clozapine

Clozapine is a new generation antipsychotic drug and - as such - has reduced extrapyramidal side effects and does not produce tardive dyskinesia following long-term therapy.

Clozapine - Chemical Structure

However, clozapine can cause other very serious adverse effects, therefore it is not a first choice drug.

Indications

For what it uses

The use of clozapine is indicated for the treatment of:

• Schizophrenia that does not respond to treatment with other drugs;
• Schizophrenia in patients who - undergoing other antipsychotic therapy - have developed serious undesirable neurological side effects;
• Psychotic disorders occurring during Parkinson's disease.

Warnings

Clozapine should not be administered in the following cases:

• Patients who have lost consciousness;
• Patients in whom psychotic disorders are caused by alcohol, poisoning or drug poisoning;
• In patients with brain damage and reduced brain function.

Clozapine can only be used in patients who have a normal concentration of white blood cells in the bloodstream. Therefore, before, during and after treatment with the drug, appropriate controls must be performed.

Patients on clozapine therapy who have suffered from disorders such as liver, kidney and / or cardiovascular disease, prostate enlargement, epilepsy, diabetes or stroke risk should be closely monitored.

Elderly patients aged 60 or over 60 years on clozapine therapy must be constantly monitored and must undergo regular check-ups.

Elderly patients with dementia should not take clozapine because of the increased risk of stroke and death.

Since clozapine can cause inhibition of intestinal peristalsis, care must be taken when administering the drug to patients who have suffered from severe intestinal disorders and / or who have undergone abdominal surgery.

Since clozapine promotes the formation of blood clots, it is necessary to pay attention to the administration of the drug in patients with a family history of coagulation disorders.

Clozapine may increase blood sugar levels and may lead to a worsening of diabetes in patients with this condition. Therefore, regular analyzes are recommended.

Clozapine can cause inflammation of the myocardium (heart muscle), if this occurs, treatment with the drug must be stopped immediately.

Furthermore, clozapine can cause prolongation of the QT interval (the interval of time required for the myocardium to depolarize and repolarize), therefore, patients suffering from cardiovascular diseases - or who have a family history of QT interval prolongation - must be carefully monitored.

Clozapine can cause an increase in body weight and lipids in the bloodstream, therefore the doctor must monitor these parameters.

Clozapine can cause blood pressure reduction with dizziness and fainting during the first few weeks of use. Patients with Parkinson's disease must monitor blood pressure, both upright and supine.

The use of alcohol during clozapine treatment should be avoided.

Clozapine can cause side effects that can affect the ability to drive and / or operate machinery.

Interactions

Clozapine-induced myelosuppression (bone marrow suppression) may be increased by concomitant administration of myelosuppressive drugs as well, so this combination should be avoided. Among these drugs, we recall:

• Carbamazepine, a drug used to treat epilepsy;
• Chloramphenicol, an antibiotic;
• sulfa drugs, synthetic drugs with antibacterial action;
• Pyrazolonic analgesics ;
• Cytotoxic drugs (toxic to cells), such as - for example - anticancer drugs;
• Depot injections of antipsychotics (special pharmaceutical formulations that allow the accumulation of the drug in the tissues and its release gradually).

Concomitant use of clozapine and benzodiazepines increases the risk of fainting.

Co-administration of clozapine and the following drugs may increase side effects in the central nervous system:

• Antihistamine drugs;
• IMAO (monoamine oxidase inhibitors);
• Antidepressant drugs;
• Benzodiazepines ;
• Narcotics ;
• Anesthetics ;
• Opioid analgesics .

Concomitant use of clozapine and drugs capable of prolonging the QT interval (such as - for example - other antipsychotic drugs and drugs that cause electrolyte imbalance) may increase the risk of developing heart problems and therefore should be avoided .

Clozapine may increase the hypotensive effects of antihypertensive drugs.

Co-administration of clozapine and SSRI (selective serotonin reuptake inhibitors) may increase the clozapine blood concentration itself.

The efficacy of clozapine may be reduced by concomitant administration of the following drugs:

• Phenytoin, a drug used to treat epilepsy;
• Rifampicin, a drug used to treat tuberculosis;
• Omeprazole, a drug used to treat gastritis.

Concomitant use of clozapine and lithium (a drug used to treat bipolar disorder) may increase the risk of developing neuroleptic malignant syndrome.

Clozapine can antagonize the effect of adrenaline and noradrenaline .

Concomitant use of clozapine and valproic acid (an anti-epileptic drug) may promote the onset of epileptic seizures, even in patients without epilepsy.

Clozapine may increase the activity of warfarin (an oral anticoagulant) and digoxin (a drug used to increase the strength of cardiac contraction), this increase can cause potentially dangerous effects.

Other drugs that can give rise to interactions when given with clozapine are:

• Ketoconazole and itraconazole, antifungal drugs;
• Cimetidine, a drug used to treat gastric ulcer;
• Erythromycin, an antibiotic;
• Antivirals used to treat HIV.

Smoking and coffee can alter the therapeutic efficacy of clozapine.

Side effects

Clozapine may induce various side effects, although not all patients experience them. This happens because each individual has his own sensitivity to the drug, therefore, each patient responds to therapy differently.

The following are the main side effects that may occur following clozapine therapy.

