Mellaril^® (thioridazine HCl) is 2-methylmercapto-10-[2-(N-methyl-2-piperidyl) ethyl] phenothiazine.

10 mg, 15 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg Tablets

Active Ingredient: thioridazine HCl, USP

Inactive Ingredients: acacia, calcium sulfate dihydrate, carnauba wax, D&C Yellow #10, FD&C Blue #1, FD&C Yellow #6, gelatin, lactose, methylparaben, povidone, propylparaben, sodium benzoate, starch, stearic acid, sucrose, synthetic black iron oxide, talc, titanium dioxide, and other ingredients.

Inactive Ingredients: acacia, calcium sulfate dihydrate, carnauba wax, D&C Red #7, gelatin, lactose, methylparaben, povidone, propylparaben, starch, stearic acid, sucrose, synthetic black iron oxide, talc, titanium dioxide, and other ingredients.

Inactive Ingredients: acacia, calcium sulfate dihydrate, carnauba wax, gelatin, lactose, methylparaben, povidone, propylparaben, sodium benzoate, starch, stearic acid, sucrose, synthetic black iron oxide, synthetic iron oxide, talc, titanium dioxide, and other ingredients.

Inactive Ingredients: acacia, calcium sulfate dihydrate, carnauba wax, gelatin, lactose, sodium benzoate, starch, stearic acid, sucrose, synthetic black iron oxide, talc, titanium dioxide, and other ingredients.

Inactive Ingredients: acacia, calcium sulfate dihydrate, carnauba wax, D&C Yellow #10, FD&C Blue #1, FD&C Blue #2, FD&C Yellow #6, lactose, methylparaben, povidone, propylparaben, sodium benzoate, sorbitol, starch, stearic acid, sucrose, synthetic black iron oxide, talc, titanium dioxide, and other ingredients.

Inactive Ingredients: acacia, calcium sulfate dihydrate, carnauba wax, D&C Yellow #10, FD&C Green #3, FD&C Yellow #6, lactose, methylparaben, povidone, propylparaben, sodium benzoate, starch, stearic acid, sucrose, synthetic black iron oxide, talc, titanium dioxide, and other ingredients.

Inactive Ingredients: acacia, ammonium calcium alginate, calcium sulfate dihydrate, carnauba wax, colloidal silicon dioxide, D&C Red #7, lactose, magnesium stearate, methylparaben, povidone, propylparaben, sodium benzoate, starch, stearic acid, sucrose, synthetic black iron oxide, talc, titanium dioxide, and other ingredients.

Active Ingredient: thioridazine HCl, USP

Inactive Ingredients: alcohol, 3.0%, flavor, methylparaben, propylparaben, purified water, and sorbitol solution. May contain sodium hydroxide or hydrochloric acid to adjust the pH.

Inactive Ingredients: alcohol, 4.2%, flavor, glycerin, methylparaben, propylparaben, purified water, sorbitol solution, and sucrose. May contain sodium hydroxide or hydrochloric acid to adjust pH.

Active Ingredient: each mL contains thioridazine, USP, equivalent to 5 mg and 20 mg thioridazine HCl, USP, respectively.

Inactive Ingredients: carbomer 934, flavor, polysorbate 80, purified water, sodium hydroxide, and sucrose.

Inactive Ingredients: carbomer 934, D&C Yellow #10, FD&C Yellow #6, flavor, polysorbate 80, purified water, sodium hydroxide, and sucrose.

Mellaril^® (thioridazine HCl) is indicated for the management of schizophrenic patients who fail to respond adequately to treatment with other antipsychotic drugs. Due to the risk of significant, potentially life-threatening, proarrhythmic effects with Mellaril treatment, Mellaril should be used only in patients who have failed to respond adequately to treatment with appropriate courses of other antipsychotic drugs, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. Consequently, before initiating treatment with Mellaril, 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 (see WARNINGS and CONTRAINDICATIONS).

However, the prescriber should be aware that Mellaril has not been systematically evaluated in controlled trials in treatment refractory schizophrenic patients and its efficacy in such patients is unknown.

Since Mellaril^® (thioridazine HCl) is associated with a dose-related prolongation of the QTc interval, which is a potentially life-threatening event, its use should be reserved for schizophrenic patients who fail to respond adequately to treatment with other antipsychotic drugs. Dosage must be individualized and the smallest effective dosage should be determined for each patient (see INDICATIONS and WARNINGS).

