Pimozide – Pr PIMOZIDE®

Brand name

  • Pr PIMOZIDE

Drug Class

  • Antipsychotic, 1st generation

Preparations

  • Pimozide Tablets USP 2 mg and 4 mg

Indications

  • Management of the manifestations of chronic schizophrenia in which the main manifestations do not include excitement, agitation or hyperactivity.

Pharmacology

  • Mechanism of Action:
    • The basic mechanism of action is related to its action on central aminergic receptors.
    • It has a selective ability to block central dopaminergic receptors, although it affects noradrenaline turnover at higher doses.

Metabolism

  • Pharmacokinetics
    • Absorption: More than 50%
    • Peak serum level: 6-8 hours
    • Metabolism:
      • Undergo significant first-pass metabolism.
      • Pimozide is extensively metabolized in the liver.
    • Mean elimination half-life: 55 hours.
    • Excretion: kidney

Dosing

  • Adults:
    • Usual Starting Dose: 2 to 4 mg once daily, with weekly increments of 2 to 4 mg until a satisfactory level of therapeutic effect is attained or excessive adverse effects occur.
    • Maintenance Therapy: 6 mg daily
    • Max dose: 20 mg
  • Missed Dose:
    • Patient should take the dose as soon as possible and continue with their regular schedule.
    • If it is almost time for the next dose: patient should skip the missed dose and continue with the next scheduled dose.

Drug Interactions

  1. Drugs acting on CNS:
    1. Anesthetics, opiates, alcohol, atropine, organophosphorous, amphetamines.
  2. Levodopa
  3. Anti-hypertensives
  4. Drugs That Inhibit Cytochrome P450:
    1. aprepitant, azole antimycotics, antiviral protease inhibitors, macrolide antibiotics, nefazodone.
  5. Drugs That Prolong QT Interval:
    1. Class IA antiarrhythmics (quinidine, procainamide, disopyramide)
    2. Class III antiarrhythmics (amiodarone, sotalol, ibutilide)
    3. Class 1C antiarrhythmics (flecainide, propafenone)
    4. antipsychotics (chlorpromazine, pimozide, haloperidol, droperidol)
    5. antidepressants (fluoxetine, venlafaxine, tricyclic/tetracyclic antidepressants)
    6. opioids (methadone)
    7. macrolide antibiotics and analogues (erythromycin, clarithromycin, telithromycin)
    8. quinolone antibiotics (moxifloxacin, gatifloxacin)
    9. pentamidine
    10. antimalarials (quinine)
    11. azole antifungals (fluconazole, itraconazole, ketoconazole, voriconazole)
    12. domperidone
    13. 5-HT3 antagonists (dolasetron, ondansetron)
    14. tacrolimus
    15. beta-2 adrenoceptor agonists (salmeterol, formoterol)
    16. Lithium
  6. Drugs causing electrolyte alteration:
    1. Diuretics (particular those causing hypokalemia.)
    2. Laxatives and enemas
    3. Amphotericin B
    4. High dose corticosteroids
  7. SSRI (Selective Serotonin Reuptake Inhibitor) Antidepressants:
    1. sertraline
    2. citalopram
    3. paroxetine
  8. Drug-Food Interactions
    1. Grapefruit Juice
  9. Drug-Herb Interactions
    1. Betel Nut

