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Neuroleptic Malignant Syndrome (NMS): Neuroleptic malignant syndrome
is a potentially fatal symptom complex that has been reported in
association with antipsychotic drugs, including thiothixene. The
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 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 required 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.
Tardive
Dyskinesia: Tardive dyskinesia, a syndrome consisting of potentially
irreversible, involuntary, dyskinetic movements may develop in patients
treated with neuroleptic (antipsychotic) drugs, including Navane.
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 administered
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treatment is withdrawn.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.
What effect suppression has upon the long-term course of the syndrome
is unknown.
Pregnancy: Safe use in pregnancy has not been established.
It should, therefore, not be used in women of childbearing potential
unless, in the opinion of the physician, the expected benefits of
the drug outweigh the potential hazard to the fetus.
PRECAUTIONS
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In consideration
of the known capability of thiothixene and certain other antipsychotic
drugs to precipitate convulsions, extreme caution should be used
in patients with a history of convulsive disorders or those in a
state of alcohol withdrawal, since it may lower the convulsive threshold.
Although the drug potentiates the actions of the barbiturates, the
dosage of the anticonvulsant therapy should not be reduced when
it is administered concurrently.
Production or aggravation of ECG changes has occurred with thiothixene
and therefore caution should be observed when there is increased
risk to the patient (see Adverse Effects).
Though exhibiting rather weak anticholinergic properties, thiothixene
should be used with caution in patients who are known or are suspected
to have glaucoma, and in those who might be exposed to extreme heat
or who are receiving atropine or related drugs.
Undue exposure to sunlight should be avoided. Photosensitive reactions
have been reported in patients.
Neuroleptic drugs, including thiothixene, may elevate prolactin
levels in humans; the elevation persists during chronic administration.
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.
Careful observation should be made for pigmentary retinopathy, and
lenticular pigmentation (fine lenticular pigmentation has been noted
in a small number of patients treated with thiothixene for prolonged
periods). Blood dyscrasias (agranulocytosis, pancytopenia, thrombocytopenic
purpura), and liver damage (jaundice, biliary stasis), have been
reported with related drugs.
Caution as well as careful adjustment of the dosages is indicated
when thiothixene is used in conjunction with other CNS depressants.
Hepatic microsomal enzyme including agents, such as carbamazepine,
were found to significantly increase the clearance of thiothixene.
Patients receiving these drugs should be observed for signs of reduced
effectiveness of thiothixene.
Due to a possible additive effect with hypotensive agents, patients
receiving these drugs should be observed closely for signs of excessive
hypotension when thiothixene is added to their drug regimen.
An antiemetic effect observed in animal studies may also occur in
man; therefore, it is possible that thiothixene may mask signs of
overdosage of toxic drugs and it may obscure conditions such as
intestinal obstruction and brain tumor.
To lessen the likelihood of adverse reactions related to drug accumulation,
patients on long-term therapy, particularly on high doses, should
be evaluated periodically to decide whether the maintenance dosage
could be lowered or drug therapy discontinued. Periodic blood counts
and liver function tests should be performed. Sudden onset of severe
CNS or vasomotor symptoms should be kept in mind.
ADVERSE
EFFECTS
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Since
thiothixene has pharmacologic properties similar to those of the
phenothiazines, all the known adverse reactions of that class of
drugs should be borne in mind when it is used. Behavioral: The most
common side effects are initial and transient drowsiness, restlessness
and agitation and
insomnia. (The incidence of sedation appears to be similar to that
of the piperazine group of phenothiazines, but less than that of
certain aliphatic phenothiazines.)
Other adverse reactions reported less frequently are weakness or
fatigue, excitement, depression and headache.
Hyperactivity, both psychic and motor, should be considered a pharmacologic
effect of the drug which may be desirable, except in the patient
who is already agitated and excited. Activation of psychotic symptomatology
has been observed, but it usually responds to reduction of dosage
or temporary discontinuation of the drug. Toxic confusional states
may occur on rare occasions.
Neurological: The incidence and nature of extrapyramidal
symptoms, including akathisia, pseudo-parkinsonism and dystonic
reactions, are similar to those encountered with the piperazine
phenothiazines, but thiothixene is more likely to produce akathisia.
They are usually controlled by reduction of dosage and/or administration
of antiparkinson drugs depending on the type and severity of symptoms.
Cerebral seizures have been reported (see Precautions).
Phenothiazine derivatives have been associated with cerebral edema
and cerebrospinal fluid abnormalities.
Hyperreflexia has been reported in infants delivered from mothers
having received structurally related drugs.
Tardive Dyskinesias: Since early detection of tardive dyskinesia
is important, patients should be monitored on an ongoing basis.
It has been reported that fine vermicular movement of the tongue
may be an early sign of the syndrome. If this or any other presentation
of the syndrome is observed, the clinician should consider possible
discontinuation of neuroleptic medication (see Warnings).
Neuroleptic Malignant Syndrome (NMS): (See Warnings).
Autonomic: Dry mouth, blurred vision, nasal congestion, constipation,
increased salivation and sweating, and impotence have occurred infrequently.
Phenothiazines have been associated with miosis, mydriasis and adynamic
ileus.
Cardiovascular: tachycardia, hypotension, lightheadedness,
and syncope. In the event hypotension occurs, epinephrine should
not be used as a pressor agent since a paradoxical further lowering
of blood pressure may result.
