Thioridazine

Name: Thioridazine

Side effects

In the recommended dosage ranges with thioridazine hydrochloride most side effects are mild and transient.

Central Nervous System: Drowsiness may be encountered on occasion, especially where large doses are given early in treatment. Generally, this effect tends to subside with continued therapy or a reduction in dosage. Pseudoparkinsonism and other extrapyramidal symptoms may occur but are infrequent. Nocturnal confusion, hyperactivity, lethargy, psychotic reactions, restlessness, and headache have been reported but are extremely rare.

Autonomic Nervous System: Dryness of mouth, blurred vision, constipation, nausea, vomiting, diarrhea, nasal stuffiness, and pallor have been seen.

Endocrine System: Galactorrhea, breast engorgement, amenorrhea, inhibition of ejaculation, and peripheral edema have been described.

Skin:Dermatitis and skin eruptions of the urticarial type have been observed infrequently. Photosensitivity is extremely rare.

Cardiovascular System: Thioridazine produces a dose related prolongation of the QTc interval, which is associated with the ability to cause torsade de pointes-type arrhythmias, a potentially fatal polymorphic ventricular tachycardia, and sudden death (see WARNINGS). Both torsade de pointes-type arrhythmias and sudden death have been reported in association with thioridazine. A causal relationship between these events and thioridazine therapy has not been established but, given the ability of thioridazine to prolong the QTc interval, such a relationship is possible. Other ECG changes have been reported (see Phenothiazine Derivatives: Cardiovascular Effects).

Other: Rare cases described as parotid swelling have been reported following administration of thioridazine.

Post Introduction Reports: These are voluntary reports of adverse events temporally associated with thioridazine that were received since marketing, and there may be no causal relationship between thioridazine use and these events: priapism.

Phenothiazine Derivatives: It should be noted that efficacy, indications, and untoward effects have varied with the different phenothiazines. It has been reported that old age lowers the tolerance for phenothiazines. The most common neurological side effects in these patients are parkinsonism and akathisia. There appears to be an increased risk of agranulocytosis and leukopenia in the geriatric population. The physician should be aware that the following have occurred with one or more phenothiazines and should be considered whenever one of these drugs is used:

Autonomic Reactions:Miosis, obstipation, anorexia, paralytic ileus.

Cutaneous Reactions: Erythema, exfoliative dermatitis, contact dermatitis.

Blood Dyscrasias: Agranulocytosis, leukopenia, eosinophilia, thrombocytopenia, anemia, aplastic anemia, pancytopenia.

Allergic Reactions: Fever, laryngeal edema, angioneurotic edema, asthma.

Hepatotoxicity: Jaundice, biliary stasis.

Cardiovascular Effects: Changes in the terminal portion of the electrocardiogram to include prolongation of the QT interval, depression and inversion of the T wave, and the appearance of a wave tentatively identified as a bifid T wave or a U wave have been observed in patients receiving phenothiazines, including thioridazine. To date, these appear to be due to altered repolarization, not related to myocardial damage, and reversible. Nonetheless, significant prolongation of the QT interval has been associated with serious ventricular arrhythmias and sudden death (see WARNINGS). Hypotension, rarely resulting in cardiac arrest, has been reported.

Extrapyramidal Symptoms: Akathisia, agitation, motor restlessness, dystonic reactions, trismus, torticollis, opisthotonus, oculogyric crises, tremor, muscular rigidity, akinesia.

Tardive Dyskinesia:Chronic use of antipsychotics may be associated with the development of tardive dyskinesia. The salient features of this syndrome are described in the WARNINGS section and subsequently.

The syndrome is characterized by involuntary choreoathetoid movements which variously involve the tongue, face, mouth, lips, or jaw (e.g., protrusion of the tongue, puffing of cheeks, puckering of the mouth, chewing movements), trunk, and extremities. The severity of the syndrome and the degree of impairment produced vary widely.

The syndrome may become clinically recognizable either during treatment, upon dosage reduction, or upon withdrawal of treatment. Movements may decrease in intensity and may disappear altogether if further treatment with antipsychotics is withheld. It is generally believed that reversibility is more likely after short rather than long-term antipsychotic exposure. Consequently, early detection of tardive dyskinesia is important. To increase the likelihood of detecting the syndrome at the earliest possible time, the dosage of antipsychotic drug should be reduced periodically (if clinically possible) and the patient observed for signs of the disorder. This maneuver is critical, for antipsychotic drugs may mask the signs of the syndrome.

Neuroleptic Malignant Syndrome (NMS): Chronic use of antipsychotics may be associated with the development of Neuroleptic Malignant Syndrome. The salient features of this syndrome are described in the WARNINGS section and subsequently. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).

Endocrine Disturbances:Menstrual irregularities, altered libido, gynecomastia, lactation, weight gain, edema. False positive pregnancy tests have been reported.

Urinary Disturbances: Retention, incontinence.

