Thioridazine

Pronunciation

(thye oh RID a zeen)

U.S. Brand Names

Mellaril® [DSC]; Thioridazine Intensol™

Synonyms

Thioridazine Hydrochloride

Generic Available

Yes

Canadian Brand Names

Apo-Thioridazine®; Mellaril®

Use

Management of schizophrenic patients who fail to respond adequately to treatment with other antipsychotic drugs, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those medications

Use - Unlabeled/Investigational

Psychosis

Pregnancy Risk Factor

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to thioridazine or any component of the formulation (cross-reactivity between phenothiazines may occur); severe CNS depression; circulatory collapse; severe hypotension; bone marrow suppression; blood dyscrasias; coma; in combination with other drugs that are known to prolong the QTc interval; in patients with congenital long QT syndrome or a history of cardiac arrhythmias; concurrent use with medications that inhibit the metabolism of thioridazine (fluoxetine, paroxetine, fluvoxamine, propranolol, pindolol); patients known to have genetic defect leading to reduced levels of activity of CYP2D6

Warnings/Precautions

Thioridazine has dose-related effects on ventricular repolarization leading to QTc prolongation, a potentially life-threatening effect. Therefore, it should be reserved for patients with schizophrenia who have failed to respond to adequate levels of other antipsychotic drugs. May cause orthostatic hypotension - use with caution in patients at risk of this effect or those who would tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, or other medications which may predispose).

Highly sedating, use with caution in disorders where CNS depression is a feature. Use with caution in Parkinson's disease. Caution in patients with hemodynamic instability; bone marrow suppression; predisposition to seizures; subcortical brain damage; severe cardiac, hepatic, renal, or respiratory disease. Esophageal dysmotility and aspiration have been associated with antipsychotic use - use with caution in patients at risk of pneumonia (ie, Alzheimer's disease). Caution in breast cancer or other prolactin-dependent tumors (may elevate prolactin levels). May alter temperature regulation or mask toxicity of other drugs due to antiemetic effects.

Phenothiazines may cause anticholinergic effects (confusion, agitation, constipation, xerostomia, blurred vision, urinary retention); therefore, they should be used with caution in patients with decreased gastrointestinal motility, urinary retention, BPH, xerostomia, or visual problems. Conditions which also may be exacerbated by cholinergic blockade include narrow-angle glaucoma (screening is recommended) and worsening of myasthenia gravis. Relative to other neuroleptics, thioridazine has a high potency of cholinergic blockade.

May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is low relative to other neuroleptics). May be associated with neuroleptic malignant syndrome (NMS). Doses exceeding recommended doses may cause pigmentary retinopathy.

Adverse Reactions

Cardiovascular: Hypotension, orthostatic hypotension, peripheral edema, ECG changes

Central nervous system: EPS (pseudoparkinsonism, akathisia, dystonias, tardive dyskinesia), dizziness, drowsiness, neuroleptic malignant syndrome (NMS), impairment of temperature regulation, lowering of seizure threshold, seizure

Dermatologic: Increased sensitivity to sun, rash, discoloration of skin (blue-gray)

Endocrine & metabolic: Changes in menstrual cycle, libido (changes in), breast pain, galactorrhea, amenorrhea

Gastrointestinal: Constipation, weight gain, nausea, vomiting, stomach pain, xerostomia, diarrhea

Genitourinary: Difficulty in urination, ejaculatory disturbances, urinary retention, priapism

Hematologic: Agranulocytosis, leukopenia

Hepatic: Cholestatic jaundice, hepatotoxicity

Neuromuscular & skeletal: Tremor

Ocular: Pigmentary retinopathy, blurred vision, cornea and lens changes

Respiratory: Nasal congestion

Overdosage/Toxicology

Symptoms of overdose include deep sleep, coma, extrapyramidal symptoms, abnormal involuntary muscle movements, hypotension, and arrhythmias.

