thioridazine
Mellaril-S

thioridazine hydrochloride
Apo-Thioridazine ◆, Mellaril

Available forms
Available by prescription only
Oral concentrate: 30 mg/ml, 100 mg/ml (3% to 4.2% alcohol)
Suspension: 25 mg/5 ml, 100 mg/5 ml
Tablets: 10 mg, 15 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg

Indications and dosages
 Management of symptoms of psychotic disorders in patients intolerant of other antipsychotics. Adults: Initially, 50 to 100 mg P.O. t.i.d., with gradual increments up to 800 mg daily in divided doses, if needed. Dosage varies.
 Dysthymic disorder (neurotic depression), dementia in elderly patients, behavioral problems in children. Adults: Initially, 25 mg P.O. t.i.d. Maintenance dosage is 20 to 200 mg daily.
Children older than age 2: Usually, 0.5 to 3 mg/kg P.O. daily in divided doses. Give 10 mg b.i.d. or t.i.d. to children with moderate disorders and 25 mg b.i.d. or t.i.d. to hospitalized children.

Pharmacodynamics
Antipsychotic action: Thioridazine is thought to exert antipsychotic effects by postsynaptic blockade of CNS dopamine receptors, inhibiting dopamine-mediated effects.
Thioridazine has many other central and peripheral effects: It produces both alpha and ganglionic blockade and counteracts histamine- and serotonin-mediated activity. Its most common adverse reactions are antimuscarinic and sedative; it causes fewer extrapyramidal effects than other antipsychotics.

Pharmacokinetics
Absorption: Absorption varies with administration route. Oral tablet absorption is erratic and variable, with onset ranging from 1/2 to 1 hour. Oral concentrates and suspensions are much more predictable.
Distribution: Distributed widely throughout the body, including breast milk. Steady state serum level is achieved within 4 to 7 days. Drug is 91% to 99% protein-bound.
Metabolism: Metabolized extensively by the liver and forms the active metabolite mesoridazine.
Excretion: Mostly excreted as metabolites in urine; some is excreted in feces by way of the biliary tract.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug and in those experiencing coma, CNS depression, or severe hypertensive or hypotensive cardiac disease. Contraindicated with fluvoxamine, propranolol, pindolol, fluoxetine, and any drug that inhibits the cytochrome P-450 2D6 enzyme and agents known to prolong the QTc interval. Also contraindicated in patients with reduced levels of cytochrome P-450 2D6 isoenzyme, patients with congenital long QT syndrome, and patients with a history of cardiac arrhythmias.
  Use cautiously in elderly or debilitated patients and in those with hepatic or CV disease, respiratory or seizure disorders, hypocalcemia, severe reactions to insulin or electroconvulsive therapy, and exposure to extreme cold or heat or to organophosphate insecticides.

Interactions
Drug-drug. Aluminum- and magnesium-containing antacids and antidiarrheals, phenobarbital: Decreases therapeutic effect. Avoid use together.
Analgesics, anesthetics (epidural, general, spinal), antiarrhythmics, anticholinergics (including atropine, disopyramide, quinidine), antidepressants, antihistamines, barbiturates, CNS depressants, MAO inhibitors, meperidine, narcotics, parenteral magnesium, phenothiazines, tranquilizers: Causes additive effect. Avoid use together.
Antiparkinsonians: Causes oversedation, paralytic ileus, visual changes, and severe constipation. Monitor patient closely.
Bromocriptine: Antagonizes therapeutic effect on prolactin secretion. Monitor patient closely. Dosage adjustment may be needed.
Centrally acting antihypertensive drugs, clonidine, guanabenz, guanadrel, guanethidine, methyldopa, reserpine: Inhibits blood pressure response. Monitor patient; dosage adjustment may be needed.
Dopamine (high dose): Decreases vasoconstricting effects. Monitor patient closely; dosage may need adjustment.
Drugs that inhibit P-450 2D6 (fluoxetine, paroxetine): Increases thioridazine levels, increasing cardiotoxicity and life-threatening arrhythmias. Use together is contraindicated.
Drugs that prolong the QT interval: Increases risk of cardiotoxicity and life-threatening arrhythmias. Use together is contraindicated.
Levodopa: Decreases effectiveness and increases toxicity. Monitor patient carefully.
Lithium: May cause severe neurologic toxicity with an encephalitis-like syndrome. Avoid use together.
Metrizamide: Increases risk of seizures. Avoid use together.
Nitrates: Causes hypotension. Monitor patient closely.
Phenytoin: Increases toxicity. Avoid use together.
Procainamide: Increases risk of arrhythmias and conduction defects. Avoid use together.
Propranolol: Increases thioridazine plasma levels and toxicity. Avoid use together if possible. Monitor patient closely if drugs must be given together.
Propylthiouracil: Increases risk of agranulocytosis. Monitor patient closely.
Sympathomimetics, such as appetite suppressants, ephedrine (commonly found in nasal sprays), epinephrine, phenylephrine: Decreases stimulatory and pressor effects. Monitor patient closely.
Drug-herb. Kava: May increase risk or severity of dystonic reactions. Discourage use together.
Yohimbe: Phenothiazines may increase the risk of toxicity. Discourage use together.
Drug-food. Caffeine: Increased metabolism of drug. Discourage use together.
Drug-lifestyle. Alcohol use: Increased CNS depression. Discourage alcohol use.
Heavy smoking: Increases metabolism of drug. Discourage smoking.
Sun exposure: May cause photosensitivity reactions. Advise patient to take precautions.

