Medication Guide App

Thioxanthenes (Systemic)

This monograph includes information on the following:

1) Chlorprothixene 
2) Flupenthixol  *
3) Thiothixene


INN:
Flupenthixol  *—Flupentixol

VA CLASSIFICATION
Primary: CN709

Commonly used brand name(s): Fluanxol2; Fluanxol Depot2; Navane3; Taractan1; Thiothixene HCl Intensol3.

Another commonly used name is
flupentixol .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:


Antipsychotic—

Indications

Accepted

Psychotic disorders (treatment)—Indicated for management of primary and secondary symptoms of psychotic disorders.
—The long-acting flupenthixol decanoate injection may be used in the management of nonagitated, chronic, schizophrenic patients who have been stabilized with short-acting neuroleptics.

Unaccepted
Flupenthixol is not indicated for the management of severely agitated psychotic patients, psychoneurotic patients, or geriatric patients with confusion and/or agitation {01} {02} {11}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Chlorprothixene: 315.86
    Flupenthixol decanoate: 588.82
    Flupenthixol dihydrochloride: 507.4
    Thiothixene: 443.62
    Thiothixene hydrochloride: 552.57


Other characteristics
    Structurally and pharmacologically similar to the piperazine phenothiazines, which include acetophenazine, fluphenazine, perphenazine, prochlorperazine, and trifluoperazine {12} {13} {14} {15} {16} {17}.

Mechanism of action/Effect:

Antipsychotic—Thioxanthenes are thought to benefit psychotic conditions by blocking postsynaptic dopamine receptors in the brain. They also produce an alpha-adrenergic blocking effect and depress the release of most hypothalamic and hypophyseal hormones. However, the concentration of prolactin is increased due to blockade of prolactin inhibitory factor (PIF), which inhibits the release of prolactin from the pituitary gland.


Other actions/effects:

Antiemetic—Chlorprothixene also inhibits the medullary chemoreceptor trigger zone to produce an antiemetic effect.

Sedative—Chlorprothixene is also thought to cause an indirect reduction of stimuli to the brain stem reticular system to produce a sedative effect.

Absorption:

Flupenthixol decanoate—Slowly, from the site of injection, and gradually released from the vehicle into the bloodstream, where it is rapidly hydrolyzed to flupenthixol {02} {03}.

Flupenthixol dihydrochloride—Rapid, from gastrointestinal tract {11}.

Thiothixene—Rapid.

Biotransformation:

Hepatic.

Half-life:


Elimination:


Thiothixene—

Initial phase—3.4 hours.

Late phase—Approximately 34 hours. {09}



Time to peak concentrations

Flupenthixol dihydrochloride—3 to 8 hours {01} {11}.

Flupenthixol decanoate—4 to 7 days {02} {11}.

Thiothixene—1 to 3 hours.

Duration of action:

Chlorprothixene—Intramuscular, up to 12 hours.

Flupenthixol decanoate—3 weeks. {02}

Elimination:
    Chlorprothixene and thiothixene—Primarily renal.
    Flupenthixol—Primarily fecal; some renal. {01} {11}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one thioxanthene may be sensitive to the others also, and possibly to the phenothiazines {11} {14} {15} {16} {17}.

Carcinogenicity/Tumorigenicity

Most neuroleptic medications have been found to cause increased serum prolactin concentrations {11} {14} {15} {16} {17} {19}. Although the clinical significance of this increase is not known for most patients, in vitro studies have shown approximately one-third of human breast cancers to be prolactin dependent {11} {14} {15} {16} {17} {19}. Additionally, an increase in mammary neoplasms has been found in rodents after chronic administration of neuroleptics {11} {14} {15} {16} {17} {19}. However, a definite association between the chronic administration of these medications and mammary tumorigenesis has not been established {11} {14} {15} {16} {17} {19}.

Pregnancy/Reproduction
Fertility—
Studies with thiothixene in rats and rabbits showed a decrease in fertility {14} {15} {16} {17}.

Pregnancy—
Studies in humans have not been done.

Animal studies have shown no birth defects caused by thioxanthenes. However, there have been reports of hyperreflexia in the neonate when phenothiazines were used during pregnancy {12} {13} {14} {15} {16} {17}. Also, studies with thiothixene in rats and rabbits showed an increase in resorption rate {14} {15} {16} {17}. No teratogenic effects were seen after repeated oral administration of thiothixene to rats, rabbits, and monkeys before and during gestation {09} {14} {15} {16} {17}.

Breast-feeding

It is not known if thioxanthenes are distributed into breast milk. Caution is advised since pharmacologically related phenothiazines are distributed into breast milk, causing an increased risk of tardive dyskinesia and possible drowsiness in the nursing infant. {06} {08}

Pediatrics

Children appear to be prone to develop neuromuscular or extrapyramidal reactions, especially dystonias, while receiving therapeutic doses of pharmacologically related phenothiazines and should be closely monitored. Adolescents should be monitored very carefully during parenteral therapy with thioxanthenes because they tend to experience a higher incidence of hypotensive and extrapyramidal reactions than do adults.


Geriatrics


Geriatric patients tend to develop higher plasma concentrations of neuroleptics because of changes in distribution due to decreases in lean body mass, total body water, and albumin, and often an increase in total body fat composition {07}. These patients usually require a lower initial dosage and a more gradual titration of dose.

