Chlorpromazine Hydrochloride – LARGACTIL®

• LARGACTIL^®

• 1st generation Antipsychotics, Phenothiazines
• Tranquillizer

• Tablet: 10 mg, 25 mg, 100 mg
• Syrup (100ml): 25mg/5ml:
• Ampoules (2ml): 25mg/ml

1. Acute functional psychosis (e.g. schizophrenia, mania or psychotic depression).
2. Long-term treatment of schizophrenia.
3. Short-term treatment of:
   1. Agitation and behavioral disturbance in patients with delirium or dementia.
   2. Agitation and severe depression.
4. Severe behavioral disturbances, as can be found in some children with mental retardation or autism (including self-injurious, aggressive behavior or over activity.)
5. In management of terminal illness:
   1. To enhance the effect of analgesics.
   2. To control nausea and vomiting.
6. Control of intractable hiccough.

• Antagonize dopamine D2 receptors in brain;
• Depresses release of hypothalamic and hypophyseal hormones;
• Depress reticular activating system;
• Inhibits prolactin-release-inhibitory factor and stimulating the release of prolactin.

• Absorption:
  • Absorption route: gastrointestinal tract
  • Bioavailability: extensive first pass metabolism in the gut and the liver
  • Onset of action: 30-60 min
  • Duration of action: 4-6 hours, extended release: 10-12 hours
  • Peak plasma level:
    • following oral administration: 1-4 hours
    • Following intramuscular injection: 15 – 30 minutes.
• Distribution:
  • Widely distributed to the body tissue.
  • It crosses the blood-brain barrier and achieves higher concentrations in the brain than in the plasma.
  • Protein-bound: 90 – 99%
• Metabolism:
  • Metabolize pathway: by hepatic P450 enzyme CYP2D6
  • extensive first pass metabolism after oral administration
  • Chlorpromazine is almost completely metabolized.
• Elimination:
  • Half-life: 30 hours
  • Excretion: Significantly in the urine, in small amounts in faeces and in lesser amounts in sweat and hair.

• Adults:
  • Oral:
    • initial dose for ambulant patients: 25 mg three times daily
    • Max dose: 600mg-800mg per day.
    • maintenance doses: 25 to 100 mg three times daily
    • Crushing the tablets is not recommended, therefore Syrup should be replaced.
  • Parenteral:
    • deep intramuscular injection or intravenous infusion (after dilution with normal saline)
    • Blood pressure and vital signs should be taken before and monitored closely after injections.
    • Usual single dose: 25 to 50 mg by deep intramuscular injection (if necessary; repeat three to four times in 24 hours.)
    • Intramuscular injection part: upper outer quadrant of the buttock or upper portion of the deltoid muscle.
• Children:
  • Over 5 years of age: one third to one half of adult dosage is given
  • Younger than 5 years old: oral dose is calculated on the basis of 0.5 mg/kg bodyweight.
    • 5 mg at 1 year
    • 5 mg at 3 years
    • 10 mg at 6 years.
  • Doses may be repeated three or four times a day.
  • Children need to be monitored for hypothermia and hypotension.
• Hepatic or Renal Impairment:
  • The dosage in these patients may need to be reduced
• Elderly or Debilitated:
  • The dosage in these patients may need to be reduced

1. Interactions resulting in decreased chlorpromazine levels:
   • Food,
   • Alcohol
   • Benztropine
   • Antacids
   • Lithium
   • Chronic administration of barbiturates
2. Interactions resulting in increased chlorpromazine levels:
   • Tricyclic antidepressants
   • CYP1A2 inhibitors: ciprofloxacin, fluvoxamine, oral contraceptives, thiabendazole, vemurafenib
3. Interactions in which other drugs are affected by chlorpromazine:
   • Central nervous system depressants, benzodiazepines, anesthetic drugs, opioids, barbiturates, lithium, valproic acid, phenytoin, propranolol, adrenaline, guanethidine, clonidine, antidiabetic agents, levodopa, amphetamines, oral anticoagulants, Thiazide diuretics, quinidine, MAOIs, suxamethonium, organophosphorus insecticides, atropine, desferrioxamine.
4. Interaction with drugs that:
   • increase risk of QT prolongation:
     • Class Ia antiarrhythmic agents: quinidine and disopyramide.
     • Class III antiarrhythmic agents: amiodarone and sotalol.
     • Other medications: bepridil, cisapride, sultopride, thioridazine, methadone, intravenous erythromycin, intravenous vincamine, halofantrine, pentamidine, sparfloxacin.
   • Induce bradycardia:
     • Calcium channel blockers (diltiazem, verapamil), beta-blockers, clonidine, guanfacine, and digitalis.
   • Cause hypokalemia:
     • Diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactides.

