PIMOZIDE
DESCRIPTION:
ORAP (pimozide) is an orally active antipsychotic agent of the diphenyl-
butylpiperidine series. The structural formula of pimozide, 1-(1-(4,4-bis(4-
fluorophenyl)butyl)-4-piperidinyl )-1,3-dihydro-2H-benzimidazole-2-one.
The solubility of pimozide in water is less than 0.01 mg/mL; it is slightly
soluble in most organic solvents.
ACTIONS/CLINICAL PHARMACOLOGY:
PHARMACODYNAMIC ACTIONS
ORAP (pimozide) is an orally active antipsychotic drug product which shares with
other antipsychotics the ability to blockade dopaminergic receptors on neurons
in the central nervous system. Although its exact mode of action has not been
established, the ability of pimozide to suppress motor and phonic tics in
Tourette's Disorder is thought to be a function of its dopaminergic blocking
activity. However, receptor blockade is often accompanied by a series of
secondary alterations in central dopamine metabolism and function which may
contribute to both pimozide's therapeutic and untoward effects. In addition,
pimozide, in common with other antipsychotic drugs, has various effects on other
central nervous system receptor systems which are not fully characterized.
METABOLISM AND PHARMACOKINETICS
More than 50% of a dose of pimozide is absorbed after oral administration. Based
on the pharmacokinetic and metabolic profile, pimozide appears to undergo
significant first pass metabolism. Peak serum levels occur generally six to
eight hours (range 4-12 hours) after dosing.
Pimozide is extensively metabolized, primarily by N-dealkylation in the liver.
Two major metabolites have been identified, 1-(4-piperidyl)-2-benzimidazolinone
and 4,4-bis(4- fluorophenyl) butyric acid. The antipsychotic activity of these
metabolites is undetermined. The major route of elimination of pimozide and its
metabolites is through the kidney.
The mean serum elimination half-life of pimozide in schizophrenic patients was
approximately 55 hours. There was a 13-fold interindividual difference in the
area under the serum pimozide level-time curve and an equivalent degree of
variation in peak serum levels among patients studied. The significance of this
is unclear since there are few correlations between plasma levels and clinical
findings.
Effects of food, disease or concomitant medication upon the absorption,
distribution, metabolism and elimination of pimozide are not known.
INDICATIONS AND USAGE:
ORAP (pimozide) is indicated for the suppression of motor and phonic tics in
patients with Tourette's Disorder who have failed to respond satisfactorily to
standard treatment. ORAP is not intended as a treatment of first choice nor is
it intended for the treatment of tics that are merely annoying or cosmetically
troublesome. ORAP should be reserved for use in Tourette's Disorder patients
whose development and/or daily life function is severely compromised by the
presence of motor and phonic tics.
Evidence supporting approval of pimozide for use in Tourette's Disorder was
obtained in two controlled clinical investigations which enrolled patients
between the ages of 8 and 53 years. Most subjects in the two trials were 12 or
older.
CONTRAINDICATIONS:
1. ORAP (pimozide) is contraindicated in the treatment of simple tics or tics
other than those associated with Tourette's Disorder.
2. ORAP should not be used in patients taking drugs that may, themselves, cause
motor and phonic tics (e.g., pemoline, methylphenidate and amphetamines) until
such patients have been withdrawn from these drugs to determine whether or not
the drugs, rather than Tourette's Disorder, are responsible for the tics.
3. Because ORAP prolongs the QT interval of the electrocardiogram it is
contraindicated in patients with congenital long QT syndrome, patients with a
history of cardiac arrhythmias, or patients taking other drugs which prolong the
QT interval of the electrocardiogram (see DRUG INTERACTIONS).
4. ORAP is contraindicated in patients with severe toxic central nervous system
depression or comatose states from any cause.
5. ORAP is contraindicated in patients with hypersensitivity to it. As it is not
known whether cross-sensitivity exists among the antipsychotics, pimozide should
be used with appropriate caution in patients who have demonstrated
hypersensitivity to other antipsychotic drugs.
