Flupenthixol Decanoate
A yellow viscous oil. Very slightly soluble in water; soluble
in alcohol; freely soluble in chloroform and in ether. Store at
a temperature below -15Β° and protect from light.
Adverse Effects, Precautions, Interactions and Treatment as for Chlorpromazine whose record is displayed below.
CHLORPROMAZINE
WARNINGS:
THE EXTRAPYRAMIDAL SYMPTOMS WHICH CAN OCCUR SECONDARY TO MEGATIL
(CHLORPROMAZINE) MAY BE CONFUSED WITH THE CENTRAL NERVOUS SYSTEM SIGNS OF AN
UNDIAGNOSED PRIMARY DISEASE RESPONSIBLE FOR THE VOMITING, E.G., REYE'S SYNDROME
OR OTHER ENCEPHALOPATHY. THE USE OF MEGATIL AND OTHER POTENTIAL HEPATOTOXINS
SHOULD BE AVOIDED IN CHILDREN AND ADOLESCENTS WHOSE SIGNS AND SYMPTOMS SUGGEST
REYE'S SYNDROME.
TARDIVE DYSKINESIA: Tardive dyskinesia, a syndrome consisting of potentially
irreversible, involuntary, dyskinetic movements, may develop in patients treated
with neuroleptic (antipsychotic) drugs. Although the prevalence of the syndrome
appears to be highest among the elderly, especially elderly women, it is
impossible to rely upon prevalence estimates to predict, at the inception of
neuroleptic treatment, which patients are likely to develop the syndrome.
Whether neuroleptic drug products differ in their potential to cause tardive
dyskinesia is unknown.
Both the risk of developing the syndrome and the likelihood that it will become
irreversible are believed to increase as the duration of treatment and the total
cumulative dose of neuroleptic drugs administered to the patient increase.
However, the syndrome can develop, although much less commonly, after relatively
brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia,
although the syndrome may remit, partially or completely, if neuroleptic
treatment is withdrawn. Neuroleptic treatment itself, however, may suppress (or
partially suppress) the signs and symptoms of the syndrome and thereby may
possibly mask the underlying disease process. The effect that symptomatic
suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, neuroleptics should be prescribed in a manner that
is most likely to minimize the occurrence of tardive dyskinesia. Chronic
neuroleptic treatment should generally be reserved for patients who suffer from
a chronic illness that, 1) is known to respond to neuroleptic drugs, and, 2) for
whom alternative, equally effective, but potentially less harmful treatments are
Not available or appropriate. In patients who do require chronic treatment, the
smallest dose and the shortest duration of treatment producing a satisfactory
clinical response should be sought. The need for continued treatment should be
reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on neuroleptics,
drug discontinuation should be considered. However, some patients may require
treatment despite the presence of the syndrome.
For further information about the description of tardive dyskinesia and its
clinical detection, please refer to the sections on PRECAUTIONS and ADVERSE
REACTIONS.
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 and evidence of autonomic
instability (irregular pulse or blood pressure, tachycardia, diaphoresis and
cardiac dysrhythmias).
The diagnostic evaluation of patients with this syndrome is complicated. In
arriving at a diagnosis, it is important to identify cases where the clinical
presentation includes both serious medical illness (e.g., pneumonia, systemic
infection, etc.) and untreated or inadequately treated extrapyramidal signs and
symptoms (EPS). Other important considerations in the differential diagnosis
include central anticholinergic toxicity, heat stroke, drug fever and primary
central nervous system (CNS) pathology.
The management of NMS should include 1) immediate discontinuation of
antipsychotic drugs and other drugs not essential to concurrent therapy, 2)
intensive symptomatic treatment and medical monitoring, and 3) treatment of any
concomitant serious medical problems for which specific treatments are
available. There is no general agreement about specific pharmacological
treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the
potential reintroduction of drug therapy should be carefully considered. The
patient should be carefully monitored, since recurrences of NMS have been
reported.
An encephalopathic syndrome (characterized by weakness, lethargy, fever,
tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated
serum enzymes, BUN and FBS) has occurred in a few patients treated with lithium
plus a neuroleptic. In some instances, the syndrome was followed by irreversible
brain damage. Because of a possible causal relationship between these events and
the concomitant administration of lithium and neuroleptics, patients receiving
such combined therapy should be monitored closely for early evidence of
neurologic toxicity and treatment discontinued promptly if such signs appear.
This encephalopathic syndrome may be similar to or the same as neuroleptic
malignant syndrome (NMS).
