Clozapine

Products

Clozapine is commercially available in tablet form (Leponex, generic). It has been approved in many countries since 1972. It is also known as Clozaril in some countries. Clozapine was developed at Wander and Sandoz.

Structure and properties

Clozapine (C18H19ClN4, Mr = 326.8 g/mol) exists as a yellow crystalline powder that is practically insoluble in water. It is a tricyclic and chlorinated dibenzodiazepine and piperazine derivative related to olanzapine (Zyprexa, generics).

Effects

Clozapine (ATC N05AH02) has sedative and antipsychotic properties. The effects are due to interaction with various neurotransmitter systems. Clozapine is an antagonist at dopamine D2 receptors, at alpha-adrenoceptors, muscarinic receptors (anticholinergic), at histamine receptors (antihistamine), and at serotonin receptors (5-HT2A, antiserotoninergic). The half-life is in the range of 12 hours.

Indications

  • Therapy-resistant schizophrenia (lack of responsiveness, intolerance of classical neuroleptics).
  • Longer-term reduction of repeated suicidal behavior in schizophrenia and schizoaffective disorder.
  • Psychosis in the course of Parkinson’s disease.

Dosage

According to the professional information. The dose is adjusted individually. Tablets are taken once or twice daily, independent of meals. Discontinuation must be gradual. Dangerous agranulocytosis occasionally occurs as an adverse effect. Therefore, the prescribing physician must regularly check the blood count. The prescriptions must be marked “BBK sic” (“Blood count check was performed”). If the note is missing, it must be clarified with the attending physician at the pharmacy whether the control takes place.

Contraindications

  • Hypersensitivity
  • No regular blood tests
  • Granulocytopenia or agranulocytosis in the patient history.
  • Impaired bone marrow function
  • Uncontrolled epilepsy
  • Alcoholic psychosis, intoxication psychosis, drug intoxication, comatose states.
  • Circulatory collapse and/or CNS depression.
  • Severe renal or cardiac disease, myocarditis.
  • Acute liver disease, progressive liver disease, liver failure.
  • Paralytic ileus
  • Combination with drugs that may cause agranulocytosis

For complete precautions, see the drug label.

Interactions

Clozapine is a substrate of several CYP450 isozymes. These include, in particular, CYP1A2 and CYP3A4, as well as CYP2C19 and 2D6. Corresponding interactions may occur. For example, the CYP1A2 inhibitor fluvoxamine may increase levels and adverse effects. Myelosuppressive drugs should not be combined with clozapine. Clozapine may increase the adverse effects of centrally depressant drugs. Other drugs that prolong the QT interval should be given with caution. Other interactions may occur.

Adverse Effects

The most common possible adverse effects include drowsiness, dullness, dizziness, weight gain, sometimes severe, constipation, excessive salivation, and rapid heart rate (tachycardia). Clozapine can prolong the QT interval and cause other serious side effects such as heart disease and seizures. The drug may occasionally cause potentially life-threatening agranulocytosis. Deaths have been reported in the past. Therefore, the appropriate precautions in the SmPC must be carefully followed.