6. Ventricular arrhythmias have been rarely associated with the use of macrolide
antibiotics in patients with prolonged QT intervals, as might be produced by
ORAP. Specifically, two sudden deaths have been reported when clarithromycin was
added to ongoing pimozide therapy. Therefore, ORAP is contraindicated in
patients receiving the macrolide antibiotics clarithromycin, erythromycin,
azithromycin, and dirithromycin.
WARNINGS:
The use of ORAP (pimozide) in the treatment of Tourette's Disorder involves
different risk/benefit considerations than when antipsychotic drugs are used to
treat other conditions. Consequently, a decision to use ORAP should take into
consideration the following (see also PRECAUTIONS--Information for Patients).
TARDIVE DYSKINESIA
A syndrome consisting of potentially irreversible, involuntary, dyskinetic
movements may develop in patients treated with 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 antipsychotic treatment, which patients are likely to develop
the syndrome. Whether antipsychotic drug products differ in their potential to
cause tardive dyskinesia is unknown.
Both the risk of developing tardive dyskinesia and the likelihood that it will
become irreversible are believed to increase as the duration of treatment and
the total cumulative dose of antipsychotic 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 antipsychotic
treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress
(or partially suppress) the signs and symptoms of the syndrome and thereby may
possibly mask the underlying process. The effect that symptomatic suppression
has upon the long-term course of the syndrome is unknown.
Given these considerations, antipsychotic drugs should be prescribed in a manner
that is most likely to minimize the occurrence of tardive dyskinesia. Chronic
antipsychotic treatment should generally be reserved for patients who suffer
from a chronic illness that, 1) is known to respond to antipsychotic 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
antipsychotics, 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 ADVERSE REACTIONS and PRECAUTIONS--
Information for Patients.)
NEUROLEPTIC MALIGNANT SYNDROME (NMS)
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 (including catatonic signs) and evidence of autonomic instability
(irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac
dysrhythmias). Additional signs may include elevated creatine phosphokinase,
myoglobinuria (rhabdomyolysis) and acute renal failure.
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.
Hyperpyrexia, not associated with the above symptom complex, has been reported
with other antipsychotic drugs.
OTHER
Sudden, unexpected deaths have occurred in experimental studies of conditions
other than Tourette's Disorder. These deaths occurred while patients were
receiving dosages in the range of 1mg per kg. One possible mechanism for such
deaths is prolongation of the QT interval predisposing patients to ventricular
arrhythmia. An electrocardiogram should be performed before ORAP treatment is
initiated and periodically thereafter, especially during the period of dose
adjustment.
ORAP may have a tumorigenic potential. Based on studies conducted in mice, it is
known that pimozide can produce a dose related increase in pituitary tumors. The
full significance of this finding is not known, but should be taken into
consideration in the physician's and patient's decisions to use this drug
product. This finding should be given special consideration when the patient is
young and chronic use of pimozide is anticipated. (see PRECAUTIONS--
Carcinogenesis, Mutagenesis, Impairment of Fertility)
PRECAUTIONS:
GENERAL
ORAP (pimozide) may impair the mental and/or physical abilities required for the
performance of potentially hazardous tasks, such as driving a car or operating
machinery, especially during the first few days of therapy.
ORAP produces anticholinergic side effects and should be used with caution in
individuals whose conditions may be aggravated by anticholinergic activity.
ORAP should be administered cautiously to patients with impairment of liver or
kidney function, because it is metabolized by the liver and excreted by the
kidneys.
Antipsychotics should be administered with caution to patients receiving
anticonvulsant medication, with a history of seizures, or with EEG
abnormalities, because they may lower the convulsive threshold. If indicated,
adequate anticonvulsant therapy should be maintained concomitantly.
INFORMATION FOR PATIENTS
Treatment with ORAP exposes the patient to serious risks. A decision to use ORAP
chronically in Tourette's Disorder is one that deserves full consideration by
the patient (or patient's family) as well as by the treating physician. Because
the goal of treatment is symptomatic improvement, the patient's view of the need
for treatment and assessment of response are critical in evaluating the impact
of therapy and weighing its benefits against the risks. Since the physician is
the primary source of information about the use of a drug in any disease, it is
recommended that the following information be discussed with patients and/or
their families.
ORAP is intended only for use in patients with Tourette's Disorder whose
symptoms are severe and who cannot tolerate, or who do not respond to HALDOL(R)
(haloperidol).