The usual starting dose for adult schizophrenic patients is 50-100 mg three times a day, with a gradual increment to a maximum of 800 mg daily if necessary. Once effective control of symptoms has been achieved, the dosage may be reduced gradually to determine the minimum maintenance dose. The total daily dosage ranges from 200-800 mg, divided into two to four doses.

For pediatric patients with schizophrenia who are unresponsive to other agents, the recommended initial dose is 0.5 mg/kg/day given in divided doses. Dosage may be increased gradually until optimum therapeutic effect is obtained or the maximum dose of 3 mg/kg/day has been reached.

Mellaril^® (thioridazine HCl) Tablets

Bright chartreuse, coated tablets; "" imprinted on one side, "78-2'' imprinted on the other side, in black.

Bottle of 100 .......................................... NDC 0078-0002-05

Bottle of 1000 ........................................ NDC 0078-0002-09

Unit dose package of 100............ NDC 0078-0002-06

Pink, coated tablets; "" imprinted on one side, "78-8'' imprinted on the other side, in black.

Bottle of 100 .......................................... NDC 0078-0008-05

Light tan, coated tablets; "" imprinted on one side, "MELLARIL 25'' imprinted on the other side, in black.

Bottle of 100 .......................................... NDC 0078-0003-05

Bottle of 1000 ........................................ NDC 0078-0003-09

Unit dose package of 100............ NDC 0078-0003-06

White, coated tablets; "" imprinted on one side, "MELLARIL 50'' imprinted on the other side, in black.

Bottle of 100 .......................................... NDC 0078-0004-05

Bottle of 1000 ........................................ NDC 0078-0004-09

Unit dose package of 100............ NDC 0078-0004-06

Light green, coated tablets; "" imprinted on one side, "MELLARIL 100'' imprinted on the other side, in black.

Bottle of 100 .......................................... NDC 0078-0005-05

Bottle of 1000 ........................................ NDC 0078-0005-09

Unit dose package of 100............ NDC 0078-0005-06

Yellow, coated tablets; "" imprinted on one side, "MELLARIL 150'' imprinted on the other side, in black.

Bottle of 100 .......................................... NDC 0078-0006-05

Pink, coated tablets, "" imprinted on one side, "MELLARIL 200'' imprinted on the other side, in black.

Bottle of 100 .......................................... NDC 0078-0007-05

Unit dose package of 100............ NDC 0078-0007-06

Below 86°F (30°C); tight container.

A clear, straw-yellow liquid with a cherry-like odor. Each mL contains 30 mg thioridazine hydrochloride, USP, alcohol, 3.0% by volume. Immediate container: amber glass bottles of 4 fl. oz. (118 mL) as follows: 4 fl. oz. bottles, in cartons of 12 bottles, with an accompanying dropper graduated to deliver 10 mg, 25 mg, and 50 mg of thioridazine hydrochloride, USP (NDC 0078-0001-31).

A clear, light-yellow liquid with a strawberry-like odor. Each mL contains 100 mg thioridazine hydrochloride, USP, alcohol, 4.2% by volume. Immediate container: amber glass bottles of 4 fl. oz. (118 mL), in cartons of 12 bottles, with an accompanying dropper graduated to deliver 100 mg, 150 mg, and 200 mg of thioridazine hydrochloride, USP (NDC 0078-0009-31).

Below 86°F (30°C); tight, amber glass bottle.

The oral solution (concentrate) may be diluted with distilled water, acidified tap water, or suitable juices. Each dose should be so diluted just prior to administration - preparation and storage of bulk dilutions is not recommended.

An off-white suspension with a buttermint taste and a peppermint odor. Each mL contains thioridazine, USP, equivalent to 5 mg thioridazine hydrochloride, USP. Buttermint-flavored in pint bottles (NDC 0078-0068-33).

A yellow suspension with a buttermint taste and a peppermint odor. Each mL contains thioridazine, USP, equivalent to 20 mg thioridazine hydrochloride, USP. Buttermint-flavored in pint bottles (NDC 0078-0069-33).

Below 77°F (25°C); tight, amber glass bottle.

Additional information available to physicians.

**Trademark of Medical Economics Company, Inc.

T2000-34 REV: JUNE 2000 PRINTED IN USA, 89001902, Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936, © 2000 Novartis

In the recommended dosage ranges with Mellaril^® (thioridazine HCl) 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: Mellaril 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 Mellaril. A causal relationship between these events and Mellaril therapy has not been established but, given the ability of Mellaril 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 Mellaril.