Nonspecific ECG changes have been observed in some patients receiving
thiothixene. These changes are usually reversible and frequently
disappear on continued therapy. The clinical significance of these
changes is not known.
Cardiac arrhythmias, including AV block, paroxysmal tachycardia
and ventricular fibrillation have been observed with some phenothiazines.
Note: Sudden deaths have occasionally been reported in patients
who have received certain phenothiazine derivatives.
In some cases the cause of death was apparently cardiac arrest or
asphyxia due to failure of the cough reflex. In others, the cause
could not be determined nor could it be established that death was
due to phenothiazine administration.
Endocrine: Hyperprolactinemia, lactation, menstrual irregularities,
moderate breast enlargement and amenorrhea have occurred in a small
percentage of females receiving thiothixene. If persistent, this
may necessitate a reduction in dosage or the discontinuation of
therapy. Phenothiazines have been associated with false positive
pregnancy tests, gynecomastia, hypoglycemia, hyperglycemia, and
glycosuria.
Allergic: Rash, pruritus, urticaria, and rare cases of anaphylaxis
have been reported. Undue exposure to sunlight should be avoided.
Although not experienced with thiothixene, exfoliative dermatitis,
contact dermatitis (in nursing personnel), have been reported with
certain phenothiazines.
Hematologic: As is true with certain other antipsychotic
drugs, leukopenia and leukocytosis, which are usually transient,
can occur occasionally. Other antipsychotic drugs have been associated
with agranulocytosis, eosinophilia, hemolytic anemia, thrombocytopenia
and pancytopenia.
Hepatic: Elevations of serum transaminase and alkaline phosphatase,
usually transient, have been infrequently observed in some patients.
No clinically confirmed cases of jaundice attributable to the drug
have been reported.
Ophthalmological: fine lenticular pigmentation has been noted after
prolonged therapy.
Miscellaneous: hyperpyrexia, anorexia, nausea, vomiting,
diarrhea, increase in appetite and weight, weakness or fatigue,
polydipsia and peripheral edema. Although not reported with thiothixene,
evidence indicates there is a relationship between phenothiazine
therapy and the occurrence of a systemic lupus erythematosus-like
syndrome.
OVERDOSAGE
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Symptoms:
Manifestations include muscular twitching, drowsiness, and dizziness.
Symptoms of gross overdosage may include CNS depression, rigidity,
weakness, torticollis, tremor, salivation, dysphagia, hypotension,
disturbances of gait, or coma.
Treatment: Essentially symptomatic and supportive. Early
gastric lavage may be helpful. Keep patient under careful observation
and maintain an open airway, since involvement of the extrapyramidal
system may produce dysphagia and respiratory difficulty in severe
overdosage. If hypotension occurs, the standard measures for managing
circulatory shock should be used (i.v. fluids and/or vasoconstrictors).
If a vasoconstrictor is needed, norepinephrine and phenylephrine
are the most suitable drugs. Other pressor agents, including epinephrine,
are not recommended, since phenothiazine derivatives may reverse
the usual pressor elevating action of these agents and cause further
lowering of blood pressure.
If CNS depression is present, recommended stimulants include caffeine
and sodium benzoate. Picrotoxin or pentylenetetrazol should be avoided.
Extrapyramidal symptoms may be treated with antiparkinson drugs.
There are no data on the use of peritoneal or hemodialysis, but
they are known to be of little value in phenothiazine intoxication.
DOSAGE
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The
use of thiothixene in children under 12 years of age is not recommended,
as safety and efficacy data for its use have not yet been accumulated
in sufficient quantities (see Contraindications). The usual optimal
dosage of thiothixene is in the range of 15 to 30 mg daily. In most
conditions, the initial dosage should be 5 to 10 mg daily.
The dosage should be gradually increased to the optimally effective
level based on patient response. An increase to 60 mg/day may be
necessary; however, exceeding a total daily dosage of 60 mg/day
rarely increases beneficial response. Patients on the average therapeutic
dosage may be maintained on once-a-day therapy. Higher dosage can
be given in 2 or 3 equally divided doses. The dosage should be reduced
to the lowest possible maintenance level as soon as possible.
SUPPLIED
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2 mg: Each white, hard gelatin
capsule contains: thiothixene 2 mg. Nonmedicinal ingredients: cornstarch,
lactose, magnesium stearate and sodium lauryl sulfate; capsule shell:
gelatin, silicon dioxide, sodium lauryl sulfate and titanium dioxide.
Tartrazine-free. Bottles of 100.
5 mg: Each orange and white, hard gelatin capsule contains:
thiothixene 5 mg. Nonmedicinal ingredients: cornstarch, lactose,
magnesium stearate and sodium lauryl sulfate; capsule shell: FD&C
Red No. 3, FD&C Yellow No. 6, gelatin, silicon dioxide, sodium
lauryl sulfate and titanium dioxide. Tartrazine-free. Bottles of
100.
10 mg: Each orange, hard gelatin capsule contains: thiothixene
10 mg. Nonmedicinal ingredients: cornstarch, lactose, magnesium
stearate and sodium lauryl sulfate; capsule shell: FD&C Red
No. 3, FD&C Yellow No. 6, gelatin, silicon dioxide, sodium lauryl
sulfate and titanium dioxide. Tartrazine-free. Bottles of 100.
Store between 15 and 30°C.
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