OLANZAPINE–SAMIDORPHAN

Class

• Atypical antipsychotic (serotonin– dopamine antagonist; second-generation antipsychotic; also a mood stabilizer) and mu opioid receptor antagonist

OLANZAPINE–SAMIDORPHAN commonly prescribed for

(Bold for FDA approved)

How OLANZAPINE–SAMIDORPHAN works

• Blocks dopamine 2 receptors, reducing positive symptoms of psychosis and stabilizing affective symptoms

• Blocks serotonin 2A receptors, causing enhancement of dopamine release in certain brain regions and thus reducing motor side effects and possibly improving cognitive and affective symptoms

• Interactions at a myriad of other neurotransmitter receptors may contribute to its efficacy

• Blocks mu opioid receptors, ameliorating antipsychotic-induced weight gain and possibly metabolic abnormalities

How long until OLANZAPINE–SAMIDORPHAN works

• Clinical trials show improvement of psychotic symptoms after 2 weeks of treatment with olanzapine–samidorphan

• Psychotic and manic symptoms can improve within 1 week of olanzapine monotherapy treatment, but it may take several weeks for full effect on behavior as well as on cognition and affective stabilization

• Classically recommended to wait at least 4–6 weeks to determine efficacy of drug, but in practice some patients require up to 16–20 weeks to show a good response, especially on negative or cognitive symptoms

Notable Side Effects

• Probably increases risk for diabetes and dyslipidemia

• Dizziness, sedation, weakness

• Dry mouth, constipation, dyspepsia, weight gain, increased appetite

• Peripheral edema

• Headache, back pain, abnormal gait

• Tachycardia

• Orthostatic hypotension, usually during initial dose titration

• Tardive dyskinesia (reduced risk compared to conventional antipsychotics)

• Risk of potentially irreversible, involuntary dyskinetic movements may increase with cumulative dose and treatment duration

• Rare rash on exposure to sunlight

Life Threatening Side Effects

• Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking atypical antipsychotics

• Rare but serious skin condition known as drug reaction with eosinophilia and systemic symptoms (DRESS)

• Rare neuroleptic malignant syndrome may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability with elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure

• Rare seizures

• As a class, antipsychotics are associated with an increased risk of death and cerebrovascular events in elderly patients with dementia; not approved for treatment of dementia-related psychosis

• As a class, antidepressants have been reported to increase the risk of suicidal thoughts and behaviors in children and young adults

• Precipitation of opioid withdrawal in patients who are dependent on opioids

• Vulnerability to life-threatening opioid overdose via risk of opioid overdose from attempts to overcome olanzapine– samidorphan opioid blockade and risk of resuming opioids in patients with prior opioid use

weight gain

common

sedation

common

What to do about OLANZAPINE–SAMIDORPHAN side effects

• Wait

• Wait

• Wait

• Take at bedtime to help reduce daytime sedation

• Anticholinergics may reduce drug-induced parkinsonism when present

• Beta blockers, benzodiazepines, or serotonin 2A antagonists (e.g., mirtazapine, cyproheptadine) may reduce akathisia

• Weight loss, exercise programs, and medical management for high BMIs, diabetes, dyslipidemia

• Metformin may help prevent or reverse antipsychotic-induced weight gain

• Switch to another atypical antipsychotic

usual dosage range

• 5 mg/10 mg–20 mg/10 mg olanzapine/ samidorphan

Dosage Forms

• Olanzapine–samidorphan combination capsule (mg equivalent olanzapine/mg equivalent samidorphan) 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg, and 20 mg/10 mg

long term use

• Has been studied in trials up to 1 year

• Should periodically reevaluate long-term usefulness in individual patients, but treatment may need to continue for many years

habit forming

• No

Renal Impairment

• No dosage adjustment is needed in patient with mild, moderate, or severe renal impairment

• Not recommended in patients with end- stage renal disease

Hepatic Impairment

• No dose adjustment is needed in patients with hepatic impairment

Cardiac Impairment

• Use in patients with cardiac impairment has not been studied, so use with caution because of risk of orthostatic hypotension

• Use with caution if patient is taking concomitant antihypertensive or alpha 1 antagonist

Elderly

• Some patients may tolerate lower doses better

• Consider a lower dosage of the olanzapine component of olanzapine– samidorphan in elderly patients who have decreased clearance or an exaggerated pharmacodynamic response to olanzapine (e.g., oversedation)

• Although atypical antipsychotics are commonly used for behavioral disturbances in dementia, no agent has been approved for treatment of elderly patients with behavioral symptoms of dementia such as agitation

• Elderly patients with dementia-related psychosis treated with atypical antipsychotics are at an increased risk of death compared to placebo, and also have an increased risk of cerebrovascular events

• Consider pimavanserin for dementia-related psychosis or Parkinson’s disease psychosis instead of an atypical antipsychotic

Children and Adolescents

• Safety and efficacy have not been established in pediatric patients

• Children and adolescents using olanzapine– samidorphan may need to be monitored more often than adults and may tolerate lower doses better

Pregnancy

• Controlled studies have not been conducted in pregnant women

• There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester; symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding

• Symptoms of schizophrenia and bipolar I disorder may worsen during pregnancy, and some form of treatment may be necessary

• Early findings of infants exposed to olanzapine in utero currently do not show adverse consequences

• When administered to pregnant rats during the period of organogenesis, olanzapine– samidorphan produced adverse effects on embryofetal development and fetal toxicity at doses that are 6 times and >400 times the maximum recommended human dose (MRHD)

• When administered to pregnant rats and rabbits, olanzapine was not teratogenic at doses that are 9- and 30-times the MRHD; some fetal toxicities were observed at these doses

• When administered to pregnant rats and rabbits during the period of organogenesis, samidorphan caused fetal toxicities in rats only at doses that are >248 times the MRHD; administration of samidorphan to pregnant rats during pregnancy and lactation resulted in lower pup survival and decreased pup weight at 188 times the MRHD

• Olanzapine–samidorphan may be preferable to anticonvulsant mood stabilizers if treatment is required during pregnancy

Breast Feeding

• Olanzapine is found in mother’s breast milk

• There are reports of excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine through breast milk

• Unknown if samidorphan or the combination of olanzapine and samidorphan is secreted into human breast milk

• Recommended either to discontinue drug or formula feed

• Infants of women who choose to breast feed while on olanzapine–samidorphan should be monitored for possible adverse effects