Given the likelihood that a proportion of patients exposed chronically to
antipsychotics 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.
There is limited information available on the use of ORAP in children under 12
years of age.
The information available on ORAP from foreign marketing experience and from
U.S. clinical trials indicates that ORAP has a side effect profile similar to
that of other antipsychotic drugs. Patients should be informed that all types of
side effects associated with the use of antipsychotics may be associated with
the use of ORAP.
In addition, sudden, unexpected deaths have occurred in patients taking high
doses of ORAP for conditions other than Tourette's Disorder. These deaths may
have been the result of an effect of ORAP upon the heart. Therefore, patients
should be instructed not to exceed the prescribed dose of ORAP and they should
realize the need for the initial ECG and for follow-up ECGs during treatment.
Also, pimozide, at a dose about 15 times that given humans, caused an increase
in the number of benign tumors of the pituitary gland in female mice. It is not
possible to say how important this is. Similar tumors were not seen in rats
given pimozide, nor at lower doses in mice, which is reassuring. However, any
such finding must be considered to suggest a possible risk of long term use of
the drug.
LABORATORY TESTS
An ECG should be done at baseline and periodically thereafter throughout the
period of dose adjustment. Any indication of prolongation of QTc interval beyond
an absolute limit of 0.47 seconds (children) or 0.52 seconds (adults), or more
than 25% above the patient's original baseline should be considered a basis for
stopping further dose increase (see CONTRAINDICATIONS) and considering a lower
dose.
Since hypokalemia has been associated with ventricular arrhythmias, potassium
insufficiency, secondary to diuretics, diarrhea, or other cause, should be
corrected before ORAP therapy is initiated and normal potassium maintained
during therapy.
DRUG INTERACTIONS
Because ORAP prolongs the QT interval of the electrocardiogram, an additive
effect on QT interval would be anticipated if administered with other drugs,
such as phenothiazines, tricyclic antidepressants or antiarrhythmic agents,
which prolong the QT interval. Also, the use of macrolide antibiotics in
patients with prolonged QT intervals has been rarely associated with ventricular
arrhythmias. Such concomitant administration should not be undertaken (see
CONTRAINDICATIONS).
ORAP may be capable of potentiating CNS depressants, including analgesics,
sedatives, anxiolytics, and alcohol.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Carcinogenicity studies were conducted in mice and rats. In mice, pimozide
causes a dose-related increase in pituitary and mammary tumors.
When mice were treated for up to 18 months with pimozide, pituitary gland
changes developed in females only. These changes were characterized as
hyperplasia at doses approximating the human dose and adenoma at doses about
fifteen times the maximum recommended human dose on a mg per kg basis. The
mechanism for the induction of pituitary tumors in mice is not known.
Mammary gland tumors in female mice were also increased, but these tumors are
expected in rodents treated with antipsychotic drugs which elevate prolactin
levels. Chronic administration of an antipsychotic also causes elevated
prolactin levels in humans. 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 with antipsychotic drugs, the clinical significance of elevated
serum prolactin levels is unknown for most patients. Neither clinical studies
nor epidemiologic studies conducted to date have shown an association between
chronic administration of these drugs and mammary tumorigenesis. The available
evidence, however, is considered too limited to be conclusive at this time.
In a 24 month carcinogenicity study in rats, animals received up to 50 times the
maximum recommended human dose. No increased incidence of overall tumors or
tumors at any site was observed in either sex. Because of the limited number of
animals surviving this study, the meaning of these results is unclear.
Pimozide did not have mutagenic activity in the Ames test with four bacterial
test strains, in the mouse dominant lethal test or in the micronucleus test in
rats.
Reproduction studies in animals were not adequate to assess all aspects of
fertility. Nevertheless, female rats administered pimozide had prolonged estrus
cycles, an effect also produced by other antipsychotic drugs.