Others: Hyperpyrexia. Behavioral effects suggestive of a paradoxical reaction have been reported. These include excitement, bizarre dreams, aggravation of psychoses, and toxic confusional states. More recently, a peculiar skin-eye syndrome has been recognized as a side effect following long-term treatment with phenothiazines. This reaction is marked by progressive pigmentation of areas of the skin or conjunctiva and/or accompanied by discoloration of the exposed sclera and cornea. Opacities of the anterior lens and cornea described as irregular or stellate in shape have also been reported. Systemic lupus erythematosus-like syndrome.

Overdose

Many of the symptoms observed are extensions of the side effects described under ADVERSE REACTIONS. Thioridazine can be toxic in overdose, with cardiac toxicity being of particular concern. Frequent ECG and vital sign monitoring of overdosed patients is recommended. Observation for several days may be required because of the risk of delayed effects.

Signs and Symptoms

Effects and clinical complications of acute overdose involving phenothiazines may include:

Cardiovascular: Cardiac arrhythmias, hypotension, shock, ECG changes, increased QT and PR intervals, non-specific ST and T wave changes, bradycardia, sinus tachycardia, atrioventricular block, ventricular tachycardia, ventricular fibrillation, Torsade de pointes, myocardial depression.

Central Nervous System: Sedation, extrapyramidal effects, confusion, agitation, hypothermia, hyperthermia, restlessness, seizures, areflexia, coma.

Autonomic Nervous System: Mydriasis, miosis, dry skin, dry mouth, nasal congestion, urinary retention, blurred vision.

Respiratory: Respiratory depression, apnea, pulmonary edema.

Gastrointestinal: Hypomotility, constipation, ileus.

Renal: Oliguria, uremia.

Toxic dose and blood concentration ranges for the phenothiazines have not been firmly established. It has been suggested that the toxic blood concentration range for thioridazine begins at 1 mg/dL, and 2 to 8 mg/dL is the lethal concentration range.

Treatment

An airway must be established and maintained. Adequate oxygenation and ventilation must be ensured.

Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Treatment may include one or more of the following therapeutic interventions: correction of electrolyte abnormalities and acid-base balance, lidocaine, phenytoin, isoproterenol, ventricular pacing, and defibrillation. Disopyramide, procainamide, and quinidine may produce additive QT-prolonging effects when administered to patients with acute overdosage of thioridazine and should be avoided (see WARNINGS and CONTRAINDICATIONS). Caution must be exercised when administering lidocaine, as it may increase the risk of developing seizures.

Treatment of hypotension may require intravenous fluids and vasopressors. Phenylephrine, levarterenol, or metaraminol are the appropriate pressor agents for use in the management of refractory hypotension. The potent a adrenergic blocking properties of the phenothiazines makes the use of vasopressors with mixed α and β adrenergic agonist properties inappropriate, including epinephrine and dopamine. Paradoxical vasodilation may result. In addition, it is reasonable to expect that the α adrenergic-blocking properties of bretylium might be additive to those of thioridazine, resulting in problematic hypotension.

In managing overdosage, the physician should always consider the possibility of multiple drug involvement. Gastric lavage and repeated doses of activated charcoal should be considered. Induction of emesis is less preferable to gastric lavage because of the risk of dystonia and the potential for aspiration of vomitus. Emesis should not be induced in patients expected to deteriorate rapidly, or those with impaired consciousness.

Acute extrapyramidal symptoms may be treated with diphenhydramine hydrochloride or benztropine mesylate.

Avoid the use of barbiturates when treating seizures, as they may potentiate phenothiazine-induced respiratory depression.

Forced diuresis, hemoperfusion, hemodialysis and manipulation of urine pH are of unlikely benefit in the treatment of phenothiazine overdose due to their large volume of distribution and extensive plasma protein binding.

Up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center.

Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians' Desk Reference®.

What should i avoid while taking thioridazine (mellaril)?

Thioridazine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Drinking alcohol can increase certain side effects of thioridazine.

Avoid exposure to sunlight or tanning beds. Thioridazine can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Thioridazine Genetic Information

CYP2D6 is a protein in your body that is involved in the elimination of thioridazine and other drugs from your body. Some patients have less of this protein in their bodies, affecting how much of the drug gets eliminated. Levels of CYP2D6 can vary greatly between individuals, and those having less of this protein are known as "poor metabolizers." 

CYP2D6 testing is done to determine whether you are a poor metabolizer. If you are a poor metabolizer, the levels of thioridazine in your blood can become too high. As a result you may be at an increased risk of having more side effects from thioridazine. 

Your doctor may adjust your dose of thioridazine if you are a poor metabolizer.