Megatil (chlorpromazine) ampuls and multi-dose vials contain sodium bisulfite
and sodium sulfite, sulfites that may cause allergic-type reactions including
anaphylactic symptoms and life-threatening or less severe asthmatic episodes in
certain susceptible people. The overall prevalence of sulfite sensitivity in the
general population is unknown and probably low. Sulfite sensitivity is seen more
frequently in asthmatic than in nonasthmatic people.
Patients with bone marrow depression or who have previously demonstrated a
hypersensitivity reaction (e.g., blood dyscrasias, jaundice) with a
phenothiazine should not receive any phenothiazine, including Megatil, unless
in the judgment of the physician the potential benefits of treatment outweigh
the possible hazard.
Megatil may impair mental and/or physical abilities, especially during the
first few days of therapy. Therefore, caution patients about activities
requiring alertness (e.g., operating vehicles or machinery).
The use of alcohol with this drug should be avoided due to possible additive
effects and hypotension.
Megatil may counteract the antihypertensive effect of guanethidine and related
compounds.
USAGE IN PREGNANCY: Safety for the use of Megatil (chlorpromazine) during
pregnancy has not been established. Therefore, it is not recommended that the
drug be given to pregnant patients except when, in the judgment of the
physician, it is essential. The potential benefits should clearly outweigh
possible hazards. There are reported instances of prolonged jaundice,
extrapyramidal signs, hyperreflexia or hyporeflexia in newborn infants whose
mothers received phenothiazines.
Reproductive studies in rodents have demonstrated potential for embryotoxicity,
increased neonatal mortality and nursing transfer of the drug. Tests in the
offspring of the drug-treated rodents demonstrate decreased performance. The
possibility of permanent neurological damage cannot be excluded.
NURSING MOTHERS: There is evidence that chlorpromazine is excreted in the breast
milk of nursing mothers. Because of the potential for serious adverse reactions
in nursing infants from chlorpromazine, 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.
PRECAUTIONS:
GENERAL
Given the likelihood that some patients exposed chronically to neuroleptics will
develop tardive dyskinesia, it is advised that all patients in whom chronic use
is contemplated be given, if possible, full information about this risk. The
decision to inform patients and/or their guardians must obviously take into
account the clinical circumstances and the competency of the patient to
understand the information provided.
Megatil (chlorpromazine) should be administered cautiously to persons with
cardiovascular, liver or renal disease. There is evidence that patients with a
history of hepatic encephalopathy due to cirrhosis have increased sensitivity to
the C.N.S. effects of Megatil (i.e., impaired cerebration and abnormal slowing
of the EEG).
Because of its C.N.S. depressant effect, Megatil should be used with caution
in patients with chronic respiratory disorders such as severe asthma, emphysema
and acute respiratory infections, particularly in children (1 to 12 years of
age).
Because Megatil can suppress the cough reflex, aspiration of vomitus is
possible.
Megatil (chlorpromazine) prolongs and intensifies the action of CNS
depressants such as anesthetics, barbiturates and narcotics. When Megatil is
administered concomitantly, about 1/4 to 1/2 the usual dosage of such agents is
required. When Megatil is not being administered to reduce requirements of CNS
depressants, it is best to stop such depressants before starting Megatil
treatment. These agents may subsequently be reinstated at low doses and
increased as needed.
Note: Megatil does Not intensify the anticonvulsant action of barbiturates.
Therefore, dosage of anticonvulsants, including barbiturates, should Not be
reduced if Megatil is started. Instead, start Megatil at low doses and
increase as needed.
Use with caution in persons who will be exposed to extreme heat,
organophosphorus insecticides, and in persons receiving atropine or related
drugs.
Neuroleptic drugs elevate prolactin levels; the elevation persists during
chronic administration. Tissue culture experiments indicate that approximately
1/3 of human breast cancers are prolactin-dependent In Vitro, a factor of
potential importance if the prescribing of these drugs is contemplated in a
patient with a previously detected breast cancer. Although disturbances such as
galactorrhea, amenorrhea, gynecomastia and impotence have been reported, the
clinical significance of elevated serum prolactin levels is unknown for most
patients. An increase in mammary neoplasms has been found in rodents after
chronic administration of neuroleptic drugs. Neither clinical nor epidemiologic
studies conducted to date, however, have shown an association between chronic
administration of these drugs and mammary tumorigenesis; the available evidence
is considered too limited to be conclusive at this time.
Chromosomal aberrations in spermatocytes and abnormal sperm have been
demonstrated in rodents treated with certain neuroleptics.
As with all drugs which exert an anticholinergic effect, and/or cause mydriasis,
chlorpromazine should be used with caution in patients with glaucoma.
Chlorpromazine diminishes the effect of oral anticoagulants.
