Mean infant exposure (mg/kg) at steady-state was estimated to be 1.8% of the maternal olanzapine dose (mg/kg). Patients should be advised not to breastfeed an infant if they are taking olanzapine

International manufacturer recommendations

• Caution; not recommended
• In a study in breastfeeding, healthy women, olanzapine was excreted in breast milk
• Mean infant exposure (mg/kg) at steady-state was estimated to be 1.8% of the maternal olanzapine dose (mg/kg). Patients should be advised not to breastfeed an infant if they are taking olanzapine

Fertility

• Effects on fertility are unknown

Renal Impairment

South African manufacturer recommendations

• Caution; no dose adjustment recommended 
  Olanzapine is not removed by haemodialysis
  The effect of renal impairment on metabolite elimination has not been studied

International manufacturer recommendations

• Caution; dose adjustment recommended
  Lower starting dose of 5mg should be considered 

Hepatic Impairment

South African manufacturer recommendations

• Mild: Caution; no dose adjustment recommended 
• Moderate: Caution; dose adjustment recommended 
  A 5mg starting dose should be considered for patients with moderate hepatic impairment
• Severe: Caution; no information available 
  In cases where hepatitis (including hepatocellular, cholestatic or mixed liver injury) has been diagnosed, olanzapine treatment should be discontinued

International manufacturer recommendations

• Child-Pugh class A & B and cirrhosis: Caution; dose adjustment recommended
  Starting dose should be 5mg and only increased with caution
• Child-Pugh class C: Caution; no information available
  In cases where hepatitis (including hepatocellular, cholestatic or mixed liver injury) has been diagnosed, olanzapine treatment should be discontinued

Elderly

South African manufacturer recommendations

• Caution; dose adjustment recommended 
  IM: A lower starting dose of 2,5-5mg per injection should be considered
  Oral (tab): A 5mg starting dose may be considered

International manufacturer recommendations

• Caution; dose adjustment recommended
  Lower starting dose of 5mg, dly is not routinely indicated but should be considered for those ≥65 years when clinical factors warrant 

Smokers

South African manufacturer recommendations

• Plasma clearance of olanzapine is higher in smokers
• The combined effects of age, smoking and gender could lead to substantial pharmacokinetic differences in population
• The clearance in young smoking males is 3 times higher than that in elderly non-smoking females
• Dosing modification may be necessary in patients who exhibit a combination of factors that may result in slower metabolism of olanzapine

International manufacturer recommendations

• The starting dose and dose range need not be routinely altered for non-smokers relative to smokers
• The metabolism of olanzapine may be induced by smoking. Clinical monitoring is recommended and an increase of olanzapine dose may be considered if necessary
• When more than one factor is present which might result in slower metabolism (female gender, geriatric age, non-smoking status), consideration should be given to decreasing the starting dose. Dose escalation, when indicated, should be conservative in such patients

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Somnolence
• Dizziness
• Akathisia
• Parkinsonism
• Dyskinesia
• Seizures
• Dystonia
  - Oculogyration
• Tardive dyskinesia
• Amnesia
• Dysarthria
• Stuttering
• Restless legs syndrome
• Neuroleptic malignant syndrome
  - Hyperpyrexia
  - Muscle rigidity
  - Altered mental status
  - Autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia)
  - Elevated creatine phosphokinase
  - Myoglobinuria (rhabdomyolysis)
  - Acute renal failure
• Discontinuation symptoms
  - Sweating
  - Insomnia
  - Tremor
  - Anxiety
  - Nausea and vomiting
• Asthenia
• Neonatal drug withdrawal syndrome

Cardiovascular Disorders

• Bradycardia
• QT prolongation
• Ventricular tachycardia
• Ventricular fibrillation
• Sudden death
• Orthostatic hypotension
• Thromboembolism
  - Pulmonary embolism
  - Deep vein thrombosis

Respiratory Disorders

• Epistaxis

Gastrointestinal Disorders

• Mild, transient anticholinergic effects
  - Constipation
  - Dry mouth
• Abdominal distension
• Salivary hypersecretion
• Pancreatitis

Hepatobiliary Disorders

• Transient, asymptomatic elevations of hepatic aminotransferases
  - Alanine transferase
  - Aspartate transferase 
• Hepatitis
  - Hepatocellular, cholestatic or mixed liver injury
• Increased alkaline phosphatase
• Increased gamma-glutamyltransferase
• Increased total bilirubin