Elderly patients appear to be more prone to orthostatic hypotension, and exhibit an increased sensitivity to the anticholinergic and sedative effects of neuroleptics. They are also more prone to develop extrapyramidal side effects, such as tardive dyskinesia and parkinsonism. The signs of tardive dyskinesia are persistent, difficult to control, and, in some patients, appear to be irreversible. There is no known effective treatment. Careful observation during treatment for early signs of tardive dyskinesia and dosage adjustment of the thioxanthene may prevent a more severe manifestation of the syndrome.


Dental

The peripheral anticholinergic effects of thioxanthenes may decrease or inhibit salivary flow, especially in middle-aged or elderly patients, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort.

Extrapyramidal reactions induced by thioxanthenes will result in increased motor activity of the head, face, and neck. Occlusal adjustments, bite registrations, and treatment for bruxism may be made less reliable. {07}

The leukopenic and thrombocytopenic effects of thioxanthenes may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal, and patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Although not all of the following interactions have been documented specifically for thioxanthenes, a potential exists for their occurrence because of the close similarity of the pharmacological effects of thioxanthenes with those of phenothiazine medications.

» Alcohol{10}{11}{12}{13}{14}{15}{16}{17}{19}{20} or
» Central nervous system (CNS) depression–producing medications, other, especially anesthetics, barbiturates, and opioid (narcotic) analgesics{10}{11}{12}{13}{14}{15}{16}{17}{19}{20}{22} (See Appendix II )    (concurrent use may potentiate and prolong the CNS depressant effects of either these medications or the thioxanthenes; dosage adjustments may be necessary)


Amphetamines{22}    (concurrent use with thioxanthenes may inhibit the CNS-stimulating effects of amphetamines due to alpha-adrenergic blockade by the thioxanthenes; also, the antipsychotic effects of thioxanthenes may be reduced when they are used concurrently with amphetamines)


Antacids or
Antidiarrheals, adsorbent    (concurrent use may inhibit the absorption of an orally administered thioxanthene {22})


Anticholinergics or other medications with anticholinergic action{10}{11}{12}{13}{14}{15}{16}{17}{19}{20}{22} (See Appendix II ) or
Antidyskinetic agents or
Antihistamines{07}    (anticholinergic effects, especially confusion, hallucinations, nightmares, and increased intraocular pressure, {07} may be potentiated when these medications are used concurrently with thioxanthenes, because of secondary anticholinergic action of thioxanthenes)


Anticonvulsants    (thioxanthenes may lower the seizure threshold {11} {12} {13} {14} {15} {16} {17} {19} {23}; dosage adjustment of anticonvulsant medications may be necessary; potentiation of anticonvulsant effects does not occur)


Antidepressants, tricyclic or
Maprotiline or
Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, or selegiline or
Trazodone    (concurrent use with thioxanthenes may prolong and intensify the sedative and anticholinergic effects of either these medications or the thioxanthenes {22})


Bromocriptine{22}    (concurrent use with thioxanthenes may increase serum prolactin concentrations and interfere with effects of bromocriptine; dosage adjustment of bromocriptine may be necessary)


Dopamine    (concurrent use may antagonize peripheral vasoconstriction produced by high doses of dopamine, because of the alpha-adrenergic blocking action of thioxanthenes)


Ephedrine    (alpha-adrenergic blocking action of thioxanthenes may decrease the pressor response to ephedrine when it is used concurrently with thioxanthenes)


» Epinephrine{10}{11}{12}{13}{14}{15}{16}{17}{20}{22}    (alpha-adrenergic effects of epinephrine may be blocked when it is used concurrently with thioxanthenes, possibly resulting in severe hypotension and tachycardia)


» Extrapyramidal reaction–causing medications, other{22} (See Appendix II )    (concurrent use with thioxanthenes may increase the severity and frequency of extrapyramidal effects)


Guanadrel or
Guanethidine{22}    (concurrent use with thioxanthenes may decrease the hypotensive effects of these medications because of their displacement from and inhibition of uptake by adrenergic neurons)


» Levodopa{22}    (concurrent use with thioxanthenes may inhibit the antiparkinsonian effects of levodopa because thioxanthenes block dopamine receptors in the brain)


Metaraminol    (concurrent use usually decreases, but does not reverse or completely block, the pressor response to metaraminol, because of the alpha-adrenergic blocking action of thioxanthenes)


Methoxamine    (prior administration of thioxanthenes may decrease the pressor effect and duration of action of methoxamine because of the alpha-adrenergic blocking action of thioxanthenes)


Ototoxic medications, especially ototoxic antibiotics (See Appendix II )    (concurrent use with thioxanthenes may mask the symptoms of ototoxicity such as tinnitus, dizziness, or vertigo)


Phenylephrine    (prior administration of thioxanthenes may decrease the pressor response to phenylephrine because of the alpha-adrenergic blocking action of thioxanthenes)


Photosensitizing medications, other    (concurrent use with thioxanthenes may cause additive photosensitizing effects {04})


» Quinidine    (concurrent use with thioxanthenes may result in additive cardiac effects {04})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
For chlorprothixene
Bilirubin tests, urine    (false-positive results may occur)


Electrocardiogram (ECG) readings{19}{20}    (Q- and T-wave changes may occur)


Immunologic urine pregnancy tests{20}    (depending on the test used, false-positive or false-negative results may occur)