Phenothiazines can produce alpha-adrenergic blockade.
Chlorpromazine may lower the convulsive threshold; dosage adjustments of
anticonvulsants may be necessary. Potentiation of anticonvulsant effects does
not occur. However, it has been reported that chlorpromazine may interfere with
the metabolism of Dilantin(R)* and thus precipitate Dilantin toxicity.
----------
*phenytoin, Parke-Davis.
----------
Concomitant administration with propranolol results in increased plasma levels
of both drugs.
Thiazide diuretics may accentuate the orthostatic hypotension that may occur
with phenothiazines.
The presence of phenothiazines may produce false- positive phenylketonuria (PKU)
test results.
Drugs which lower the seizure threshold, including phenothiazine derivatives,
should not be used with Amipaque(R)**. As with other phenothiazine derivatives,
Megatil should be discontinued at least 48 hours before myelography, should
not be resumed for at least 24 hours postprocedure, and should not be used for
the control of nausea and vomiting occurring either prior to myelography or
postprocedure with Amipaque.
----------
**metrizamide, Sanofi-Winthrop Pharmaceuticals.
----------
LONG-TERM THERAPY: To lessen the likelihood of adverse reactions related to
cumulative drug effect, patients with a history of long-term therapy with
Megatil and/or other neuroleptics should be evaluated periodically to decide
whether the maintenance dosage could be lowered or drug therapy discontinued.
ANTIEMETIC EFFECT: The antiemetic action of Megatil may mask the signs and
symptoms of overdosage of other drugs and may obscure the diagnosis and
treatment of other conditions such as intestinal obstruction, brain tumor and
Reye's syndrome. (See WARNINGS.)
When Megatil is used with cancer chemotherapeutic drugs, vomiting as a sign of
the toxicity of these agents may be obscured by the antiemetic effect of
Megatil.
ABRUPT WITHDRAWAL: Like other phenothiazines, Megatil (chlorpromazine) is not
known to cause psychic dependence and does not produce tolerance or addiction.
There may be, however, following abrupt withdrawal of high-dose therapy, some
symptoms resembling those of physical dependence such as gastritis, nausea and
vomiting, dizziness and tremulousness. These symptoms can usually be avoided or
reduced by gradual reduction of the dosage or by continuing concomitant anti-
parkinsonism agents for several weeks after Megatil is withdrawn.
DRUG INTERACTIONS:
SEE PRECAUTIONS
ADVERSE REACTIONS:
Note: Some adverse effects of Megatil may be more likely to occur, or occur
with greater intensity, in patients with special medical problems, e.g.,
patients with mitral insufficiency or pheochromocytoma have experienced severe
hypotension following recommended doses.
DROWSINESS, usually mild to moderate, may occur, particularly during the first
or second week, after which it generally disappears. If troublesome, dosage may
be lowered.
JAUNDICE: Overall incidence has been low, regardless of indication or dosage.
Most investigators conclude it is a sensitivity reaction. Most cases occur
between the second and fourth weeks of therapy. The clinical picture resembles
infectious hepatitis, with laboratory features of obstructive jaundice, rather
than those of parenchymal damage. It is usually promptly reversible on
withdrawal of the medication; however, chronic jaundice has been reported.
There is no conclusive evidence that preexisting liver disease makes patients
more susceptible to jaundice. Alcoholics with cirrhosis have been successfully
treated with Megatil (chlorpromazine) without complications. Nevertheless, the
medication should be used cautiously in patients with liver disease. Patients
who have experienced jaundice with a phenothiazine should not, if possible, be
reexposed to Megatil or other phenothiazines.
If fever with grippe-like symptoms occurs, appropriate liver studies should be
conducted. If tests indicate an abnormality, stop treatment.
Liver function tests in jaundice induced by the drug may mimic extrahepatic
obstruction; withhold exploratory laparotomy until extrahepatic obstruction is
confirmed.
HEMATOLOGICAL DISORDERS, including agranulocytosis, eosinophilia, leukopenia,
hemolytic anemia, aplastic anemia, thrombocytopenic purpura and pancytopenia
have been reported.
AGRANULOCYTOSIS--Warn patients to report the sudden appearance of sore throat or
other signs of infection. If white blood cell and differential counts indicate
cellular depression, stop treatment and start antibiotic and other suitable
therapy.
Most cases have occurred between the fourth and tenth weeks of therapy; patients
should be watched closely during that period.
Moderate suppression of white blood cells is not an indication for stopping
treatment unless accompanied by the symptoms described above.