Immediate cardiac monitoring, including continuous electrocardiographic monitoring, to detect arrhythmias. Avoid use of medications that also prolong the QTc interval, such as disopyramide, procainamide, and quinidine. Following initiation of essential overdose management, toxic symptom treatment and supportive treatment should be initiated. Hypotension usually responds to I.V. fluids or Trendelenburg positioning. If unresponsive to these measures, the use of a parenteral inotrope may be required (eg, norepinephrine 0.1-0.2 mcg/kg/minute titrated to response); do not use epinephrine or dopamine. Seizures commonly respond to diazepam (I.V. 5-10 mg bolus in adults every 15 minutes if needed up to a total of 30 mg; I.V. 0.25-0.4 mg/kg/dose up to a total of 10 mg in children) or to phenytoin. Avoid barbiturates (may potentiate respiratory depression). Neuroleptics often cause extrapyramidal symptoms (eg, dystonic reactions) requiring management with diphenhydramine 1-2 mg/kg (adults) up to a maximum of 50 mg I.M. or I.V. slow push followed by a maintenance dose for 48-72 hours. When these reactions are unresponsive to diphenhydramine, benztropine mesylate I.V. 1-2 mg (adults) may be effective. These agents are generally effective within 2-5 minutes.

Drug Interactions

Substrate of CYP2C19 (minor), 2D6 (major); Inhibits CYP1A2 (weak), 2C8/9 (weak), 2D6 (moderate), 2E1 (weak)

Aluminum salts: May decrease the absorption of phenothiazines; monitor

Amphetamines: Efficacy may be diminished by antipsychotics; in addition, amphetamines may increase psychotic symptoms; avoid concurrent use

Anticholinergics: May inhibit the therapeutic response to phenothiazines and excess anticholinergic effects may occur; includes benztropine, trihexyphenidyl, biperiden, and drugs with significant anticholinergic activity (TCAs, antihistamines, disopyramide)

Antihypertensives: Concurrent use of phenothiazines with an antihypertensive may produce additive hypotensive effects (particularly orthostasis)

Beta-blockers: May increase the risk of arrhythmia; propranolol and pindolol are contraindicated

Bromocriptine: Phenothiazines inhibit the ability of bromocriptine to lower serum prolactin concentrations

Carvedilol: Serum concentrations may be increased, leading to hypotension and bradycardia; avoid concurrent use

CNS depressants: Sedative effects may be additive with phenothiazines; monitor for increased effect; includes barbiturates, benzodiazepines, narcotic analgesics, ethanol, and other sedative agents

CYP2D6 inhibitors: May increase the levels/effects of thioridazine. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole. Thioridazine is contraindicated with inhibitors of this enzyme.

CYP2D6 substrates: Thioridazine may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, tricyclic antidepressants, and venlafaxine.

CYP2D6 prodrug substrates: Thioridazine may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.

Epinephrine: Chlorpromazine (and possibly other low potency antipsychotics) may diminish the pressor effects of epinephrine

Guanethidine and guanadrel: Antihypertensive effects may be inhibited by phenothiazines

Levodopa: Phenothiazines may inhibit the antiparkinsonian effect of levodopa; avoid this combination

Lithium: Phenothiazines may produce neurotoxicity with lithium; this is a rare effect

Metoclopramide: May increase extrapyramidal symptoms (EPS) or risk.

Phenytoin: May reduce serum levels of phenothiazines; phenothiazines may increase phenytoin serum levels

Polypeptide antibiotics: Rare cases of respiratory paralysis have been reported with concurrent use of phenothiazines

Potassium-depleting agents: May increase the risk of serious arrhythmias with thioridazine; includes many diuretics, aminoglycosides, and amphotericin; monitor serum potassium closely

Propranolol: Serum concentrations of phenothiazines may be increased; propranolol also increases phenothiazine concentrations; may also occur with pindolol. These agents are contraindicated with thioridazine.

QTc-prolonging agents: Effects on QTc interval may be additive with phenothiazines, increasing the risk of malignant arrhythmias; includes type Ia antiarrhythmics, TCAs, and some quinolone antibiotics (sparfloxacin, moxifloxacin and gatifloxacin). These agents are contraindicated with thioridazine.

Sulfadoxine-pyrimethamine: May increase phenothiazine concentrations

Trazodone: Phenothiazines and trazodone may produce additive hypotensive effects

Tricyclic antidepressants: Concurrent use may produce increased toxicity or altered therapeutic response

Valproic acid: Serum levels may be increased by phenothiazines

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Herb/Nutraceutical: Avoid kava kava, valerian, St John's wort, gotu kola (may increase CNS depression). Avoid dong quai, St John's wort (may also cause photosensitization).