PREGNANCY
CATEGORY C. Reproduction studies performed in rats and rabbits at oral doses up
to 8 times the maximum human dose did not reveal evidence of teratogenicity. In
the rat, however, this multiple of the human dose resulted in decreased
pregnancies and in the retarded development of fetuses. These effects are
thought to be due to an inhibition or delay in implantation which is also
observed in rodents administered other antipsychotic drugs. In the rabbit,
maternal toxicity, mortality, decreased weight gain, and embryotoxicity
including increased resorptions were dose related. Because animal reproduction
studies are not always predictive of human response, pimozide should be given to
a pregnant woman only if the potential benefits of treatment clearly outweigh
the potential risks.
LABOR AND DELIVERY
This drug has no recognized use in labor or delivery.
NURSING MOTHERS
It is not known whether pimozide is excreted in human milk. Because many drugs
are excreted in human milk and because of the potential for tumorigenicity and
unknown cardiovascular effects in the infant, a decision should be made whether
to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
PEDIATRIC USE
Although Tourette's Disorder most often has its onset between the ages of 2 and
15 years, information on the use and efficacy of ORAP in patients less than 12
years of age is limited. A 24 week open label study in 36 children between the
ages of 2 and 12 demonstrated that pimozide has a similar safety profile in this
age group as in older patients and there were no safety findings that would
preclude its use in this age group.
Because its use and safety have not been evaluated in other childhood disorders,
ORAP is not recommended for use in any condition other than Tourette's Disorder.
DRUG INTERACTIONS:
Because ORAP prolongs the QT interval of the electrocardiogram, an additive
effect on QT interval would be anticipated if administered with other drugs,
such as phenothiazines, tricyclic antidepressants or antiarrhythmic agents,
which prolong the QT interval. Such concomitant administration should not be
undertaken (see CONTRAINDICATIONS).
ORAP may be capable of potentiating CNS depressants, including analgesics,
sedatives, anxiolytics, and alcohol.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
GENERAL
Extrapyramidal Reactions: Neuromuscular (extrapyramidal) reactions during the
administration of ORAP (pimozide) have been reported frequently, often during
the first few days of treatment. In most patients, these reactions involved
Parkinson-like symptoms which, when first observed, were usually mild to
moderately severe and usually reversible.
Other types of neuromuscular reactions (motor restlessness, dystonia, akathisia,
hyperreflexia, opisthotonos, oculogyric crises) have been reported far less
frequently. Severe extrapyramidal reactions have been reported to occur at
relatively low doses. Generally the occurrence and severity of most
extrapyramidal symptoms are dose related since they occur at relatively high
doses and have been shown to disappear or become less severe when the dose is
reduced. Administration of antiparkinson drugs such as benztropine mesylate or
trihexyphenidyl hydrochloride may be required for control of such reactions. It
should be noted that persistent extrapyramidal reactions have been reported and
that the drug may have to be discontinued in such cases.
Withdrawal Emergent Neurological Signs: Generally, patients receiving short term
therapy experience no problems with abrupt discontinuation of antipsychotic
drugs. However, some patients on maintenance treatment experience transient
dyskinetic signs after abrupt withdrawal. In certain of these cases the
dyskinetic movements are indistinguishable from the syndrome described below
under "Tardive Dyskinesia" except for duration. It is not known whether gradual
withdrawal of antipsychotic drugs will reduce the rate of occurrence of
withdrawal emergent neurological signs but until further evidence becomes
available, it seems reasonable to gradually withdraw use of ORAP.
Tardive Dyskinesia: ORAP may be associated with persistent dyskinesias. Tardive
dyskinesia, a syndrome consisting of potentially irreversible, involuntary,
dyskinetic movements, may appear in some patients on long-term therapy or may
occur after drug therapy has been discontinued. The risk appears to be greater
in elderly patients on high-dose therapy, especially females. The symptoms are
persistent and in some patients appear irreversible. The syndrome is
characterized by rhythmical involuntary movements of tongue, face, mouth or jaw
(e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing
movements). Sometimes these may be accompanied by involuntary movements of
extremities and the trunk.
There is no known effective treatment for tardive dyskinesia; antiparkinson
agents usually do not alleviate the symptoms of this syndrome. It is suggested
that all antipsychotic agents be discontinued if these symptoms appear. Should
it be necessary to reinstitute treatment, or increase the dosage of the agent,
or switch to a different antipsychotic agent, this syndrome may be masked.