With physiology/laboratory test values
Uric acid{19}    (serum concentrations may be decreased with use of neuroleptics)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Blood dyscrasias{11}{12}{13}{14}{15}{17} or
» Bone marrow depression{05} or
» Circulatory collapse{10}{12}{13}{14}{15}{17}{19}{20} or
» CNS depression{10}{11}{12}{13}{14}{15}{17} or
» Comatose states, drug-induced{10}{11}{12}{13}{14}{15}{17}{19}{20}    (may be exacerbated)


Risk-benefit should be considered when the following medical problems exist
» Alcoholism{12}{13}{14}{15}{16}{17}    (CNS depression may be potentiated)


» Cardiovascular disease{10}{11}{14}{15}{17}{19}{20}    (increased risk of transient hypotension)


Glaucoma, or predisposition to{11}{12}{13} or
Peptic ulcer or
Respiratory disorders due to acute infections, asthma, or emphysema{19} or
Urinary retention    (may be exacerbated)


» Hepatic function impairment{10}{11}    (metabolism may be altered)


Parkinson's disease{11}    (potentiation of extrapyramidal effects)


Prostatic hypertrophy, symptomatic    (increased risk of urinary retention)


» Reye's syndrome{08}    (increased risk of hepatotoxicity in children and adolescents with signs and symptoms suggesting Reye's syndrome)


Seizure disorders{11}{12}{13}{14}{15}{16}{17}{19}{20}    (seizures may be precipitated because of lowered seizure threshold)


Sensitivity to thioxanthenes or phenothiazines{10}{11}{12}{13}{14}{15}{16}{17}{19}{20}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood cell counts and differential, especially in patients with sore throat and fever{10}{11}{12}{13}{20}    (may be required at periodic intervals during high-dose or prolonged therapy; agranulocytosis is more likely to occur between the 4th and 10th weeks of therapy; if significant cellular depression occurs, medication should be discontinued and appropriate therapy initiated)


Careful observation for early symptoms of tardive dyskinesia{11}{12}{13}{14}{15}{16}{17}{19}{20}    (recommended at periodic intervals, especially during high-dose or prolonged therapy and in the elderly; since there is no known effective treatment if syndrome should develop, thioxanthenes should be discontinued, if clinically feasible, at the earliest signs, usually fine, worm-like movements of the tongue)


Careful observation for early symptoms of tardive dystonia    (recommended at periodic intervals; since there is no known effective treatment if syndrome should develop, thioxanthenes should be discontinued, if clinically feasible, at the earliest signs)


Liver function tests{10}{11}{12}{13}{20} and
Urine tests for bilirubin and bile    (may be required if jaundice or grippe-like symptoms occur; these side effects are more likely to occur between the 2nd and 4th weeks of therapy)


Ophthalmologic examinations{12}{14}{15}{16}{17}    (may be required at periodic intervals during high-dose or prolonged therapy since deposition of particulate matter in the lens and cornea has occurred)




Side/Adverse Effects

Note: A few cases of sudden death have been reported in patients who were receiving phenothiazine derivatives. However, there is no definite evidence that the phenothiazines are causative agents. {04}
Although not all of these side effects have been attributed specifically to each thioxanthene or its phenothiazine analog, a potential exists for their occurrence during the use of any thioxanthene or its analog.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Akathisia{11}{12}{13}{14}{15}{16}{17}{19}{20} (severe restlessness or need to keep moving)—may appear within first 6 hours after dose
    
dystonic reactions{11}{12}{13}{14}{15}{16}{17}{19}{20} (difficulty in swallowing; inability to move eyes; muscle spasms, especially of neck and back; unusual twisting movements of body)
    
extrapyramidal effects, parkinsonian{10}{11}{12}{13}{14}{15}{16}{17}{19}{20} (difficulty in talking; loss of balance control; mask-like face; shuffling walk; stiffness of arms and legs; trembling and shaking of fingers and hands)
    
tardive dyskinesia, persistent{10}{11}{12}{13}{14}{15}{16}{17}{19}{20} (lip smacking or puckering; puffing of cheeks; rapid or worm-like movements of tongue; uncontrolled chewing movements; uncontrolled movements of arms and legs)

Note: Dystonic reactions appear most often in children and young adults; usually appear early in treatment and may subside within 24 to 48 hours after medication has been discontinued.
Parkinsonian extrapyramidal effects may be seen in the first few days of treatment, but frequency usually increases with increase of dosage; may be more frequent in elderly patients and older children.
Tardive dyskinesia is initially dose related, but may increase with long-term treatment and total cumulative dose; may persist after discontinuation of thioxanthenes.


Incidence less frequent
    
Allergic reaction{10}{12}{13}{14}{15}{16}{17}{19}{20} (skin rash)
    
anticholinergic effect{11} (difficult urination)
    
deposition of opaque substances in lens and cornea{11}{12}{13}{14}{15}{16}{17}{19} or retinopathy{11}{12}{13}{14}{15}{16}{17}{19}{20} (blurred vision or other eye problems)
    
hypotension{10}{14}{15}{16}{17}{20} (fainting)
    
skin discoloration{11}{19}{20} —more frequent in females on high-dose and prolonged therapy

Incidence rare
    
Agranulocytosis or other blood dyscrasias{11}{12}{13}{14}{15}{16}{17}{19}{20} (sore throat and fever; unusual bleeding or bruising)
    
heat stroke{10}{11}{12}{13} (hot, dry skin or lack of sweating; muscle weakness)
    
jaundice, obstructive{10}{12}{13}{14}{15}{16}{17}{19}{20} (yellow eyes or skin)
    
neuroleptic malignant syndrome{14}{15}{16}{17}{19} (NMS) (convulsions; difficulty in breathing; fast heartbeat; high fever; high or low blood pressure; increased sweating; loss of bladder control; severe muscle stiffness; unusually pale skin; tiredness)
    
tardive dystonia{23}{25} (increased blinking or spasms of eyelid; unusual facial expressions or body positions; uncontrolled twisting movements of neck, trunk, arms, or legs)