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

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 pheno-thiazines. 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 Mellaril. 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 neuroleptics 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 neuroleptics is withheld. It is generally believed that reversibility is more likely after short rather than long-term neuroleptic 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 neuroleptic drug should be reduced periodically (if clinically possible) and the patient observed for signs of the disorder. This maneuver is critical, for neuroleptic drugs may mask the signs of the syndrome.

Neuroleptic Malignant Syndrome (NMS): Chronic use of neuroleptics 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.

Reduced cytochrome P450 2D6 isozyme activity, drugs which inhibit this isozyme (e.g., fluoxetine and paroxetine), and certain other drugs (e.g., fluvoxamine, propranolol, and pindolol) appear to appreciably inhibit the metabolism of thioridazine. The resulting elevated levels of thioridazine would be expected to augment the prolongation of the QTc interval associated with Mellaril and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes-type arrhythmias. Such an increased risk may result also from the additive effect of co-administering Mellaril with other agents that prolong the QTc interval. Therefore, Mellaril is contraindicated with these drugs as well as in patients, comprising about 7% of the normal population, who are known to have a genetic defect leading to reduced levels of activity of P450 2D6 (see WARNINGS and CONTRAINDICATIONS).

In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher C_max and a 4.5- fold higher AUC for thioridazine in the slow hydroxylators compared to rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of cytochrome P450 2D6 isozyme activity. Thus, this study suggests that drugs that inhibit P450 2D6 or the presence of reduced activity levels of this isozyme will produce elevated plasma levels of thioridazine. Therefore, the co-administration of drugs that inhibit P450 2D6 with Mellaril and the use of Mellaril in patients known to have reduced activity of P450 2D6 are contraindicated.

Fluvoxamine: The effect of fluvoxamine (25 mg b.i.d. for one week) on thioridazine steady state concentration was evaluated in 10 male in-patients with schizophrenia. Concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, increased three-fold following co-administration of fluvoxamine. Fluvoxamine and Mellaril should not be co-administered.

Propranolol: Concurrent administration of propranolol (100-800 mg daily) has been reported to produce increases in plasma levels of thioridazine (approximately 50%-400%) and its metabolites (approximately 80%-300%). Propranolol and Mellaril should not be co-administered.

Pindolol: Concurrent administration of pindolol and thioridazine have resulted in moderate, dose-related increases in the serum levels of thioridazine and two of its metabolites, as well as higher than expected serum pindolol levels. Pindolol and Mellaril should not be co-administered.

There are no studies of the co-administration of Mellaril and other drugs that prolong the QTc interval. However, it is expected that such co-administration would produce additive prolongation of the QTc interval and, thus, such use is contraindicated.

DUE TO THE POTENTIAL FOR SIGNIFICANT, POSSIBLY LIFE-THREATENING, PROARRHYTHMIC EFFECTS WITH MELLARIL^® (THIORIDAZINE HCl) TREATMENT, MELLARIL SHOULD BE RESERVED FOR USE IN 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 DUE TO INTOLERABLE ADVERSE EFFECTS FROM THOSE DRUGS. CONSEQUENTLY, BEFORE INITIATING TREATMENT WITH MELLARIL, IT IS STRONGLY RECOMMENDED THAT A PATIENT BE GIVEN AT LEAST TWO TRIALS, EACH WITH A DIFFERENT ANTIPSYCHOTIC DRUG PRODUCT, AT AN ADEQUATE DOSE, AND FOR AN ADEQUATE DURATION. MELLARIL HAS NOT BEEN SYSTEMATICALLY EVALUATED IN CONTROLLED TRIALS IN THE TREATMENT OF REFRACTORY SCHIZOPHRENIC PATIENTS AND ITS EFFICACY IN SUCH PATIENTS IS UNKNOWN.

A crossover study in nine healthy males comparing single doses of thioridazine 10 mg and 50 mg with placebo demonstrated a dose-related prolongation of the QTc interval. The mean maximum increase in QTc interval following the 50 mg dose was about 23 msec; greater prolongation may be observed in the clinical treatment of unscreened patients.

Prolongation of the QTc interval has been associated with the ability to cause torsade de pointes-type arrhythmias, a potentially fatal polymorphic ventricular tachycardia, and sudden death. There are several published case reports of torsade de pointes and sudden death associated with thioridazine treatment. A causal relationship between these events and Mellaril therapy has not been established but, given the ability of Mellaril to prolong the QTc interval, such a relationship is possible.