More Common Adverse Effects

• Cardiovascular: Postural hypotension, ECG Changes.
• Dermatological: Contact dermatitis, photosensitivity, urticarial, maculopapular, petechial or edematous reactions.
• Endocrine: Elevated prolactin levels, impaired thermoregulation, hyperglycemia, other hypothalamic effects.
• Gastrointestinal: Dry mouth, constipation.
• Immunological: Raised ANA titer, positive SLE cells.
• Genitourinary: Urinary retention.
• Hematological: Leucopenia, agranulocytosis, eosinophilia, hemolytic anemia, aplastic anemia, thrombocytopenic purpura and pancytopenia have been reported.
• Nervous System:
  • Autonomic: dry mouth, mental confusion, postural hypotension, nasal congestion, nausea, obstipation, constipation, adynamic ileus, urinary retention, priapism, miosis and mydriasis, atonic colon, ejaculatory disorders/impotence.
  • Central: extrapyramidal reactions (Parkinsonism, akathisia) tardive dyskinesia, non-extrapyramidal effects including lowering of seizure threshold and paradoxical effects, e.g. agitation, excitement and aggravation of schizophrenic symptoms; drowsiness, dystonia, motor restlessness.
• Ocular: Blurred vision, photophobia, miosis, mydriasis, corneal deposits.
• Respiratory: Stuffy nose, respiratory depression.
• Local Reactions (injection): Pain at injection site, injection abscess.
• General: Weight gain.

 Less Common Adverse Effects

• Cardiovascular: Arrhythmias, hypertensive crisis (following abrupt withdrawal), A-V block, ventricular tachycardia, QT interval prolongation and fibrillation, sudden death
• Dermatological: Skin pigmentation and purpura, exfoliative dermatitis and toxic epidermal necrolysis.
• Endocrine: Hyperthermia, hypothermia, lactation and moderate breast engorgement in females on large doses, false-positive pregnancy tests, amenorrhea, gynecomastia, hypoglycemia, glycosuria.
• Gastrointestinal: Paralytic ileus.
• General: systemic lupus erythematosus, Allergic reactions
• Genitourinary: Inappropriate ADH secretion, water retention, edema, incontinence.
• Hematological: Coagulation defects.
• Hepatic: Cholestatic jaundice and liver injury.
• Musculoskeletal: Neuroleptic malignant syndrome, myasthenia gravis.
• Nervous System: Fits, cerebral edema, nightmares, abnormality of cerebrospinal fluid proteins.
• Ocular: Precipitation/aggravation of narrow angle glaucoma, optic atrophy, pigmentary retinopathy, lens opacities.
• Psychiatric: Dysphoria, catatonic excitement.

 Serious or Life Threatening Reactions

• Hypothermia or hyperthermia
• Cardiac arrhythmia
• Agranulocytosis
• Progressive hepatic fibrosis
• Malignant hyperpyrexia
• Sudden Death
• Tardive Dyskinesia
• Neuroleptic Malignant Syndrome

 Other adverse effects

• Metabolism and nutrition disorders: Hyper-triglyceridaemia, hyponatremia, Glucose intolerance and hyperglycemia
• Gastrointestinal disorders: Colitis ischemic, gastrointestinal necrosis, necrotizing colitis, intestinal perforation.
• Skin and subcutaneous tissue disorders: Angioedema, urticaria.

1. Circulatory collapse
2. CNS depression (e.g. coma or drug intoxication.)
3. Previous history of a hypersensitivity reaction
4. Bone marrow depression
5. Pheochromocytoma
6. Hepatic failure or active hepatic disease.
7. LARGACTIL Syrup contains sodium metabisulfite, sodium sulfite and sodium benzoate and LARGACTIL Injection contains sodium metabisulfite and sodium sulfite and may cause allergic-type reactions including anaphylactic symptoms and asthmatic episodes in susceptible people.