Note: Heat stroke may occur in environmental conditions of high heat and high humidity. Adequate interior temperature control (air-conditioning) must be maintained for institutionalized patients during hot weather because of the increased risk of heat stroke and neuroleptic malignant syndrome (NMS). {07}
NMS may occur at any time during neuroleptic therapy, but is more commonly seen soon after start of therapy, after patient has switched from one neuroleptic to another, during combined therapy with another psychotropic medication, or after a dosage increase. Along with the overt signs of skeletal muscle rigidity, hyperthermia, autonomic dysfunction, and altered consciousness, differential diagnosis may reveal leukocytosis (9500 to 26,000 cells per cubic millimeter), elevated liver enzymes, and elevated creatine phosphokinase (CPK). {07}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Constipation{11}{12}{13}{14}{15}{17}{19}{20}
    
decreased sweating
    
drowsiness, mild{10}{12}{13}{14}{15}{16}{17}{19}
    
dryness of mouth{11}{12}{13}{14}{15}{16}{17}{19}{20}
    
increased appetite and weight{11}{12}{13}{14}{15}{16}{17}{19}{20}
    
increased sensitivity of skin to sunlight{11}{12}{13}{14}{15}{16}{17}{19}
    
nasal congestion (stuffy nose){12}{13}{14}{15}{16}{17}{19}{20}
    
orthostatic hypotension (dizziness, lightheadedness, or fainting){11}{12}{13}{14}{15}{16}{17}{19}{20}

Incidence less frequent
    
Changes in menstrual period{11}{12}{13}{14}{15}{16}{17}{19}{20}
    
decreased sexual ability{11}{12}{13}{14}{15}{16}{17}{19}{20}
    
swelling of breasts —in males and females{11}{12}{13}{14}{15}{16}{17}{19}{20}
    
unusual secretion of milk{11}{12}{13}{14}{15}{16}{17}{19}{20}



Those indicating need for medical attention if they occur after medication is discontinued
    
Dyskinesia, withdrawal emergent{11}{19} (dizziness; nausea and vomiting; stomach pain; trembling of fingers and hands; uncontrolled, repetitive movements of mouth, tongue, or jaw)




Overdose
For specific information on the agents used in the management of thioxanthene overdose, see:
   • Amphetamine or dextroamphetamine in Amphetamines (Systemic) monograph;
   • Benztropine in Antidyskinetics (Systemic) monograph;
   • Charcoal, Activated (Oral-Local) monograph;
   • Diazepam in Benzodiazepines (Systemic) monograph;
   • Digitalis Glycosides (Systemic) monograph;
   • Diphenhydramine in Antihistamines (Systemic) monograph;
   • Norepinephrine or phenylephrine in Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph; and/or
   • Phenytoin in Anticonvulsants, Hydantoin (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Convulsions{19}{20}
    
difficulty in breathing, severe{11}{19}{20}
    
drowsiness, severe, or coma{11}{12}{13}{14}{15}{17}{19}{20}
    
fast heartbeat{11}{19}
    
fever{19}
    
hypotension (dizziness, severe){12}{13}{14}{15}{17}
    
muscle trembling, jerking, stiffness, or uncontrolled movements, severe{11}{12}{13}{14}{15}{16}{17}
    
small pupils{19}
    
unusual excitement{11}{19}{20}
    
unusual tiredness or weakness, severe{12}{13}{17}


Treatment of overdose
Treatment is essentially symptomatic and supportive {12} {13} {14} {15} {16} {17} {19} and may consist of the following:


To decrease absorption:
Early gastric lavage is often helpful {11} {12} {13} {14} {15} {16} {17} {19} {20}.

Not attempting to induce emesis because a dystonic reaction of the head and neck may develop that could result in aspiration of vomitus.

Administering activated charcoal slurry.

Administering saline cathartic.



Specific treatment:
Controlling cardiac arrhythmias with intravenous phenytoin, 9 to 11 mg per kg of body weight (mg/kg).

Digitalizing for cardiac failure.

Administering a vasopressor, such as norepinephrine or phenylephrine, for hypotension (not using epinephrine, which may cause paradoxical hypotension) {11} {12} {13} {14} {15} {16} {17} {20}.

Controlling convulsions with diazepam followed by phenytoin, 15 mg/kg, administered at a rate no faster than 50 mg per minute.

Benztropine or diphenhydramine may be administered to manage acute parkinsonian symptoms.

Severe CNS depression may require administration of a stimulant such as amphetamine or dextroamphetamine {14} {15} (picrotoxin or pentylenetetrazol should be avoided as it may induce convulsions {12} {13} {14} {15}).



Monitoring:
Monitoring cardiovascular function {11} (for not less than 5 days).



Supportive care:
Maintaining respiratory function and body temperature {11}.

Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.