Thioridazine Brand Names

Thioridazine may be found in some form under the following brand names:

  • Mellaril

  • Mellaril-S

Thioridazine Interactions

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

  • Medications that block a protein in the body (CYP2D6) such as quinidine (Qualaquin), fluoxetine (Prozac, Sarafem), amitriptyline (Elavil, Amitril), and paroxetine (Paxil)
  • Drugs that can cause an arrhythmia called Torsades des Pointes such as
    • certain anti-arrhythmia medications including procainamide, sotalol (Betapace), quinidine, dofetilide (Tikosyn), amiodarone (Nexterone, Pacerone, Cordarone), ibutilide (Corvert)
    • certain fluoroquinolone antibiotics including levofloxacin (Levaquin), ciprofloxacin (Cipro), gatifloxacin (Zymar), moxifloxacin (Avelox)
    • certain macrolide antibiotics including clarithromycin (Biaxin), erythromycin (EES, others)
    • certain azole antifungals including ketoconazole (Nizoral), itraconazole (Sporanox, Onmel)
    • certain antidepressants including amitriptyline, desipramine (Norpramin), imipramine (Tofranil), doxepin (Silenor), fluoxetine (Prozac, Sarafem), sertraline (Zoloft), venlafaxine (Effexor XR)
    • certain antipsychotics including haloperidol (Haldol), droperidol (Inapsine), quetiapine (Seroquel XR), thioridazine, ziprasidone (Geodon)
    • and other medications including sumatriptan (Treximet, Imitrex, Alsuma, Zecuity), zolmitriptan (Zomig), dolasetron (Anzemet), and methadone (Methadone, Dolophine)
  • Fluvoxamine (Luvox)
  • Propranolol (Hemangeol, Inderal, InnoPran XL)
  • Pindolol

This is not a complete list of drug interactions. Ask your doctor or pharmacist for more information.

How should I take thioridazine?

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

While using thioridazine, you may need frequent blood tests. Your heart function may need to be checked using an electrocardiograph or ECG (sometimes called an EKG).

If you need surgery, tell the surgeon ahead of time that you are using thioridazine.

Store at room temperature away from moisture, heat, and light.

Thioridazine side effects

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using thioridazine and call your doctor at once if you have:

  • uncontrolled muscle movements in your face (chewing, lip smacking, frowning, tongue movement, blinking or eye movement);

  • tremor (uncontrolled shaking), drooling, trouble swallowing, problems with balance or walking;

  • headache with chest pain and severe dizziness, fainting, fast or pounding heartbeats;

  • confusion, slurred speech;

  • seizure (convulsions);

  • sudden weakness or ill feeling, fever, chills, sore throat, swollen gums, painful mouth sores, pain when swallowing, skin sores, cold or flu symptoms, cough;

  • little or no urinating;

  • decreased night vision, tunnel vision, watery eyes, increased sensitivity to light; or

  • severe nervous system reaction--very stiff (rigid) muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, feeling like you might pass out.

Common side effects may include:

  • drowsiness;

  • dry mouth, blurred vision;

  • nausea, vomiting, constipation, diarrhea;

  • breast swelling or discharge;

  • changes in your menstrual periods; or

  • swelling in your hands or feet.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

PRINCIPAL DISPLAY PANEL - 25 mg Bottle Label

Thioridazine HCl Tablets USP

Pharmacologic Category

  • First Generation (Typical) Antipsychotic
  • Phenothiazine Derivative

Pharmacology

Thioridazine is a piperidine phenothiazine which blocks postsynaptic mesolimbic dopaminergic receptors in the brain; also has activity at serotonin, noradrenaline, and histamine receptors (Fenton, 2007).

Absorption

Rapid (Vanderdeeren 1977)

Distribution

Vd: 1.8 to 6.7 L/kg (Vanderdeeren 1977)

Metabolism

Hepatic metabolism by sulphoxidation (primarily), demethylation (2%), and hydroxylation (limited); active metabolites mesoridazine and sulphoridazine (Vanderdeeren 1977).

Time to Peak

Serum: ~1 to 4 hours (Martensson 1973)

Half-Life Elimination

5 to 27 hours (Martensson 1973; Muusze 1977; Vanderdeeren 1977)

Protein Binding

96% to 99.3% (Cooper, 1978)

Use Labeled Indications

Schizophrenia: 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 because of intolerable adverse effects from those medications. Before initiating treatment with thioridazine, it is strongly recommended that a patient be given at least 2 trials, each with a different antipsychotic drug product, at an adequate dose and for an adequate duration.

ALERT U.S. Boxed Warning

Proarrhythmic effects:

Thioridazine has been shown to prolong the QTc interval in a dose-related manner. Drugs with this potential, including thioridazine, have been associated with torsades de pointes–type arrhythmias and sudden death. Because of its potential for significant, possibly life-threatening, proarrhythmic effects, reserve thioridazine use for the treatment of schizophrenic patients who fail to show an acceptable response to adequate courses of treatment with other antipsychotic drugs, either because of insufficient effectiveness or the inability to achieve an effective dose because of intolerable adverse effects from those drugs.

Increased mortality in elderly patients with dementia-related psychosis:

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 and 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was approximately 4.5% compared with a rate of approximately 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Thioridazine is not approved for the treatment of patients with dementia-related psychosis.

What are some other side effects of this drug?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Hard stools (constipation).
  • Loose stools (diarrhea).
  • Dry mouth.
  • Feeling sleepy.
  • Stuffy nose.
  • Upset stomach or throwing up.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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