• Pregnancy: Category C
• Lactation: not recommended for nursing mothers

1. Should not be used in: Epilepsy, Parkinson’s disease, hypoparathyroidism, myasthenia gravis and prostatic hypertrophy.
2. Antiemetic Effects: The antiemetic effects of chlorpromazine may mask signs of over-dose of toxic drugs or diagnosis of intestinal obstruction and brain tumor.
3. Temperature Regulation: Phenothiazine depress the mechanism for regulation of temperature >>> Severe hypothermia may occur during swimming in cold water or in patients receiving antipyretic therapy, and heat stroke may occur in hot weather.
4. Prolonged Usage: Long term usage could cause the development of tardive dyskinesia.
5. Alertness: Chlorpromazine impair mental and physical abilities (especially during the first few days of therapy.) >>> caution patients about activities requiring alertness.
6. Agranulocytosis:
   1. Agranulocytosis has been reported at an incidence of between 1:1,300 and 1:500,000. Most reported cases have occurred between the fourth and tenth week of treatment.
   2. Warn patients to report the sudden appearance of sore throat, fever or other signs of infection. If white blood cell and differential counts indicate cellular depression, stop treatment and start antibiotic and other suitable therapy, subject to the expert guidance of a hematologist.
7. Liver Dysfunction:
   1. Because of extensive hepatic metabolism chlorpromazine >>> caution should be taken in treating patients with hepatic impairment >>> Dose reduction is necessary.
   2. If bilirubinemia, bilirubinuria or icterus occur >>> discontinued treatment
8. Retinopathy: Periodic eye examinations should be performed during prolonged therapy.
9. Respiratory Disease: Chlorpromazine might suppress cough reflex >>> aspiration of vomitus is possible >>> Chlorpromazine should be used with caution in patients with chronic respiratory disorders.
10. Reye’s syndrome:
    1. Chlorpromazine should be avoided in children and adolescents with signs and symptoms of Reye’s syndrome.
    2. The extrapyramidal symptoms which can occur secondary to chlorpromazine may be confused with the central nervous system signs of Reye’s syndrome or other encephalopathy.
11. Renal disease: Chlorpromazine should be given cautiously to patients with renal disease.
12. Glaucoma and Neuroleptic Malignant Syndrome: Should be used with caution in patients with glaucoma and features of neuroleptic malignant syndrome include autonomic dysfunction.
13. Photosensitivity: Patients should be warned about photosensitivity in sunny weather.
14. Hypotension: Extreme caution in cardiovascular disease, hemochromocytoma, conditions with a sudden drop in blood pressure, usage in conjunction with other drugs which cause postural hypotension.
15. QT Intervals: Phenothiazines potentiate QT interval prolongation >>> increases the risk of the torsade de pointes.
16. Cerebrovascular Events: There is an increased risk of cerebrovascular events in elderly patients with dementia.
17. Venous Thromboembolism: chlorpromazine should be used with caution in patients with risk factors for thromboembolism
18. Use in the Elderly: Elderly are more susceptible to the adverse effects >>> starting dose should be about half the usual adult dose and dosage increments should be gradual and reviewed regularly.
19. Elderly Patients with Dementia: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
20. Hyperglycemia: Hyperglycemia or glucose intolerance might happen >>> Diabetic patients or patients with risk factors of diabetes should get glycemic monitoring during treatment.
21. Effects on Fertility: Chlorpromazine may cause hyperprolactinemia >>> associated with impaired fertility in women.
22. Effect on Laboratory Tests: Phenothiazines might produce false positive phenylketonuria (PKU) test results.
23. Over-dose:
    1. Symptoms: CNS depression, drowsiness, coma, areflexia, restlessness, confusion, excitement, hypotension, tachycardia, hypothermia, pupillary constriction, tremor, muscle twitching, spasm or rigidity, convulsions, muscular hypotonia, difficulty in swallowing and breathing, cyanosis and respiratory and/or vasomotor collapse, sudden apnea, Polyuria has also been noted which may result in dehydration
    2. Treatment: Symptomatic and supportive treatment should be administered.