Adverse Effects

  • Blood and Lymphatic System Disorders:
    • Blood dyscrasias (agranulocytosis, anemia, aplastic anemia, eosinophilia, granulocytopenia, leukopenia, neutropenia, pancytopenia, and thrombocytopenic purpura), bone marrow failure, disseminated intravascular coagulation, leukocytosis, lymphadenopathy, polycythaemia, and thrombocytopenia.
  • Cardiac Disorders:
    • angina pectoris, arrhythmia, coronary atherosclerosis, atrioventricular block, cardiac arrest, cardiac failure, cardiac valve disease, cardio-respiratory arrest, cardiomegaly, coronary artery disease, myocardial infarction, myocardial ischemia, myocarditis, stress cardiomyopathy, torsade de pointes, ventricular tachycardia, ventricular fibrillation.
  • Congenital, Familial and Genetic Disorders:
    • Congenital anomaly, congenital hydronephrosis, double ureter, dysmorphism, macrocephaly, microphthalmos, skull malformation, Tourette’s disorder, urinary tract malformation, ventricular septal defect.
  • Endocrine Disorder:
    • Increased blood prolactin, hyperglycemia (in patients with pre-existing diabetes), hyperprolactinemia, hyperthyroidism, inappropriate antidiuretic hormone secretion.
  • Eye Disorder:
    • Accommodation disorder, glaucoma, oculogyration, blurred vision, visual impairment.
  • Gastrointestinal Disorders:
    • Constipation, diarrhea, dry mouth, hemorrhagic enterocolitis, fecal incontinence, intestinal ischemia, pancreatitis, salivary hypersecretion, sub ileus, vomiting.
  • General Disorder and Administration Site Conditions:
    • Asthenia, death, drug interaction, face edema, fatigue, hyperthermia, hypothermia, macrosomia, malaise, pyrexia.
  • Hepatobiliary Disorders:
    • Abnormal hepatic function, hepatitis, hepatomegaly, liver injury.
  • Immune System Disorders:
    • Antiphospholipid syndrome.
  • Infections and Infestations:
    • Bacterial infection, bacterial toxemia, bronchitis, bronchopneumonia, pneumonia, pustular rash.
  • Injury, Poisoning and Procedural Complications:
    • Accidental exposure, contusion, drug dispensing error, drug toxicity, fall, femoral neck fracture, overdose, wound.
  • Investigations:
    • increased blood creatinine phosphokinase, increased blood phosphorus, decreased blood pressure, increased blood pressure, breath sounds, circulating coagulant, increased drug level, abnormal electrocardiogram (repolarization, ST segment depression, T wave inversion, T wave peaked), prolonged electrocardiogram QT interval, abnormal electroencephalogram, decreased hematocrit, decreased hemoglobin, increased hepatic enzyme, decreased red blood cell count, increased red cell distribution width, increased respiratory rate, increased transaminases, increased weight, decreased white blood cell count, increased white blood cell count.
  • Metabolism and Nutrition Disorders:
    • Decreased appetite, diabetes mellitus (type I and type II), dyslipidemia, reduced fluid intake, hyper-phagia, hypoglycemia, hypokalemia, hyponatremia, ketoacidosis.
  • Musculoskeletal and Connective Tissue Disorders:
    • Arthralgia, muscle rigidity, myalgia, nuchal rigidity, rhabdomyolysis, soft tissue hemorrhage, systemic lupus erythematosus.
  • Benign, Malignant and Unspecified Neoplasms (Including Cysts and Polyps):
    • Endometrial cancer, myelodysplastic syndrome.
  • Nervous System Disorders:
    • akathisia, altered state of consciousness, bradykinesia, cognitive disorder, cogwheel rigidity, coma, convulsion, dementia, disturbance in attention, dizziness, drooling, dyskinesia, dystonia, epilepsy, extrapyramidal disorder, grand mal convulsion, hemorrhagic cerebral infarction, headache, hypoesthesia, hypo-kinesia, hypoxic-ischemic encephalopathy, loss of consciousness (syncope), lethargy, masked facies, mental retardation, neuroleptic malignant syndrome, parkinsonism, somnolence, stupor, tardive dyskinesia, tremor, unresponsive to stimuli.
  • Pregnancy, Puerperium and Prenatal Conditions:
    • Missed abortion, spontaneous abortion.
  • Psychiatric Disorder:
    • abnormal behavior, aggression, agitation, apathy, confusional state, decreased activity, delusion, depression, disorientation, drug dependence, euphoric mood, hallucination, insomnia, decreased libido, mutism, psychomotor retardation, restlessness, schizophrenia, self-injurious behavior, sleep disorder, suicide, suicide attempt, withdrawal syndrome.
  • Renal and Urinary Disorders:
    • Anuria, glycosuria, hematuria, nephrotic syndrome, renal failure, urinary incontinence, urinary retention.
  • Reproductive System and Breast Disorder:
    • Amenorrhea, breast cysts, erectile dysfunction, galactorrhea, gynecomastia.
  • Respiratory, Thoracic and Mediastinal Disorders:
    • Asphyxia, bradypnea, dyspnea, hypoxia, lung disorder, oropharyngeal spasm, pulmonary congestion, pulmonary embolism, pulmonary edema, pulmonary thrombosis, respiratory arrest.
  • Skin and Subcutaneous Tissue Disorders:
    • Angioedema, hyperhidrosis, photosensitivity reaction, pruritus, rash (exfoliative, erythematous, and popular), skin exfoliation, skin toxicity, toxic skin eruption, urticarial.
  • Vascular Disorders:
    • Arteriosclerosis, circulatory collapse, deep vein thrombosis, venous embolism, hematoma, hypertension (orthostatic), phlebitis, shock, thrombosis.

Contraindications

  1. Hypersensitive to drug
  2. Central nervous system depression
  3. Brain damage
  4. Comatose states
  5. Liver disorders
  6. Renal insufficiency
  7. Pheochromocytoma
  8. Blood dyscrasias
  9. Depressive disorders
  10. Parkinson’s syndrome
  11. congenital long QT syndrome or a family history of this syndrome
  12. cardiac arrhythmias or Torsade de Pointes
  13. Combination with CYP 3A4 and CYP 2D6 inhibiting drugs:
    1. Azole anti-mycotics, antiviral protease inhibitors, macrolide antibiotics and nefazodone, quinidine.
  14. The treatment of simple tics or tics other than those associated with Tourette’s Disorder.
  15. Combination with serotonin reuptake inhibitors:
    1. sertraline, paroxetine, citalopram and escitalopram
  16. A scheduled regional or spinal anesthesia.