Note: Dialysis of thioxanthenes has not been successful {12} {13} {14} {15} {16} {17}.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Thioxanthenes (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to thioxanthenes or phenothiazines

Pregnancy—Reports of hyperreflexia in neonates when pharmacologically related phenothiazines were used during pregnancy; animal studies have shown an increase in resorption rates and decreased fertility with phenothiazines





Breast-feeding—Pharmacologically related phenothiazines are distributed into breast milk causing tardive dyskinesia and possible drowsiness in nursing baby





Use in children—Children are more prone to extrapyramidal symptoms






Use in the elderly—Elderly patients are more likely to develop extrapyramidal, anticholinergic, hypotensive, and sedative effects; reduced dosage recommended





Dental—Thioxanthene-induced blood dyscrasias may result in infections, delayed healing, and bleeding; dry mouth may cause caries and candidiasis; increased motor activity of face, head, and neck may interfere with some dental procedures
Other medications, especially alcohol or other CNS depression–producing medications, epinephrine, other extrapyramidal reaction–causing medications, levodopa, or quinidine
Other medical problems, especially blood dyscrasias, bone marrow depression, circulatory collapse, CNS depression, alcoholism, cardiovascular disease, hepatic function impairment, or Reye's syndrome

Proper use of this medication
Taking with food or milk to reduce gastrointestinal irritation

» Diluting thiothixene oral solution with recommended beverages prior to use

» Compliance with therapy; not taking more medication or more often than directed

» May require several weeks of therapy to obtain desired effects

» Proper dosing
Missed dose: Taking as soon as possible; not taking if within 2 hours of next scheduled dose; continuing on regular schedule; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress of therapy

Checking with physician before discontinuing medication; gradual dosage reduction may be needed

» Avoiding use of alcoholic beverages or other CNS depressants during therapy

Avoiding use of antacids or medicine for diarrhea within 2 hours of taking thioxanthenes

» Caution if any kind of surgery, dental treatment, or emergency treatment is required

» Possible drowsiness; caution when driving, using machines, or doing other things requiring alertness {10} {11} {12} {13} {14} {15} {16} {17} {19} {20}

» Possible dizziness or lightheadedness; caution when getting up suddenly from a lying or sitting position

» Possible heatstroke: caution during exercise or hot weather, or when taking hot baths

» Possible skin photosensitivity; avoiding unprotected exposure to sun; using protective clothing; using a sun block product that includes protection against both UVA-caused photosensitivity reactions and UVB-caused sunburn reactions; avoiding use of sunlamp, tanning bed, or tanning booth

Possible dryness of mouth; using sugarless gum or candy, ice, or saliva substitute for relief; checking with physician or dentist if dry mouth continues for more than 2 weeks

» Avoiding spilling liquid medication on skin or clothing; may cause contact dermatitis

Observing precautions for long-acting parenteral form for up to 3 weeks


Side/adverse effects
» Stopping medication and notifying physician immediately if symptoms of neuroleptic malignant syndrome (NMS) appear

» Notifying physician as soon as possible if early signs of tardive dyskinesia appear

Possibility of withdrawal symptoms

Signs of potential side effects, especially akathisia, dystonias, parkinsonian effects, tardive dyskinesia or dystonia, allergic reactions, anticholinergic effects, deposition of opaque substances in lens and cornea or retinopathy, hypotension, skin discoloration, blood dyscrasias, heat stroke, obstructive jaundice, and NMS


General Dosing Information
Dosage must be individualized by titration from the lower dose range {10}. After a favorable psychiatric response is noted (within several days to several months), that dosage should be continued for about 2 weeks, then gradually decreased to the lowest level that will maintain an adequate clinical response.

When extended therapy is discontinued, a gradual reduction in thioxanthene dosage over several weeks is recommended {11}. Abrupt withdrawal may cause some patients on high or long-term dosage to experience transient dyskinetic signs, nausea, vomiting, gastritis, trembling, and dizziness.

The antiemetic effect of thioxanthenes may mask signs of drug toxicity or may obscure diagnosis of conditions whose primary symptom is nausea {11} {12} {13} {14} {15} {16} {17} {20}.

Avoid skin contact with liquid forms of this medication; contact dermatitis has resulted with use of similar medications {12} {13} {14} {15} {16} {17}.

For parenteral dosage forms only
Because hypotension is a common side effect of thioxanthenes, parenteral administration should be used only for patients who are bedfast or for appropriate acute, ambulatory patients who can be closely monitored. A possible exception may be those patients who are dose-stabilized on the extended-action injectable form. {04}

Intramuscular injections should be administered slowly and deeply into the upper outer quadrant of the buttock {11} or midlateral thigh {21}. Patient should remain lying down for at least half an hour after injection to avoid possible hypotensive effects.

Effects of the extended-action injectable form may last for up to 3 weeks. The precautions and side effects information applies during this period of time. {11}

Geriatric patients and children should be monitored very carefully during parenteral therapy because of a higher incidence of hypotensive and extrapyramidal reactions {04}.

The changeover from other neuroleptic medication to long-acting flupenthixol should be done gradually and under close supervision to prevent overdosage or insufficient suppression of psychotic symptoms before the next injection {02} {11}.

Diet/Nutrition
This medication may be taken with food or a full glass (240 mL) of water or milk, if necessary, to lessen stomach irritation.