It has been reported that fine vermicular movement of the tongue may be an early
sign of tardive dyskinesia and if the medication is stopped at that time the
full syndrome may not develop.
Electrocardiographic Changes: Electrocardiographic changes have been observed in
clinical trials of ORAP in Tourette's Disorder and schizophrenia. These have
included prolongation of the QT interval, flattening, notching and inversion of
the T wave and the appearance of U waves. Sudden, unexpected deaths and grand
mal seizure have occurred at doses above 20 mg/day.
Neuroleptic Malignant Syndrome: Neuroleptic malignant syndrome (NMS) has been
reported with ORAP. (See WARNINGS for further information concerning NMS.)
Hyperpyrexia: Hyperpyrexia has been reported with other antipsychotic drugs.
CLINICAL TRIALS
The following adverse reaction tabulation was derived from 20 patients in a 6
week long placebo controlled clinical trial of ORAP in Tourette's Disorder.
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BODY SYSTEM/ PIMOZIDE PLACEBO
ADVERSE REACTION (N = 20) (N = 20)
------------------------------------------------------------------------------------------------------------------------------------------
BODY AS A WHOLE
Headache 1 2
GASTROINTESTINAL
Dry mouth 5 1
Diarrhea 1 0
Nausea 0 2
Vomiting 0 1
Constipation 4 2
Eructations 0 1
Thirsty 1 0
Appetite increase 1 0
ENDOCRINE
Menstrual disorder 0 1
Breast secretions 0 1
MUSCULOSKELETAL
Muscle cramps 0 1
Muscle tightness 3 0
Stooped posture 2 0
CNS
Drowsiness 7 3
Sedation 14 5
Insomnia 2 2
Dizziness 0 1
Akathisia 8 0
Rigidity 2 0
Speech disorder 2 0
Handwriting change 1 0
Akinesia 8 0
PSYCHIATRIC
Depression 2 3
Excitement 0 1
Nervous 1 0
Adverse behavior 5 0
effect
SPECIAL SENSES
Visual disturbance 4 0
Taste change 1 0
Sensitivity of eyes 1 0
to light
Decreased accom- 4 1
modation
Spots before eyes 0 1
UROGENITAL
Impotence 3 0
------------------------------------------------------------------------------------------------------------------------------------------------------
The following adverse event tabulation was derived from 36 children (age 2 to
12) in a 24 week open trial of ORAP in Tourette's Disorder.
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BODY SYSTEM/ NUMBER OF PATIENTS
ADVERSE REACTION EXPERIENCING EACH
EVENT(%)
-----------------------------------------------------------------------------------------------------------------------------
DRUG-RELATED
ALL EVENTS EVENTS
(N=36) (N=36)
----------------------------------------------------------------------------------------------------------------------------
BODY AS A WHOLE
Asthenia 9 (25.0) 5 (13.8)
Headache 8 (22.2) 1 (2.7)
----------------------------------------------------------------------------------------------------------------------------
GASTROINTESTINAL
Dysphagia 1 (2.7) 1 (2.7)
Increased
Salivation 5 (13.8) 2 (5.5)
---------------------------------------------------------------------------------------------------------------------------
MUSCULOSKELETAL
Myalgia 1 (2.7) 1 (2.7)
--------------------------------------------------------------------------------------------------------------------------
CENTRAL NERVOUS SYSTEM
Dreaming
Abnormal 1 (2.7) 1 (2.7)
Hyperkinesia 2 (5.5) 1 (2.7)
Somnolence 10 (27.7) 9 (25.0)
Torticollis 1 (2.7) 1 (2.7)
Tremor
Limbs 1 (2.7) 1 (2.7)
------------------------------------------------------------------------------------------------------------------------
PSYCHIATRIC
Adverse
Behavior
Effect 10 (27.7) 8 (22.2)
Nervous 3 (8.3) 2 (5.5)
-----------------------------------------------------------------------------------------------------------------------
SKIN
Rash 3 (8.3) 1 (2.7)
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SPECIAL SENSES
Visual
Disturbance 2 (5.5) 1 (2.7)
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CARDIOVASCULAR
ECG
Abnormal 1 (2.7) 1 (2.7)
---------------------------------------------------------------------------------------------------------------------
Because clinical investigational experience with ORAP in Tourette's Disorder is
limited, uncommon adverse reactions may not have been detected. The physician
should consider that other adverse reactions associated with antipsychotics may
occur.