Stability

Protect all dosage forms from light

Mechanism of Action

Thioridazine is a piperidine phenothiazine which blocks postsynaptic mesolimbic dopaminergic receptors in the brain; exhibits a strong alpha-adrenergic blocking effect and depresses the release of hypothalamic and hypophyseal hormones

Pharmacodynamics/Kinetics

Duration: 4-5 days

Half-life elimination: 21-25 hours

Time to peak, serum: ~1 hour

Dosage

Oral:

Children >2-12 years: Range: 0.5-3 mg/kg/day in 2-3 divided doses; usual: 1 mg/kg/day; maximum: 3 mg/kg/day

Behavior problems: Initial: 10 mg 2-3 times/day, increase gradually

Severe psychoses: Initial: 25 mg 2-3 times/day, increase gradually

Children >12 years and Adults:

Schizophrenia/psychoses: Initial: 50-100 mg 3 times/day with gradual increments as needed and tolerated; maximum: 800 mg/day in 2-4 divided doses

Depressive disorders/dementia: Initial: 25 mg 3 times/day; maintenance dose: 20-200 mg/day

Elderly: Behavioral symptoms associated with dementia: Oral: Initial: 10-25 mg 1-2 times/day; increase at 4- to 7-day intervals by 10-25 mg/day; increase dose intervals (once daily, twice daily, etc) as necessary to control response or side effects. Maximum daily dose: 400 mg; gradual increases (titration) may prevent some side effects or decrease their severity.

Hemodialysis: Not dialyzable (0% to 5%)

Administration

Oral concentrate must be diluted in 2-4 oz of liquid (eg, water, fruit juice, carbonated drinks, milk, or pudding) before administration. Do not take antacid within 2 hours of taking drug. Thioridazine concentrate is not compatible with carbamazepine suspension; schedule dosing at least 1-2 hours apart from each other. Note: Avoid skin contact with oral suspension or solution; may cause contact dermatitis.

Monitoring Parameters

Baseline and periodic ECG; vital signs; serum potassium, lipid profile, fasting blood glucose/Hgb A1c; BMI; mental status, abnormal involuntary movement scale (AIMS); periodic eye exam; do not initiate if QTc >450 msec

Reference Range

Toxic: >1 mg/mL; lethal: 2-8 mg/dL

Test Interactions

False-positives for phenylketonuria, urinary amylase, uroporphyrins, urobilinogen

Patient Education

Use exactly as directed; do not increase dose or frequency. Do not discontinue without consulting prescriber. Tablets/capsules may be taken with food. Mix oral solution with 2-4 oz of liquid (eg, juice, milk, water, pudding). Do not take within 2 hours of any antacid. Store away from light. Avoid alcohol or caffeine and other prescription or OTC medications not approved by prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. Avoid skin contact with liquid medication; may cause contact dermatitis (wash immediately with warm, soapy water). May turn urine red-brown (normal). You may experience excess drowsiness, lightheadedness, dizziness, or blurred vision (use caution driving or when engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, or dry mouth (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruit, or fiber may help); postural hypotension (use caution climbing stairs or when changing position from lying or sitting to standing); urinary retention (void before taking medication); ejaculatory dysfunction (reversible); decreased perspiration (avoid strenuous exercise in hot environments); or photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight). Report persistent CNS effects (eg, trembling fingers, altered gait or balance, excessive sedation, seizures, unusual movements, anxiety, abnormal thoughts, confusion, personality changes); chest pain, palpitations, rapid heartbeat, severe dizziness; unresolved urinary retention or changes in urinary pattern; altered menstrual pattern, change in libido, swelling or pain in breasts (male or female); vision changes; skin rash, irritation, or changes in color of skin (gray-blue); or worsening of condition. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Nursing Implications

Avoid skin contact with oral suspension or solution; may cause contact dermatitis

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia and changes in salivation (normal salivary flow resumes upon discontinuation). Significant hypotension may occur, especially when the drug is administered parenterally; orthostatic hypotension is due to alpha-receptor blockade, the elderly are at greater risk for orthostatic hypotension.