For treatment of adverse effects


Neuroleptic malignant syndrome (NMS):
Treatment is essentially symptomatic and supportive and may include:

   • Discontinuing thioxanthene immediately {14} {15} {16} {17} {19}.
   • Hyperthermia—Administering antipyretics (aspirin or acetaminophen); using cooling blanket.
   • Dehydration—Restoring fluid and electrolytes.
   • Cardiovascular instability—Monitoring blood pressure and cardiac rhythm closely.
   • Hypoxia—Administering oxygen; considering airway insertion and assisted ventilation.
   • Muscle rigidity—Dantrolene sodium may be administered (100 to 300 mg per day in divided doses; 1.25 to 1.5 mg per kg of body weight, intravenously). Bromocriptine (5 to 7.5 mg every eight hours) has been used to reverse hyperpyrexia and muscle rigidity.



Parkinsonism, severe:
Many authorities advise that the only appropriate treatment of extrapyramidal symptoms is reduction of the antipsychotic dosage, if possible. Oral antidyskinetic agents such as trihexyphenidyl (2 mg three times a day), or benztropine, may be effective in treating more severe parkinsonism and acute motor restlessness but should be used sparingly, and then usually for no longer than 3 months. Milder effects may be treated by adjusting dosage. However, in the elderly patient, the use of amantadine (100 to 200 mg) at bedtime minimizes the severe anticholinergic effects that may occur with other antidyskinetics. {04}



Akathisia:
May be treated with antidyskinetic agents, or with propranolol (30 to 120 mg a day); nadolol (40 mg a day); pindolol (5 to 60 mg a day); lorazepam (1 or 2 mg two or three times a day): or diazepam (2 mg two or three times a day).



Dystonia:
Acute dystonic postures or oculogyric crisis may be relieved by parenteral administration of benztropine (2 mg intramuscularly), or diphenhydramine (50 mg intravenously or intramuscularly), or diazepam (5 to 7.5 mg intravenously), to be followed by oral antidyskinetic medication for one or two days to prevent recurrent dystonic episodes. Dosage adjustments of the thioxanthene may control these effects, and discontinuation may reverse severe symptoms.



Tardive dyskinesia or tardive dystonia:
No known effective treatment. Dosage of thioxanthene should be lowered or medication discontinued, if clinically feasible, at earliest signs of tardive dyskinesia or tardive dystonia, to prevent possible irreversible effects. {11} {12} {13} {14} {15} {16} {17} {19} {20} {23}


CHLORPROTHIXENE

Summary of Differences


Pharmacology/pharmacokinetics:
Other actions/effects—Antiemetic and sedative effects are more prominent than those of thiothixene.

Duration of action—Intramuscular dosage may produce effects lasting up to 12 hours.



Precautions:


Laboratory value alterations—
More likely to cause Q-T wave changes on ECG readings than is thiothixene.

May produce false-positive results on immunologic urine pregnancy test.

May produce false-positive results on urine bilirubin test.




Oral Dosage Forms

CHLORPROTHIXENE ORAL SUSPENSION USP

Usual adult and adolescent dose
Antipsychotic
Oral, 25 to 50 mg three or four times a day {19}.


Note: Geriatric or debilitated patients usually require a lower initial dose, the dosage being increased gradually as needed and tolerated {19}.


Usual adult prescribing limits
Up to 600 mg a day.

Usual pediatric dose
Antipsychotic
Children up to 6 years of age: Safety and efficacy have not been established {19}.

Children 6 to 12 years of age: Oral, 10 to 25 mg three or four times a day {19}.


Strength(s) usually available
U.S.—


100 mg per 5 mL (Rx) [Taractan (benzoic acid) (edetate disodium) (glycerin) (hydrochloric acid) (lactic acid) (magnesium aluminum silicate) (parabens [methyl and propyl]) (polyoxyethylene [8] stearate) (silicon emulsion) (sodium hydroxide) (sorbitol) (sucrose) (FD&C Red No. 40) (FD&C Blue No. 1) (FD&C Yellow No. 6) (flavors) (water)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. Protect from freezing.

Auxiliary labeling:
   • Shake well.
   • May cause drowsiness.
   • Avoid alcoholic beverages.
   • Do not spill on skin or clothing.

Note: Avoid skin contact with liquid forms of this medication; contact dermatitis has resulted.



CHLORPROTHIXENE TABLETS USP

Usual adult and adolescent dose
Antipsychotic
Oral, 25 to 50 mg three or four times a day {10} {19}.


Note: Geriatric or debilitated patients usually require a lower initial dose, the dosage being increased gradually as needed and tolerated {19}.


Usual adult prescribing limits
Up to 600 mg a day {10} {20}.

Usual pediatric dose
Antipsychotic
Children up to 6 years of age: Safety and efficacy have not been established {19}.

Children 6 to 12 years of age: Oral, 10 to 25 mg three or four times a day {19}.


Strength(s) usually available
U.S.—


10 mg (Rx) [Taractan (tartrazine)]


25 mg (Rx) [Taractan (tartrazine)]


50 mg (Rx) [Taractan (tartrazine)]


100 mg (Rx) [Taractan (tartrazine)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.



Parenteral Dosage Forms

CHLORPROTHIXENE INJECTION USP

Usual adult and adolescent dose
Antipsychotic
Intramuscular, 25 to 50 mg three or four times a day {19}.


Note: Geriatric or debilitated patients and adolescents usually require a lower initial dose, the dosage being increased gradually as needed and tolerated {19}.


Usual pediatric dose
Antipsychotic
Children up to 12 years of age: Safety and efficacy have not been established {19}.

Children 12 years of age and over: See Usual adult and adolescent dose.


Strength(s) usually available
U.S.—


12.5 mg per mL (Rx) [Taractan (parabens [methyl and propyl] 0.2%)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing.