OTHER ADVERSE REACTIONS
In addition to the adverse reactions listed above, those listed below have been
reported in U.S. clinical trials of ORAP in conditions other than Tourette's
Disorder.
Body As A Whole: Asthenia, chest pain, periorbital edema
Cardiovascular/Respiratory: Postural hypotension, hypotension, hypertension,
tachycardia, palpitations
Gastrointestinal: Increased salivation, nausea, vomiting, anorexia, GI distress
Endocrine: Loss of libido
Metabolic/Nutritional: Weight gain, weight loss
Central Nervous System: Dizziness, tremor, parkinsonism, fainting, dyskinesia
Psychiatric: Excitement
Skin: Rash, sweating, skin irritation
Special Senses: Blurred vision, cataracts
Urogenital: Nocturia, urinary frequency
POSTMARKETING REPORTS
The following experiences were described in spontaneous postmarketing reports.
These reports do not provide sufficient information to establish a clear causal
relationship with the use of ORAP.
Gastrointestinal: Gingival hyperplasia in one patient.
Hematologic: Hemolytic anemia.
Metabolic/Nutritional: Hyponatremia.
Other: Seizure.
OVERDOSAGE:
In general, the signs and symptoms of overdosage with ORAP (pimozide) would be
an exaggeration of known pharmacologic effects and adverse reactions, the most
prominent of which would be: 1) electrocardiographic abnormalities, 2) severe
extrapyramidal reactions, 3) hypotension, 4) a comatose state with respiratory
depression.
In the event of overdosage, gastric lavage, establishment of a patent airway
and, if necessary, mechanically-assisted respiration are advised.
Electrocardiographic monitoring should commence immediately and continue until
the ECG parameters are within the normal range. Hypotension and circulatory
collapse may be counteracted by use of intravenous fluids, plasma, or
concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine
and norepinephrine. Epinephrine should not be used. In case of severe
extrapyramidal reactions, antiparkinson medication should be administered.
Because of the long half-life of pimozide, patients who take an overdose should
be observed for at least 4 days. As with all drugs, the physician should
consider contacting a poison control center for additional information on the
treatment of overdose.
DOSAGE AND ADMINISTRATION:
General:
The suppression of tics by ORAP requires a slow and gradual introduction of the
drug. The patient's dose should be carefully adjusted to a point where the
suppression of tics and the relief afforded is balanced against the untoward
side effects of the drug.
An ECG should be done at baseline and periodically thereafter, especially during
the period of dose adjustment (see WARNINGS and PRECAUTIONS--Laboratory Tests).
Periodic attempts should be made to reduce the dosage of ORAP to see whether or
not tics persist at the level and extent first identified. In attempts to reduce
the dosage of ORAP, consideration should be given to the possibility that
increases of tic intensity and frequency may represent a transient, withdrawal
related phenomenon rather than a return of disease symptoms. Specifically, one
to two weeks should be allowed to elapse before one concludes that an increase
in tic manifestations is a function of the underlying disease syndrome rather
than a response to drug withdrawal. A gradual withdrawal is recommended in any
case.
Children:
Reliable dose response data for the effects of ORAP (pimozide) on tic
manifestation in Tourette's Disorder patients below the age of twelve are not
available.
Treatment should be initiated at a dose of 0.05 mg/kg preferably taken once at
bedtime. The dose may be increased every third day to a maximum of 0.2 mg/kg not
to exceed 10 mg/day.
Adults:
In general, treatment with ORAP should be initiated with a dose of 1 to 2 mg a
day in divided doses. The dose may be increased thereafter every other day. Most
patients are maintained at less than 0.2 mg/kg per day, or 10 mg/day, whichever
is less. Doses greater than 0.2 mg/kg/day or 10 mg/day are not recommended.
ANIMAL PHARMACOLOGY:
A chronic study in dogs indicated that pimozide caused gingival hyperplasia when
administered for several months at about 5 times the maximum recommended human
dose. This condition was reversible after withdrawal.
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