Pregnancy and Breastfeeding

  • Pregnancy: Category C
  • Lactation: Not recommended in nursing mothers

Precautions

  1. Body Temperature Regulation:
    1. Disruption of the body’s ability to reduce core body temperature >>> Hyperpyrexia might happen
  2. Caution about Cardiovascular side effects:
    1. QT prolongation
    2. ventricular arrhythmias (Ventricular tachycardia, ventricular fibrillation)
    3. Sudden death and cardiac arrest (very rare)
    4. Potential for Hypotension
    5. Torsade de Pointes, Risk factors:
      1. female
      2. age 65 years or older
      3. baseline prolongation of the QT/QTc interval
      4. presence of genetic variants affecting cardiac ion channels or
      5. regulatory proteins, especially congenital long QT syndromes
      6. family history of QT prolongation, or sudden cardiac death at <50 years
      7. cardiac disease (e.g., myocardial ischemia or infarction, congestive heart failure, left ventricular hypertrophy, cardiomyopathy, conduction system disease)
      8. history of arrhythmias (especially ventricular arrhythmias, atrial fibrillation, or recent conversion from atrial fibrillation)
      9. electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia)
      10. bradycardia (<50 beats per minute)
      11. acute neurological events (e.g., intracranial or subarachnoid hemorrhage, stroke, intracranial trauma)
      12. nutritional deficits (e.g., eating disorders, extreme diets)
      13. diabetes mellitus,
      14. autonomic neuropathy
      15. hepatic dysfunction, renal dysfunction, and/or phenotypic/genotypic poor metabolizers of drug metabolizing enzyme isoforms
    6. ECG should be performed prior to initiation of treatment with pimozide, as well as periodically during treatment.
  1. Endocrine and Metabolism
    1. Hyperprolactinemia (cause galactorrhea, gynecomastia, oligo-menorrhea or amenorrhea, and erectile dysfunction.)
    2. Caution in patients with a previously detected breast cancer.
    3. Long-standing hyperprolactinemia causes hypogonadism >>> leads to decreased bone mineral density.
    4. Hyperglycemia:
      1. Diabetic ketoacidosis (DKA) might occur
      2. Patients should have baseline and periodic monitoring of blood glucose and body weight.
  2. Gastrointestinal:
    1. Pimozide has a substantial antiemetic effect >>> caution in cases where the suppression of nausea and vomiting might hinder the diagnosis of an underlying physical disorder.
  3. Genitourinary;
    1. Caution patient about priapism.
  4. Hematologic:
    1. Neutropenia, leukopenia, granulocytopenia, agranulocytosis and anemia might occur >>> complete blood count (CBC) tested should be done prior to starting pimozide.
  5. Patient should be cautioned about Venous thromboembolism (VTE)
  6. Hepatic/Biliary/Pancreatic:
    1. Caution is advised in patients with liver disease because pimozide is metabolized in the liver.
  7. Neurologic
    1. Increased Psychomotor Activity:
      1. Should not be used in the management of chronic schizophrenia with main symptoms of agitation, excitement and anxiety.
    2. Neuroleptic Malignant Syndrome:
      1. Hyperthermia (early sign), generalized muscle rigidity, autonomic instability, and altered consciousness.
    3. Tardive Dyskinesia
    4. Withdrawal Emergent Neurological Signs:
      1. Gradual withdrawal of antipsychotic drugs is recommended
    5. Schizophrenia:
      1. Response to antipsychotic drug treatment may be delayed >>> Gradual withdrawal is advisable.
    6. Extrapyramidal Symptoms
    7. Seizures:
      1. pimozide might lower the convulsive threshold >>> should be used with caution in epileptic patients
    8. Effects on Driving Ability and Use of Machinery:
      1. Patients should be warned of the risks of sedation and advised not to drive or operate machinery during treatment
  8. Pediatrics (<18 years of age):
    1. Not recommended for use in the pediatric age group.
  9. Geriatrics (≥65 years of age):
    1. Caution should be exercised with the use of pimozide in the elderly
    1. Use in Geriatric Patients with Dementia:
      1. Pimozide is not indicated in elderly patients with dementia.
  10. Over dosage:
    1. Symptoms:
      1. Exaggeration of known pharmacologic effects and adverse reactions, extrapyramidal symptoms, cardiac arrhythmias.
    2. Treatment:
      1. No specific antidote for pimozide
      2. Treatment is mainly supportive.

Warning

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

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