OLANZAPINE 10 MSQ

Indications

• Schizophrenia
• Bipolar disorder
• Acute manic episodes associated with bipolar I disorder
• Prevention of recurrence in bipolar disorder

Dosage

Children: Refer to the BNF for Children for specific dosing information, as it varies based on

Adults: Initial dose of 10 mg daily, adjusted according to response; the usual dose ranges from 5 to 20 mg daily, with a maximum dose of 20 mg daily after reassessment.

Mechanism of action

Olanzapine exerts its effects by antagonizing several neuronal receptors in the brain, including dopamine receptors (D1, D2, D3, and D4) and serotonin receptors (5HT2A, 5HT2C, 5HT3, and 5HT6). The primary mechanism is the blockade of dopamine D2 receptors in the mesolimbic pathway, which reduces dopaminergic activity associated with psychotic symptoms. Additionally, its antagonism at serotonin receptors is proposed to reduce adverse effects and enhance therapeutic outcomes.

Pharmacodynamics

Olanzapine's action at the dopamine D2 receptor is associated with alleviating positive symptoms of schizophrenia, such as hallucinations and delusions. Its effect on serotonin 5HT2A receptors contributes to the reduction of negative symptoms, including anhedonia and poor motivation. Clinical trials have demonstrated its effectiveness in reducing symptoms of schizophrenia and managing acute manic episodes in bipolar disorder.

Pharmacokinetics

Olanzapine is well-absorbed after oral administration but undergoes extensive first-pass metabolism. It has a half-life of approximately 21 to 54 hours, allowing for once-daily dosing. The drug is primarily metabolized by the liver via cytochrome P450 enzymes, particularly CYP1A2. Excretion occurs mainly through urine and feces. The pharmacokinetic profile may be altered in individuals with hepatic impairment, necessitating dose adjustments.

Contra-indications

• Hypersensitivity to olanzapine or any of its ingredients
• Severe hepatic impairment
• Concurrent use of certain medications that may significantly increase olanzapine exposure

Adverse effects

• Anxiety
• Drooling
• Gastrointestinal discomfort
• Musculoskeletal stiffness
• Nausea
• Oculogyric crisis
• Oral disorders
• Pain
• Pruritus
• Psychiatric disorders
• Sleep disorders
• Appetite decreased
• Dysarthria
• Dysuria
• Gait abnormality
• Hot flush
• Hyperhidrosis
• Hypertension
• Hyponatremia
• Joint stiffness
• Myalgia
• Nasopharyngitis
• Blurred vision
• Angioedema
• Eosinophilia
• Rhabdomyolysis
• Anemia
• Angina pectoris
• Atrioventricular block
• Breast abnormalities
• Diarrhea
• Dysmenorrhea
• Dysphagia
• Renal failure
• Stevens-Johnson syndrome
• Suicidal behavior
• Vertigo

Interactions

• Carbamazepine: Moderate (decreases exposure)
• Phenytoin: Moderate (decreases exposure)
• Leflunomide: Moderate (decreases exposure)
• Mexiletine: Moderate (increases exposure)
• Osilodrostat: Moderate (increases exposure)
• Rucaparib: Moderate (increases exposure)
• Teriflunomide: Moderate (decreases exposure)
• Vemurafenib: Moderate (increases exposure)
• Ritonavir: Moderate (decreases exposure)
• Ciprofloxacin: Moderate (increases exposure)

Precautions

• Use with caution in patients with hepatic impairment
• Monitoring for metabolic effects such as weight gain, dyslipidemia, and glucose intolerance
• Consider lower initial doses and gradual dose increases in females, elderly, and non-smokers due to slower metabolism

Mechanism of action

The activity of olanzapine is achieved by the antagonism of multiple neuronal receptors including the dopamine receptor D1, D2, D3 and D4 in the brain, the serotonin receptors 5HT2A, 5HT2C, 5HT3 and 5HT6, the alpha-1 adrenergic receptor, the histamine receptor H1 and multiple muscarinic receptors. As abovementioned, olanzapine presents a wide profile of targets, however, its antagonistic effect towards the dopamine D2 receptor in the mesolimbic pathway is key as it blocks dopamine from having a potential action at the post-synaptic receptor. The binding of olanzapine to the dopamine D2 receptors is easily dissociable and hence, it allows for a certain degree of dopamine neurotransmission. On the other hand, olanzapine acts in the serotonin 5HT2A receptors in the frontal cortex in a similar manner than the reported on dopamine D2 receptors. This determined effect allows for a decrease in adverse effects. The mechanism of action of olanzapine, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug's efficacy in schizophrenia is mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonism. The mechanism of action of olanzapine in the treatment of acute manic or mixed episodes associated with bipolar I disorder is unknown.

Pharmacodynamics

The effect of olanzapine in the D2 receptor is reported to produce the positive effects of this drug such as a decrease in hallucinations, delusions, disorganized speech, disorganized thought, and disorganized behavior. On the other hand, its effect on the serotonin 5HT2A receptor prevents the onset of anhedonia, flat affect, alogia, avolition and poor attention. Based on the specific mechanism of action, olanzapine presents a higher affinity for the dopamine D2 receptor when compared to the rest of the dopamine receptor isotypes. This characteristic significantly reduces the presence of side effects. Clinical trials for the original use of olanzapine demonstrated significant effectiveness in the treatment of schizophrenia and bipolar disorder in adults and acute manic or mixed episodes associated with bipolar disorder in adolescents. The effect of olanzapine on dopamine and serotonin receptors has been suggested to reduce chemotherapy-induced nausea and vomiting as those receptors are suggested to be involved in this process. For this effect, several clinical trials have been conducted and it has been shown that olanzapine can produce a significant increase in total control of nausea and vomiting. In a high-level study of the effect of olanzapine for this condition, a complete response on the delay phase was observed in 84% of the individual and control of emesis of over 80% despite the phase.