Note: Avoid skin contact with liquid forms of this medication; contact dermatitis has resulted with similar medications.



FLUPENTHIXOL


Additional Dosing Information
See also General Dosing Information .

For parenteral dosage form only
Flupenthixol is for intramuscular injection only. It is not for intravenous use {11}.

As with all oily injections, aspiration before injection ensures that inadvertent intravascular injection has not occurred {11}.

Administration is by deep intramuscular injection into the gluteal region {11}.

Patients not previously treated with a long-acting depot neuroleptic should be given a test dose of 5 to 20 mg of flupenthixol decanoate. The 5-mg test dose is usually recommended for elderly or debilitated patients, or for patients who may have a predisposition to extrapyramidal effects. {11}

During the 5 to 10 days following the test dose, the patient should be carefully monitored for therapeutic response and appearance of extrapyramidal side effects. Any oral neuroleptic dosage should be reduced in this period. {11}

A single injection may last for two to three weeks. However, when higher doses are used, a single injection may last for four weeks or more. Since higher doses also increase the incidence of adverse effects, dose increases should be made in increments not to exceed 20 mg. {11}


Oral Dosage Forms

FLUPENTHIXOL DIHYDROCHLORIDE TABLETS

Usual adult dose
Antipsychotic
Initial: Oral, 1 mg three times a day, the dosage being increased by 1 mg every two to three days as needed and tolerated {11}.

Maintenance: Oral, 3 to 6 mg a day in divided doses, up to 12 mg a day or more {11}.


Note: Geriatric or debilitated patients usually require a lower initial dose, the dosage being increased gradually as needed and tolerated.


Usual pediatric dose
Antipsychotic
Safety and efficacy have not been established {11}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


0.5 mg (Rx) [Fluanxol (sucrose)]


3 mg (Rx) [Fluanxol (sucrose)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. Protect from light.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.



Parenteral Dosage Forms

FLUPENTHIXOL DECANOATE INJECTION

Usual adult dose
Antipsychotic
Intramuscular, initially 20 to 40 mg, the dose being repeated in four to ten days. Dosage may be increased in increments of not more than 20 mg. {11}


Note: Most patients require 20 to 40 mg every two to three weeks.
Doses greater than 80 mg are rarely necessary, although higher doses may be used in some patients {11}.


Usual pediatric dose
Antipsychotic
Safety and efficacy have not been established {11}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


20 mg per mL (Rx) [Fluanxol Depot]


100 mg per mL (Rx) [Fluanxol Depot]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing.

Additional information:
Vehicle is a thin vegetable oil.


THIOTHIXENE

Summary of Differences
Precautions: Laboratory value alterations—With physiology/laboratory test values: Serum uric acid may be decreased.


Oral Dosage Forms

THIOTHIXENE CAPSULES USP

Usual adult and adolescent dose
Antipsychotic
Oral, initially 2 mg three times a day for milder conditions, or 5 mg two times a day for more severe conditions, the dosage being adjusted gradually as needed and tolerated, usually up to 60 mg a day {14} {15} {16} {17}.


Note: Dosages over 60 mg a day rarely increase the beneficial effect {06} {12} {13} {14} {15} {16} {17}.
Geriatric or debilitated patients usually require a lower initial dose, the dosage being increased gradually as needed and tolerated.


Usual pediatric dose
Antipsychotic
Children up to 12 years of age: Safety and efficacy have not been established {14} {15} {16} {17}.

Children 12 years of age and over: See Usual adult and adolescent dose.


Strength(s) usually available
U.S.—


1 mg (Rx) [Navane][Generic]


2 mg (Rx) [Navane][Generic]


5 mg (Rx) [Navane][Generic]


10 mg (Rx) [Navane][Generic]


20 mg (Rx) [Navane][Generic]

Canada—


2 mg (Rx) [Navane (sodium lauryl sulfate) (corn starch [gluten]) (lactose) (magnesium stearate) (gelatin) (sodium metabisulfite) (titanium dioxide) (FD&C Red No. 3)]


5 mg (Rx) [Navane (sodium lauryl sulfate) (corn starch [gluten]) (lactose) (magnesium stearate) (gelatin) (sodium metabisulfite) (titanium dioxide) (FD&C Red No. 3) (FD&C Yellow No. 6)]


10 mg (Rx) [Navane (sodium lauryl sulfate) (corn starch [gluten]) (lactose) (magnesium stearate) (gelatin) (sodium metabisulfite) (titanium dioxide) (FD&C Red No. 3) (FD&C Yellow No. 6)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.


THIOTHIXENE HYDROCHLORIDE ORAL SOLUTION USP

Note: The dosing and strengths of Thiothixene Oral Solution are expressed in terms of thiothixene base (not the hydrochloride salt).


Usual adult and adolescent dose
Antipsychotic
Oral, initially, 2 mg (base) three times a day for milder conditions, or 5 mg two times a day for severe conditions, the dosage being adjusted gradually as needed and tolerated, up to 60 mg a day {17}.


Note: Dosages over 60 mg a day rarely increase the beneficial effect {06} {17}.
Geriatric or debilitated patients usually require a lower initial dose, the dosage being increased gradually as needed and tolerated.


Usual pediatric dose
Antipsychotic
Children up to 12 years of age: Safety and efficacy have not been established {17}.

Children 12 years of age and over: See Usual adult and adolescent dose.