Certain circumstances may increase the risk of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including 1) bradycardia, 2) hypokalemia, 3) concomitant use of other drugs that prolong the QTc interval, 4) presence of congenital prolongation of the QT interval, and 5) for thioridazine in particular, its use in patients with reduced activity of P450 2D6 or its co-administration with drugs that may inhibit P450 2D6 or by some other mechanism interfere with the clearance of thioridazine (see CONTRAINDICATIONS and PRECAUTIONS).

It is recommended that patients being considered for Mellaril treatment have a baseline ECG performed and serum potassium levels measured. Serum potassium should be normalized before initiating treatment and patients with a QTc interval greater than 450 msec should not receive Mellaril treatment. It may also be useful to periodically monitor ECG's and serum potassium during Mellaril treatment, especially during a period of dose adjustment. Mellaril should be discontinued in patients who are found to have a QTc interval over 500 msec.

Patients taking Mellaril who experience symptoms that may be associated with the occurrence of torsade de pointes (e.g., dizziness, palpitations, or syncope) may warrant further cardiac evaluation; in particular, Holter monitoring should be considered.

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with neuroleptic (antipsychotic) drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of neuroleptic treatment, which patients are likely to develop the syndrome. Whether neuroleptic drug products differ in their potential to cause tardive dyskinesia is unknown.

Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of neuroleptic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if neuroleptic treatment is withdrawn. Neuroleptic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, neuroleptics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic neuroleptic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to neuroleptic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on neuroleptics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.

(For further information about the description of tardive dyskinesia and its clinical detection, please refer to the sections on Information for Patients and ADVERSE REACTIONS.)

It has been suggested in regard to phenothiazines in general, that people who have demonstrated a hypersensitivity reaction (e.g., blood dyscrasias, jaundice) to one may be more prone to demonstrate a reaction to others. Attention should be paid to the fact that phenothiazines are capable of potentiating central nervous system depressants (e.g., anesthetics, opiates, alcohol, etc.) as well as atropine and phosphorus insecticides. Physicians should carefully consider benefit versus risk when treating less severe disorders.

Reproductive studies in animals and clinical experience to date have failed to show a teratogenic effect with Mellaril. However, in view of the desirability of keeping the administration of all drugs to a minimum during pregnancy, Mellaril should be given only when the benefits derived from treatment exceed the possible risks to mother and fetus.

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. 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).

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

The management of NMS should include, 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

As in the case of other phenothiazines, Mellaril is capable of potentiating central nervous system depressants (e.g., alcohol, anesthetics, barbiturates, narcotics, opiates, other psychoactive drugs, etc.) as well as atropine and phosphorus insecticides. Severe respiratory depression and respiratory arrest have been reported when a patient was given a phenothiazine and a concomitant high dose of a barbiturate.

Leukopenia and/or agranulocytosis and convulsive seizures have been reported but are infrequent. Mellaril^® (thioridazine HCl) has been shown to be helpful in the treatment of behavioral disorders in epileptic patients, but anticonvulsant medication should also be maintained. Pigmentary retinopathy, which has been observed primarily in patients taking larger than recommended doses, is characterized by diminution of visual acuity, brownish coloring of vision, and impairment of night vision; examination of the fundus discloses deposits of pigment. The possibility of this complication may be reduced by remaining within the recommended limits of dosage.

Where patients are participating in activities requiring complete mental alertness (e.g., driving) it is advisable to administer the phenothiazines cautiously and to increase the dosage gradually. Female patients appear to have a greater tendency to orthostatic hypotension than male patients. The administration of epinephrine should be avoided in the treatment of drug-induced hypotension in view of the fact that phenothiazines may induce a reversed epinephrine effect on occasion. Should a vasoconstrictor be required, the most suitable are levarterenol and phenylephrine.

Neuroleptic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of neuroleptic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time.

Information for Patients

Patients should be informed that Mellaril has been associated with potentially fatal heart rhythm disturbances. The risk of such events may be increased when certain drugs are given together with Mellaril. Therefore, patients should inform the prescriber that they are receiving Mellaril treatment before taking any new medication.

Given the likelihood that some patients exposed chronically to neuroleptics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.

See DOSAGE section Pediatric Patients.

Many of the symptoms observed are extensions of the side effects described under ADVERSE REACTIONS. Mellaril^® (thioridazine HCl) 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.

