CLOZAPINE

brands

Class

• Neuroscience-based Nomenclature: dopamine, serotonin, norepinephrine receptor antagonist (DSN-RAn)
• Atypical antipsychotic (serotonin– dopamine antagonist; second-generation antipsychotic; also a mood stabilizer)

CLOZAPINE commonly prescribed for

(Bold for FDA approved)

How CLOZAPINE 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 clozapine’s efficacy

• Specifically, interactions at serotonin 2C and 1A receptors may contribute to efficacy for cognitive and affective symptoms in some patients

• Mechanism of efficacy for psychotic patients who do not respond to other antipsychotics is unknown but is presumed to be a mechanism other than dopamine 2 antagonism

How long until CLOZAPINE works

Likelihood of response depends on achieving trough plasma levels of at least 350 ng/mL

• Median time to response after achieving therapeutic plasma levels (350 ng/mL) is approximately 3 weeks

• If there is no response after 3 weeks of therapeutic plasma levels, recheck plasma levels and continue titration

Notable Side Effects

• Orthostasis

• Sialorrhea

• Constipation

• Sedation

• Tachycardia

• Weight gain

• Dyslipidemia and hyperglycemia

• Benign fever (~20%)

• Tardive dyskinesia (reduced risk compared to other antipsychotics)

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

Life Threatening Side Effects

• Severe neutropenia

• Myocarditis (only in first 6 weeks of treatment)

• Paralytic ileus

• Seizures (risk increases with dose)

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

• Pulmonary embolism (may include deep vein thrombosis or respiratory symptoms)

• Dilated cardiomyopathy

• Rare neuroleptic malignant syndrome may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability with elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure (more likely when clozapine is used with another agent)

• 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

weight gain

problematic

sedation

problematic

What to do about CLOZAPINE side effects

• Slow titration to minimize orthostasis and sedation

• Minimize use of other alpha 1 antagonists

• If orthostasis remains a problem, Florines 0.1–0.3 mg once a day for volume expansion (contraindicated in congestive heart failure)

• Take at bedtime to help reduce daytime sedation

• Sialorrhea management

• Atropine 1% drops, 1–3 drops sublingually at bedtime; can use up to 3 times per day if needed

• Ipratropium bromide 0.06% spray, 1–3 sprays intra-orally at bedtime; can use up to 3 times per day if needed

• Avoid use of systemic anticholinergic agents, which increase risk of ileus (benztropine, glycopyrrolate, etc.)

• Consider novel use of botulinum toxin injections for severe cases

• Constipation management

• Avoid psyllium as it may worsen symptoms

• All patients should receive docusate 250 mg when starting clozapine

• If needed, add Miralax 17 g

• If docusate + Miralax are ineffective, add either bisacodyl or sennosides

• If constipation still remains a problem, prescribe lubiprostone 8–24 μg twice per day

• Advise patients to contact a healthcare professional right away if they have difficulty having a bowel movement, do not have a bowel movement at least 3 times a week or less than their normal frequency, or are unable to pass gas

• Weight gain and metabolic effects

• Consider prophylactic metformin; start at 500 mg for 1 week, then increase dose

• All patients should be referred for lifestyle management and exercise

• Tachycardia

• Atenolol 12.5 mg once a day, increase to keep resting HR <100 bpm

• Chest pain during the first 6 weeks

• Obtain workup for myocarditis

• Fever

• In the absence of elevated troponin and myocarditis symptoms, fever is usually self-limited and there is no need to stop clozapine

• Seizures

• Valproate for myoclonic or generalized seizures

• Avoid phenytoin and carbamazepine because of kinetic interactions

usual dosage range

• Depends on plasma levels; threshold for response is trough plasma level of 350 ng/mL

Dosage Forms

• Depends on plasma levels; threshold for response is trough plasma level of 350 ng/mL

long term use

• Treatment to reduce risk of suicidal behavior should be continued for at least 2 years

• Medication of choice for treatmentre- fractory schizophrenia

habit forming

• No

Renal Impairment

• Should be used with caution

Hepatic Impairment

• Should be used with caution

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

• 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 dementiarelated psychosis or Parkinson's disease psychosis instead of an atypical antipsychotic

Children and Adolescents

• Safety and efficacy have not been established

• Preliminary research has suggested efficacy in early-onset treatment-resistant schizophrenia

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

Pregnancy

• Effective June 30, 2015, the FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

• 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

• Animal studies have not shown adverse effects

• Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

• Clozapine should be used only when the potential benefits outweigh potential risks to the fetus

Breast Feeding

• Unknown if clozapine is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

• Recommended either to discontinue drug or bottle feed

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