Strength(s) usually available
U.S.—


5 mg (base) per mL (Rx) [Navane (alcohol 7%)] [Thiothixene HCl Intensol][Generic]

Canada—
Not commercially available.

Packaging and storage:
Store below 25 °C (77 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. Protect from freezing.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.
   • Do not spill on skin or clothing.
   • Must be diluted before use.

Note: Avoid skin contact with liquid forms of this medication; contact dermatitis has resulted with similar medications.
Each dose must be diluted just before administration by adding it to a cupful of milk, tomato or fruit juice, water, soup, or carbonated beverage.
Provide a specially marked dosage dropper and explain dilution and dosage measurement to patient if medication is self-administered.




Parenteral Dosage Forms

Note: The dosing and strengths of the dosage forms available are expressed in terms of thiothixene base (not the hydrochloride salt).


THIOTHIXENE HYDROCHLORIDE INJECTION USP

Usual adult and adolescent dose
Antipsychotic
Intramuscular, 4 mg (base) two to four times a day, the dosage being adjusted gradually as needed and tolerated, but not to exceed a total of 30 mg a day {13} {18}.


Note: Geriatric or debilitated patients usually require a lower initial dose, the dosage being increased gradually as needed and tolerated.


Usual pediatric dose
Antipsychotic
Children up to 12 years of age: Safety and efficacy have not been established {18}.

Children 12 years of age and over: See Usual adult and adolescent dose.


Strength(s) usually available
U.S.—


2 mg (base) per mL (Rx) [Navane (dextrose 5% w/v) (benzyl alcohol 0.9% w/v) (propyl gallate 0.02% w/v)]

Canada—
Not commercially available.

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing.

Note: Avoid skin contact with liquid forms of this medication; contact dermatitis has resulted from use of similar medications.



THIOTHIXENE HYDROCHLORIDE FOR INJECTION USP

Usual adult and adolescent dose
Antipsychotic
Intramuscular, 4 mg (base) two to four times a day, the dosage being adjusted gradually as needed and tolerated, but not to exceed a total of 30 mg a day {13} {18}.


Note: Geriatric or debilitated patients usually require a lower initial dose, the dosage being increased gradually as needed and tolerated.


Usual pediatric dose
Antipsychotic
Children up to 12 years of age: Safety and efficacy have not been established {18}.


Strength(s) usually available
U.S.—


5 mg (base) per mL (Rx) [Navane (mannitol)]

Canada—
Not commercially available.

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F), unless otherwise specified by manufacturer. Store in a light-resistant container. Protect from freezing.

Preparation of dosage form:
Reconstitute thiothixene hydrochloride for injection with 2.2 mL of sterile water for injection {18}.

Stability:
Reconstituted product may be stored at room temperature for up to 48 hours before discarding {18}.

Note: Avoid skin contact with liquid forms of this medication; contact dermatitis has resulted with similar medications.




Revised: 08/18/1998



References
  1. Flupenthixol package insert (Fluanxol, Merrell—Canada), printed May 1982.
  1. Flupenthixol package insert (Fluanxol Depot, Merrell—Canada), printed March 1984.
  1. Reynolds JEF, editor. Martindale, the extra pharmacopeia. 28th ed. London: The Pharmaceutical Press, 1982.
  1. Phenothiazines (Systemic) monograph, USP DI, 1987.
  1. Manufacturer comment, 10/87.
  1. Manufacturer comment, 10/87.
  1. Haloperidol (Systemic) monograph, USP DI, 1989.
  1. Phenothiazines (Systemic) monograph, USP DI, 1989.
  1. Manufacturer comment, 1988.
  1. Chlorprothixene Rx Summary (Tarasan, Hoffman-La Roche—Canada), Rev 4/27/82, Rec 2/28/90.
  1. Flupenthixol product monograph (Fluanxol, Merrell—Canada), CPS 1990: 414-5.
  1. Thiothixene product monograph (Navane, Pfizer—Canada), CPS 1990: 680-1.
  1. Thiothixene product monograph (Navane, Pfizer—Canada), Rev 6/28/78, Rec 4/90.
  1. Thiothixene package insert (Cord—US), Rev 8/87, Rec 2/89.
  1. Thiothixene package insert (Danbury—US), Rev 8/87, Rec 1/89.
  1. Thiothixene package insert (Mylan—US), Rev 11/88, Rec 3/89.
  1. Thiothixene capsules and concentrate product monograph (Navane, Roerig—US), PDR 1990: 1842-3.
  1. Thiothixene IM product monograph (Navane, Roerig—US), PDR 1990: 1843-4.
  1. Chlorprothixene product monograph (Taractan, Roche—US), PDR 1990: 1811-3.
  1. Chlorprothixene product monograph (Tarasan, Roche—Canada), CPS 1990: 1064.
  1. Thiothixene product monographs (Navane, Roerig—US), PDR 1993: 2042-5.
  1. Watsky EJ, Salzman C. Psychotropic drug interactions. Hosp Comm Psychiatry 1991 Mar; 42(3): 247-9.
  1. Reviewers' responses to Psychiatric Disease Panel Memo #6 of 9/16/91.
  1. Adler LA, Angrist B, Reiter S, Rotrosen J. Neuroleptic-induced akathisia: a review. Psychopharmacology 1989; 97: 1-11.
  1. Wojcik JD, Falk WE, Fink JS, Cole JO, Gelenberg AJ. A review of 32 cases of tardive dystonia. Am J Psychiatry 1991 Aug; 148(8): 1055-9.
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