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 1.0 mg/dL, and 2-8 mg/dL is the lethal concentration range.

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 Mellaril 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 a and ß adrenergic agonist properties inappropriate, including epinephrine and dopamine. Paradoxical vasodilation may result. In addition, it is reasonable to expect that the a adrenergic-blocking properties of bretylium might be additive to those of Mellaril, 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^®.

Mellaril^® (thioridazine HCl) use should be avoided in combination with other drugs that are known to prolong the QTc interval and in patients with congenital long QT syndrome or a history of cardiac arrhythmias.

Reduced cytochrome P450 2D6 isozyme activity drugs that inhibit this isozyme (e.g., fluoxetine and paroxetine) and certain other drugs (e.g., fluvoxamine, propranolol, and pindolol) appear to appreciably inhibit the metabolism of thioridazine. The resulting elevated levels of thioridazine would be expected to augment the prolongation of the QTc interval associated with Mellaril and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes-type arrhythmias. Such an increased risk may result also from the additive effect of co-administering Mellaril with other agents that prolong the QTc interval. Therefore, Mellaril is contraindicated with these drugs as well as in patients, comprising about 7% of the normal population, who are known to have a genetic defect leading to reduced levels of activity of P450 2D6 (see WARNINGS and PRECAUTIONS).

In common with other phenothiazines, Mellaril is contraindicated in severe central nervous system depression or comatose states from any cause including drug induced central nervous system depression (see WARNINGS). It should also be noted that hypertensive or hypotensive heart disease of extreme degree is a contraindication of phenothiazine administration.

The basic pharmacological activity of Mellaril^® (thioridazine HCl) is similar to that of other phenothiazines, but is associated with minimal extrapyramidal stimulation.

However, thioridazine has been shown to prolong the QTc interval in a dose-dependent fashion. This effect may increase the risk of serious, potentially fatal, ventricular arrhythmias, such as torsade de pointes-type arrhythmias. Due to this risk, Mellaril is indicated only for schizophrenic patients who have not been responsive to or cannot tolerate other antipsychotic agents (see WARNINGS and CONTRAINDICATIONS). However, the prescriber should be aware that Mellaril has not been systematically evaluated in controlled trials in treatment refractory schizophrenic patients and its efficacy in such patients is unknown.

Patients should be informed that Mellaril has been associated with potentially fatal heart rhythm disturbances. The risk of such events may be increased when certain drugs are given together with Mellaril. Therefore, patients should inform the prescriber that they are receiving Mellaril treatment before taking any new medication.

Given the likelihood that some patients exposed chronically to neuroleptics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

THIORIDAZINE - ORAL

(thigh-oh-RID-uh-zeen)

WARNING: Thioridazine rarely has caused very serious (possibly fatal) irregular heartbeat (QT prolongation in the EKG). Therefore, it should be used only in patients who have not shown improvement with at least 2 other antipsychotic medications or who cannot tolerate other antipsychotic medications. This medication should not be used with other medications that can also cause a slow or irregular heartbeat. (See also Drug Interactions.)

There may be a slightly increased risk of serious, possibly fatal side effects (e.g., pneumonia, heart failure) when this medication is used in older adults with dementia. This medication is not approved for the treatment of dementia-related behavior problems. Discuss the risks and benefits of this medication, as well as other effective and possibly safer treatments for dementia-related behavior problems, with the doctor.

USES: This medication is used to treat certain mental/mood disorders (e.g., schizophrenia). This medication helps you to think more clearly, feel less nervous, and take part in everyday life. It can also help prevent suicide in people likely to harm themselves and reduce aggression and the desire to hurt others. It can help decrease your negative thoughts and hallucinations. Thioridazine belongs to a class of drugs known as phenothiazines.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used for short periods of time to treat very severe depression when the patient is also anxious.

HOW TO USE: Take this medication by mouth with or without food, usually 2-4 times a day or as directed by your doctor.

Dosage is based on your medical condition and response to therapy. Once your condition improves and you are better for a while, your doctor may work with you to reduce your regular dose. This may be done over time. Do not stop your medication or lower your dose without talking with your doctor first. Some conditions may become worse when the drug is stopped abruptly. Your dose may need to be gradually reduced.

Use this medication regularly in order to get the most benefit from it. To help you remember, use it at the same time(s) each day.

Inform your doctor if your condition persists or worsens.