Adverse reactions
CNS: neuroleptic malignant syndrome, extrapyramidal reactions, tardive dyskinesia, sedation, EEG changes, dizziness.
CV: orthostatic hypotension, tachycardia, ECG changes, arrhythmias, torsades de pointes.
EENT: ocular changes, blurred vision, retinitis pigmentosa.
GI: dry mouth, constipation.
GU: urine retention, dark urine, menstrual irregularities, inhibited ejaculation.
Hematologic: transient leukopenia, agranulocytosis, hyperprolactinemia.
Hepatic: cholestatic jaundice.
Metabolic: weight gain, increased appetite.
Skin: mild photosensitivity, allergic reactions.
Other: gynecomastia.

Effects on lab test results
• May increase liver enzyme levels.
• May decrease granulocyte and WBC counts.

Overdose and treatment
CNS depression is characterized by deep, unarousable sleep and possible coma, hypotension or hypertension, extrapyramidal symptoms, abnormal involuntary muscle movements, agitation, seizures, arrhythmias, ECG changes, hypothermia or hyperthermia, and autonomic nervous system dysfunction.
 Patients who have overdosed should receive immediate CV monitoring, including continuous ECG to detect arrhythmias. Drugs that may produce additive QT prolongation effects, such as disopyramide, procainamide, and quinidine, should also be avoided.
 Don’t induce vomiting: Drug inhibits cough reflex, and aspiration may occur. Use gastric lavage, then activated charcoal and sodium chloride cathartics; dialysis doesn’t help. Regulate body temperature, as needed. Treat hypotension with I.V. fluids: Don’t give epinephrine. Treat seizures with parenteral diazepam or barbiturates; arrhythmias with parenteral phenytoin (1 mg/kg with rate adjusted to blood pressure); and extrapyramidal reactions with benztropine at 1 to 2 mg or parenteral diphenhydramine at 10 to 50 mg. Contact poison information center for specific instructions.

Special considerations
• Before starting treatment, perform baseline ECG and measure serum potassium. Patients with a QTc interval above 450 msec should not receive Mellaril. Patients with a QTc over 500 msec should discontinue use.
 ALERT Serious dose-related cardiac events have been reported, including torsades de pointes and sudden death.
• Different liquid forms have different concentrations. Check dosage carefully.
• Doses of more than 300 mg daily are usually reserved for adults with severe psychosis. Don’t exceed 800 mg daily because ophthalmic toxicity may result.
• Thioridazine is linked to a high risk of sedation, anticholinergic effects, orthostatic hypotension, photosensitivity reactions, and delayed or absent ejaculation. It has the lowest potential for extrapyramidal reactions of all phenothiazines.
• Liquid forms may cause a rash if skin contact occurs.
• Protect all liquid formulations from light.
• Concentrate must be diluted in 2 to 4 oz (60 to 120 ml) of liquid, preferably water, carbonated drinks, fruit juice, tomato juice, milk, or pudding.
• Oral forms may cause stomach upset. Administer with food or fluid.
• Check patient regularly (at least every 6 months) for abnormal body movements.
• Drug can cause pink to brown discoloration of urine.
• Mellaril prolongs the QTc interval in a dose-related manner.
• Thioridazine causes false-positive test results for urinary porphyrins, urobilinogen, amylase, and 5-hydroxyindoleacetic acid because of darkening of urine by metabolites. It also causes false-positive urine pregnancy results in tests using human chorionic gonadotropin as the indicator.
Breast-feeding patients
• Thioridazine may appear in breast milk. Potential benefits to the woman should outweigh potential harm to the infant.
Pediatric patients
• Drug isn’t recommended for children younger than age 2.
Geriatric patients
• These patients tend to need lower doses, adjusted to individual response. Such patients also are more likely to develop adverse reactions, especially tardive dyskinesia and other extrapyramidal effects.

Patient education
• Explain risks of dystonic reactions and tardive dyskinesia, and tell patient to report abnormal body movements.
• Tell patient to avoid sun exposure and to wear sunscreen when going outdoors to prevent photosensitivity reactions. (Heat lamps and tanning beds also may cause burning of the skin or skin discoloration.)
• Warn patient not to spill the liquid on the skin; rash and irritation may result.
• Warn patient to avoid extremely hot or cold baths or exposure to temperature extremes, sunlamps, or tanning beds; drug may cause thermoregulatory changes.
• Advise patient to take drug exactly as prescribed and not to double missed doses.
• Explain that many drug interactions are possible. Patient should seek medical approval before taking any self-prescribed medication.
• Tell patient not to stop taking drug suddenly; most adverse reactions may be relieved by dose reduction. However, patient should report difficulty urinating, sore throat, dizziness, fainting, or visual changes.
• Patient may experience gastritis, nausea, vomiting, dizziness, tremor, feeling of warmth or cold, diaphoresis, tachycardia, headache, or insomnia after abrupt withdrawal of long-term therapy.
• Warn patient to avoid hazardous activities that require alertness until the effect of drug is established. Reassure patient that excessive sedation usually subsides after several weeks.
• Tell patient not to drink alcohol or take other medications that may cause excessive sedation.
• Advise patient to maintain adequate hydration.
• Explain which fluids are appropriate for diluting the concentrate and the dropper technique of measuring dose.
• Tell patient to store drug safely away from children.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use