Genitourinary Disorders

• Urinary incontinence
• Urinary retention
• Urinary hesitation
• Erectile dysfunction
• Decreased libido
• Amenorrhoea
• Breast enlargement
• Galactorrhoea (in females)
• Gynaecomastia
• Priapism
• Increased uric acid
• Elevated plasma prolactin levels

Endocrine and Metabolic Disorders

• Weight gain
• Increased cholesterol levels
  - Total cholesterol
  - LDL cholesterol
• Increased glucose levels
• Increased triglyceride levels
• Glucosuria
• Increased appetite
• Development or exacerbation of diabetes (occasionally associated with ketoacidosis or coma, including some fatal cases)
• Hypothermia
• Hyperglycaemia
  - Polydipsia
  - Polyuria
  - Polyphagia
  - Weakness

Musculoskeletal Disorders

• Arthralgia
• Rhabdomyolysis
• Increased creatine phosphokinase

Skin and Subcutaneous Tissue Disorders

• Rash
• Photosensitivity reaction
• Alopecia
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Immune, Blood and Lymphatic System Disorders

• Eosinophilia
• Leukopenia
• Neutropenia
• Thrombocytopenia
• Hypersensitivity
• Fever
• Oedema

• CYP1A2 inducers
• Carbamazepine
• CYP1A2 inhibitors
• Fluvoxamine
• Ciprofloxacin
• Dopamine agonists
• Central nervous system depressants
• Anti-parkinsonian agents
• QT-prolonging agents

Other interactions

• Smoking
• Activated charcoal
• Alcohol

• Mental status
• Vital signs
• Blood pressure
• Weight
• Height
• Body mass index
• Waist circumference
• Full blood count
• Electrolytes
• Hepatic function
• Fasting lipid panel

Specific cases may require

• Fasting plasma glucose level/ HbA1c
• Ocular examination

Additional observations

• Personal or family history of;
  - Obesity
  - Diabetes
  - Dyslipidemia
  - Hypertension
  - Cardiovascular disease
• Changes in menstruation, libido, development of galactorrhea, erectile and ejaculatory function
• Abnormal involuntary movements or parkinsonian signs
• Tardive dyskinesia
• Fall risk

Olanzapine Tablet - EML (Hospital) 

Olanzapine Injection - EML (Tertiary)

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Additional points - Oral

• The antipsychotic efficacy of olanzapine was established in controlled trials of schizophrenic inpatients in the treatment of positive symptoms (such as delusions, hallucinations, disordered thinking, hostility and suspiciousness) and negative symptoms (such as blunted effect, emotional and social withdrawal, poverty of speech)
• During therapy, the daily olanzapine dosage may subsequently be adjusted on the basis of individual clinical status within the range of 5-20mg/day
• An increase to a dose greater than the recommended starting dose is advised only after appropriate clinical reassessment and should generally occur at intervals of not less than 24 hours
• Gradual tapering of the dose should be considered when discontinuing olanzapine
• Olanzapine can be given without regard for meals, as absorption is not affected by food

Dispersible tablets

• Orodispersible tablets should be placed in the mouth, where it will rapidly disperse in saliva, so it can be easily swallowed
• Since the orodispersible tablet is fragile, it should be taken immediately on opening the blister
• Alternatively, it may be dispersed in a full glass of water or other suitable beverage (orange juice, apple juice, milk or coffee) immediately before the administration
• Olanzapine dispersible tablets are bioequivalent to olanzapine coated tablets, with a similar rate and extent of absorption. They have the same dosage and frequency of administration as olanzapine coated tablets. Olanzapine dispersible tablets may be used as an alternative to olanzapine coated tablets

Intramuscular use

• Administer the solution intramuscularly. Do not administer intravenously or subcutaneously
• Serious/ severe bradycardia and syncope may occur. In clinical studies, there were cases with serious symptomatic hypotension, apnoea, and ventricular tachydysrhythmias including fatalities
• In most of the serious cases, there was a temporal relationship with the use of benzodiazepines

Reconstitution of IM formulation
Reconstitution of olanzapine IM (powder for Injection) with sterile water for injection:

• Reconstitute only with water for injection using standard aseptic techniques for reconstitution of parenteral products. No other solutions should be used for reconstitution
• Withdraw 2,1ml of water for injection into a sterile syringe. Inject into a vial of olanzapine IM. Rotate the vial until the contents have completely dissolved, giving a yellow coloured solution
• The vial contains 11,0mg olanzapine as a solution of 5mg/ml (1mg olanzapine is retained in the vial and syringe, thus allowing delivery of 10mg olanzapine)
• Discard the syringe and any unused solution in accordance with appropriate clinical procedures. Use the solution immediately within 1 hour of reconstitution
• Parenteral medicines should be inspected visually for particulate matter prior to administration
• The following table provides injection volumes for delivering various doses of olanzapine:

Dose of olanzapine (mg)	Volume of injection (ml)
10.0	2.0
7.5	1.5
5.0	1.0
2.5	0.5

Major reconstitution incompatibilities

• Olanzapine IM should not be combined in a syringe with diazepam injection because precipitation occurs when these products are mixed
• Lorazepam injection should not be used to reconstitute olanzapine IM as this combination results in a delayed reconstitution time
• Olanzapine IM should not be combined in a syringe with haloperidol injection because the resulting low pH has been shown to degrade olanzapine over time

Use with benzodiazepines

• Simultaneous injection of intramuscular olanzapine and parenteral benzodiazepines has not been studied and is therefore not recommended
• If the patient is considered to need parenteral benzodiazepine treatment, this should not be given until at least 1hr after IM olanzapine administration
• If the patient has received parenteral benzodiazepines, IM olanzapine administration should only be considered after careful evaluation of clinical status and the patient should be closely monitored for excessive sedation and cardiorespiratory depression

Coadministration with benzodiazepine

• Simultaneous injection of intramuscular olanzapine IM and parenteral benzodiazepines has not been studied and is therefore not recommended
• If the patient is considered to need parenteral benzodiazepine treatment, this should not be given until at least 1 hour after olanzapine IM administration
• If the patient has received parenteral benzodiazepines, olanzapine IM administration should only be considered after careful evaluation of clinical status and the patient should be closely monitored for excessive sedation and cardiorespiratory depression

Olanzapine is an antipsychotic, antimanic, and mood stabilising agent that demonstrates a broad pharmacologic profile across a number of receptor systems. In preclinical studies, olanzapine exhibited a range of receptor affinities for serotonin 5HT2A/2C, 5HT3, 5HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors M1-M5; α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine demonstrated a greater in vitro affinity for serotonin 5HT2 than dopamine D2 receptors and greater 5HT2 than D2 activity in in vivo models. Electrophysiological studies demonstrated that olanzapine selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on the striatal (A9) pathways involved in motor function. olanzapine reduced a conditioned avoidance response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an effect indicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increases responding in an 'anxiolytic' test.

Tablet 2.5mg

• Adco Olanzapine (Adcock Ingram)
• Lanazyp (Brimpharm)
• Mylan Olanzapine (Mylan)
• Nezolap (Macleods)
• Olandus 2.5 (Arya Pharma)
• Oleanz (Ranbaxy)
• Olexar (Cipla)
• Prexolan (Pharmacare)
• Redilanz (Dr Reddy's)
• Zyprexa (Eli Lilly) originator

Tablet 5mg

• Adco Olanzapine (Adcock Ingram)
• Lanazyp (Brimpharm)
• Mylan Olanzapine (Mylan)
• Nezolap (Macleods)
• Olandus 5 (Arya Pharma)
• Olawin (Zentiva)
• Oleanz (Ranbaxy)
• Olexar (Cipla)
• Prexolan (Pharmacare)
• Redilanz (Dr Reddy's)
• Zolanz (Zydus)
• Zylena (Akacia)
• Zyprexa (Eli Lilly) originator

Tablet 10mg

• Adco Olanzapaine (Adcock Ingram)
• Lanazyp (Brimpharm)
• Mylan Olanzapine (Mylan)
• Nezolap (Macleods)
• Olandus 10 (Arya Pharma)
• Olawin (Zentiva)
• Oleanz (Ranbaxy)
• Olexar (Cipla)
• Prexolan (Pharmacare)
• Redilanz (Dr Reddy's)
• Zolanz (Zydus)
• Zylena (Akacia)
• Zyprexa (Eli Lilly) originator

Tablet dispersible 5mg

• Olawin (Zentiva) Originator
• Oleanz (Ranbaxy)
• Phrenpe 5 (Trinity Pharma)
• Prexolan ODT (Pharmacare)
• Zyprexa Velotab (Eli Lilly) originator

Tablet dispersible 10mg

• Olawin (Zentiva) Originator
• Oleanz (Ranbaxy)
• Phrenpe 10 (Trinity Pharma)
• Prexolan ODT (Pharmacare)
• Zyprexa Velotab (Eli Lilly) originator

Injection (per vial) 10mg

• Prexolan IM (Pharmacare)
• Zyprexa (Eli Lilly) originator