SIDE EFFECTS: Dizziness, drowsiness, difficulty urinating, restlessness, headache, and blurred vision may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor if any of these serious side effects occur: shakiness (tremors), muscle stiffness, mask-like facial expression, jerking movements while walking.

Thioridazine may rarely cause a condition known as tardive dyskinesia. In some cases this condition may be permanent. Tell your doctor immediately if you develop any unusual/uncontrolled movements (especially of the face, lips, tongue, arms or legs).

In rare cases, thioridazine may increase your level of a certain chemical made by the body (prolactin). For females, this increase in prolactin may result in unwanted breast milk, missed/stopped periods, or difficulty becoming pregnant. For males, it may result in decreased sexual ability, inability to produce sperm, or enlarged breasts. If you develop any of these symptoms, tell your doctor immediately.

Tell your doctor immediately if any of these rare but very serious side effects occur: signs of infection (e.g., fever, persistent sore throat), vision changes (e.g., vision loss, sudden difficulty seeing at night, brown-tinged vision).

Seek immediate medical attention if any of these rare but very serious side effects occur: severe dizziness, fainting, fast/slow/irregular heartbeat, seizures.

This medication may rarely cause a serious condition called neuroleptic malignant syndrome (NMS). Seek immediate medical attention if you develop the following rare but very serious side effects: rapid breathing, muscle stiffness, high fever, increased sweating, fast heartbeat, sudden mental/mood changes.

A very serious allergic reaction to this drug is unlikely. Seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking thioridazine, tell your doctor or pharmacist if you are allergic to it; or to other phenothiazines (e.g., chlorpromazine); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: a certain heart problem (QT prolongation in the EKG), a certain severe nervous system problem (severe CNS depression), severe blood pressure problems.

This medication should not be given to a patient that is unconscious.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: certain blood problems (e.g., low white blood cell count), other heart problems (e.g., slow heartbeat, heart failure), family history of certain heart problems (QT prolongation in the EKG, sudden cardiac death), low levels of potassium or magnesium in the blood, Parkinson's disease, history of seizures, low enzymes needed to remove drugs from the body (slow hydroxylator).

This drug may make you dizzy or drowsy; use caution while engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

To decrease dizziness and lightheadedness, get up slowly when rising from a seated or lying position.

Before having surgery, tell your doctor or dentist that you are taking this medication.

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

Caution is advised when using this drug in the elderly because they may be more sensitive to the effects of the drug, especially drowsiness, difficulty urinating, and heart problems.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: cabergoline, cisapride, duloxetine, certain SSRI antidepressants (e.g., fluoxetine, fluvoxamine, paroxetine), pergolide, pindolol, propranolol, sibutramine.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting thioridazine.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: anticholinergic medications (e.g., belladonna alkaloids, atropine, scopolamine), carbamazepine, guanethidine, guanadrel, lithium, medications for Parkinson's disease (e.g., levodopa, benztropine), certain "water pills" (potassium-wasting diuretics such as hydrochlorothiazide, furosemide).

This drug should not be used with the following medications because very serious, possibly fatal interactions may occur: amiodarone, bepridil, disopyramide, dofetilide, droperidol, halofantrine, pimozide, sparfloxacin, ziprasidone.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting thioridazine. Other drugs besides thioridazine and those listed above which may affect the heart rhythm (QT prolongation in the EKG) include quinidine, sotalol, procainamide, and erythromycin, among others. Before using thioridazine, report all medications you are currently using to your doctor or pharmacist. QT prolongation can infrequently result in serious (rarely fatal) fast/irregular heartbeat and other symptoms (e.g., severe dizziness, fainting) that require immediate medical attention. Ask your doctor or pharmacist for more details and for instructions on how you may reduce the risk of this effect.

Also report the use of drugs which might increase seizure risk (decrease seizure threshold) when combined with this drug such as bupropion, isoniazid, haloperidol, theophylline, tramadol, or tricyclic antidepressants (e.g., amitriptyline, nortriptyline), among others.

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: certain antihistamines (e.g., diphenhydramine), anti-seizure drugs (e.g., phenytoin), medicine for sleep or anxiety (e.g., alprazolam, diazepam, zolpidem), muscle relaxants, narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., chlorpromazine, risperidone, trazodone).

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain drowsiness-causing ingredients. Ask your pharmacist about the safe use of those products.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., eye exams, potassium levels, EKG) may be performed from time to time to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store in a tightly closed container at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted.

Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.