Tardive dyskinesia; Prevalence rate may be 40% in elderly; development of the syndrome and the irreversible nature are proportional to duration and total cumulative dose over time. Extrapyramidal reactions are more common in elderly with up to 50% developing these reactions after 60 years of age. Drug-induced Parkinson's syndrome occurs often; akathisia is the most common extrapyramidal reaction in elderly.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

Most pharmacology textbooks state that in presence of phenothiazines, systemic doses of epinephrine paradoxically decrease the blood pressure. This is the so called "epinephrine reversal" phenomenon. This has never been observed when epinephrine is given by infiltration as part of the anesthesia procedure.

Dosage Forms

Solution, oral concentrate, as hydrochloride (Thioridazine Intensol™): 30 mg/mL (120 mL); 100 mg/mL (120 mL) [contains alcohol <0.5%; fruit-mint flavor]

Tablet, as hydrochloride: 10 mg, 15 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg

References

Aman MG, Marks RE, Turbott SH, et al, "Clinical Effects of Methylphenidate and Thioridazine in Intellectually Subaverage Children," J Am Acad Child Adolesc Psychiatry , 1991, 30(2):246-56.

Appell RA, Shield DE, and McGuire EJ, "Thioridazine-Induced Priapism," Br J Urol , 1977, 49(2):160.

Baker PB, Merigian KS, Roberts JR, et al, "Hyperthermia, Hypertension, Hypertonia, and Coma in Massive Thioridazine Overdose," Am J Emerg Med , 1988, 6(4):346-9.

Buckley NA, Whyte IM, and Dawson AH, "Cardiotoxicity More Common in Thioridazine Overdose Than With Other Neuroleptics," J Toxicol Clin Toxicol , 1995, 33(3):199-204.

Burgess KR, Jefferis RW, and Stevenson IF, "Fatal Thioridazine Cardiotoxicity," Med J Aust , 1979, 2(4):177-8.

Cowen TD and Meythaler JM, "Hypotensive Effects of Thioridazine in an Elderly Patient With Traumatic Brain Injury," Brain Inj , 1994, 8(8):735-7.

Goss JB, "Concomitant Use of Thioridazine With Risperidone," Am J Health Syst Pharm , 1995, 52(9):1012.

Oshika T, "Ocular Adverse Effects of Neuropsychiatric Agents. Incidence and Management," Drug Saf , 1995, 12(4):256-63.

Peabody CA, Warner MD, Whiteford HA, et al, "Neuroleptics and the Elderly," J Am Geriatr Soc , 1987, 35(3):233-8.

Risse SC and Barnes R, "Pharmacologic Treatment of Agitation Associated With Dementia," J Am Geriatr Soc , 1986, 34(5):368-76.

Saltz BL, Woerner MG, Kane JM, et al, "Prospective Study of Tardive Dyskinesia Incidence in the Elderly," JAMA , 1991, 266(17):2402-6.

Seifert RD, "Therapeutic Drug Monitoring: Psychotropic Drugs," J Pharm Pract , 1984, 6:403-16.

Weisdorf D, Kramer J, Goldbarg A, et al, "Physostigmine for Cardiac and Neurologic Manifestations of Phenothiazine Poisoning," Clin Pharmacol Ther , 1978, 24(6):663-7.

International Brand Names

Aldazine® (AU, NZ); Apo-Thioridazine® (CA, SG); Calmaril® (TH); Dazine-P® (TH); Mallorol® (SE); Meleril® (AR, CL, CO, ES); Mellaril® (CA); Melleretten® (CH, DE, NL); Mellerettes® (TR); Melleril® (AT, AU, BD, BE, BR, CH, DE, DK, FI, FR, GB, HK, HR, HU, ID, IE, IT, LK, LU, MT, MX, NL, NO, NZ, PT, RU, SI, TR, YU, ZA); Melzine® (IE); Nervosan® (CL); Orsanil® (FI); Ridazine® (TH); Ridazin® (IL); Rideril® (GB); Simultan® (CL); Thiodazine® (RU); Thiomed® (TH); Thioridazin® (BG, CZ, PL); Thioridazine® (CY, GB); Thioridazin Neuraxpharm® (DE); Thioridazin prolongatum® (PL); Thioril® (IN, RU); Thiosia® (TH); Thiozine® (IE); Tinsenol® (CL); Tioridazina® (CL); Tioridazina L.CH.® (CL); Tioridazin® (RO); Trixifen® (YU)

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