Myelosuppression

Clozapine treatment can cause myelosuppression, resulting in decreased blood cell production. This can cause:

• Anemia (decrease in hemoglobin blood levels), the main symptom of the onset of anemia is the feeling of physical exhaustion;
• Leukopenia (decreased white blood cell levels), with increased susceptibility to contraction of infections;
• Plateletopenia (decrease in the number of platelets), this leads to the appearance of bruising and abnormal bleeding with an increased risk of bleeding.

Malignant Neuroleptic Syndrome

Neuroleptic Malignant Syndrome is a neurological disorder characterized by:

• Temperature;
• Dehydration;
• Muscle stiffness;
• akinesia;
• Sweating;
• Tachycardia;
• Arrhythmia;
• Changes in the state of consciousness that can progress to stupor and coma.

If such symptoms appear, clozapine treatment should be discontinued immediately and a doctor should be contacted immediately.

Metabolism and nutrition disorders

Clozapine therapy may lead to increased body weight, impaired glucose tolerance, increased blood sugar levels, diabetes mellitus, excessive increase in blood levels of triglycerides and cholesterol.

Nervous system disorders

Clozapine treatment can cause:

• Speech disorders;
• Stuttering;
• Restlessness;
• agitation;
• Sedation and drowsiness;
• dizziness;
• Headache;
• Tremors;
• Muscle stiffness;
• Muscle spasms;
• Convulsions;
• Reduced consciousness;
• Cholinergic syndrome.

Cardiac disorders

Clozapine can cause arrhythmias, myocarditis (inflammation of the heart muscle), pericarditis (inflammation of the pericardium), cardiomyopathy, prolongation of the QT interval, cardiac arrest and angina pectoris.

Vascular pathologies

Treatment with clozapine can cause hypertension, orthostatic hypotension, sudden and temporary loss of consciousness and may favor the formation of blood clots.

Lung and airway disorders

Clozapine therapy can cause choking, respiratory tract infections, pneumonia, coughing, wheezing, respiratory depression and respiratory arrest.

Gastrointestinal disorders

Clozapine can cause constipation, nausea, vomiting, dry mouth, difficulty swallowing, diarrhea, heartburn, intestinal obstruction and pancreatitis.

Hepatobiliary disorders

Clozapine treatment can cause liver damage, fatty liver, hepatitis and jaundice.

Renal and urinary tract disorders

Clozapine therapy can cause incontinence, urination difficulties, inflammation of the kidneys with blood in the urine, fever and pain, nocturnal enuresis and renal failure.

Interruption symptoms

If clozapine treatment is stopped abruptly, withdrawal symptoms such as hallucinations, headache, nausea, vomiting and diarrhea may occur. Therefore a gradual interruption is recommended.

Other side effects

Other adverse effects that may occur during clozapine therapy are:

• Temperature;
• Fatigue;
• Skin reactions;
• Blurred vision;
• Increased sweating and salivation;
• Weakness and muscle pain;
• Muscle spasms;
• Priapism (long and painful erection not accompanied by sexual excitement).

Overdose

In the event of clozapine overdose it is necessary to contact the doctor immediately and go to the nearest hospital.

Symptoms that may appear include:

• Drowsiness and lethargy;
• Motor disorders;
• Confusion;
• Hallucinations;
• Delusions;
• Restlessness;
• Convulsions;
• Excessive salivation;
• mydriasis;
• Hypotension;
• Collapse;
• arrhythmias;
• Coma.

Action mechanism

Clozapine performs its antipsychotic action by antagonizing the 5-HT2A receptors of serotonin (5-HT) and - to a lesser extent - by antagonizing dopamine D2 receptors. Furthermore, clozapine has a high affinity towards α ₁ and α ₂ adrenergic receptors, histamine H1 receptors and M1 muscarinic receptors.

Mode of Use - Posology

Clozapine is available for oral administration as tablets. The tablets should be taken whole with a glass of water. The drug can be taken before, during or after meals.

The clozapine dosage must be decided by the physician on an individual basis, depending on the pathology to be treated and the response to therapy by the patient.

In elderly patients a reduction in the dose of medication usually administered may be necessary.

Schizophrenia

For the treatment of schizophrenia, the usual starting dose used is 12.5 mg of drug, to be taken once or twice a day. The dose can be increased up to 25-100 mg of drug per day.

In any case, the maximum daily dose of 900 mg should never be exceeded.

Psychotic disorders during Parkinson's disease

The starting dose of clozapine usually administered is 12.5 mg of drug, to be administered once a day, in the evening. The dose can be gradually increased to 25-37.5 mg of drug per day.

The daily dose of 50-100 mg of clozapine should never be exceeded.

Pregnancy and breastfeeding

It is not advisable to take the drug during pregnancy, especially in the last trimester, as the newborn could have serious adverse effects. These effects are tremors, muscle stiffness and / or weakness, drowsiness, agitation, respiratory problems and feeding difficulties.

Because clozapine may be excreted in breast milk, breastfeeding mothers should not take the medicine.

Contraindications

The use of clozapine is contraindicated in the following cases:

• Known hypersensitivity to clozapine;
• In patients who suffer - or have suffered - from bone marrow disorders;
• In patients taking drugs that cause myelosuppression;
• In patients with uncontrolled epilepsy;
• In patients who suffer - or who have suffered - from cardiac and / or renal diseases;
• In patients suffering from severe liver disorders;
• In patients with paralytic ileus;
• In patients undergoing therapies based on injections of long-acting antipsychotics (depot antipsychotics);
• Pregnant;
• During breastfeeding.