CARDIOVASCULAR:
HYPOTENSIVE EFFECTS--Postural hypotension, simple tachycardia, momentary
fainting and dizziness may occur after the first injection; occasionally after
subsequent injections; rarely, after the first oral dose. Usually recovery is
spontaneous and symptoms disappear within 1/2 to 2 hours. Occasionally, these
effects may be more severe and prolonged, producing a shock-like condition.
To minimize hypotension after injection, keep patient lying down and observe for
at least 1/2 hour. To control hypotension, place patient in head-low position
with legs raised. If a vasoconstrictor is required, Levophed(R)*/* and Neo-
Synephrine(R)**/* are the most suitable. Other pressor agents, including
epinephrine, should not be used as they may cause a paradoxical further lowering
of blood pressure.
----------
*/*norepinephrine bitartrate, Sanofi Winthrop Pharmaceuticals.
**/*phenylephrine hydrochloride, Sanofi Winthrop Pharmaceuticals.
----------
EKG CHANGES--particularly nonspecific, usually reversible Q and T wave
distortions--have been observed in some patients receiving phenothiazine
tranquilizers, including Megatil (chlorpromazine).
Note: Sudden death, apparently due to cardiac arrest, has been reported.
CNS REACTIONS:
NEUROMUSCULAR (EXTRAPYRAMIDAL) REACTIONS- -Neuromuscular reactions include
dystonias, motor restlessness, pseudo-parkinsonism and tardive dyskinesia, and
appear to be dose-related. They are discussed in the following paragraphs:
DYSTONIAS: Symptoms may include spasm of the neck muscles, sometimes progressing
to acute, reversible torticollis; extensor rigidity of back muscles, sometimes
progressing to opisthotonos; carpopedal spasm, trismus, swallowing difficulty,
oculogyric crisis and protrusion of the tongue.
These usually subside within a few hours, and almost always within 24 to 48
hours after the drug has been discontinued.
In Mild Cases, reassurance or a barbiturate is often sufficient. In Moderate
Cases, barbiturates will usually bring rapid relief. In More Severe Adult Cases,
the administration of an anti- parkinsonism agent, except levodopa, usually
produces rapid reversal of symptoms. In Children, (1 to 12 years of age)
reassurance and barbiturates will usually control symptoms. (Or, parenteral
Benadryl(R)**/** may be useful. See Benadryl prescribing information for
appropriate children's dosage.) If appropriate treatment with anti-parkinsonism
agents or Benadryl fails to reverse the signs and symptoms, the diagnosis should
be reevaluated.
----------
**/**diphenhydramine hydrochloride, Parke-Davis.
----------
Suitable supportive measures such as maintaining a clear airway and adequate
hydration should be employed when needed. If therapy is reinstituted, it should
be at a lower dosage. Should these symptoms occur in children or pregnant
patients, the drug should not be reinstituted.
MOTOR RESTLESSNESS: Symptoms may include agitation or jitteriness and sometimes
insomnia. These symptoms often disappear spontaneously. At times these symptoms
may be similar to the original neurotic or psychotic symptoms. Dosage should not
be increased until these side effects have subsided.
If these symptoms become too troublesome, they can usually be controlled by a
reduction of dosage or change of drug. Treatment with anti- parkinsonian agents,
benzodiazepines or propranolol may be helpful.
PSEUDO-PARKINSONISM: Symptoms may include: mask- like facies, drooling, tremors,
pillrolling motion, cogwheel rigidity and shuffling gait. In most cases these
symptoms are readily controlled when an anti-parkinsonism agent is administered
concomitantly. Anti-parkinsonism agents should be used only when required.
Generally, therapy of a few weeks to 2 or 3 months will suffice. After this time
patients should be evaluated to determine their need for continued treatment.
(Note: Levodopa has not been found effective in neuroleptic-induced pseudo-
parkinsonism.) Occasionally it is necessary to lower the dosage of Megatil
(chlorpromazine) or to discontinue the drug.
TARDIVE DYSKINESIA: As with all antipsychotic agents, tardive dyskinesia may
appear in some patients on long-term therapy or may appear after drug therapy
has been discontinued. The syndrome can also develop, although much less
frequently, after relatively brief treatment periods at low doses. This syndrome
appears in all age groups. Although its prevalence appears to be highest among
elderly patients, 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. The symptoms are persistent and in
some patients appear to be irreversible. The syndrome is characterized by
rhythmical involuntary movements of the 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. In
rare instances, these involuntary movements of the extremities are the only
manifestations of tardive dyskinesia. A variant of tardive dyskinesia, tardive
dystonia, has also been described.
There is no known effective treatment for tardive dyskinesia; anti-parkinsonism
agents do not alleviate the symptoms of this syndrome. If clinically feasible,
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, the syndrome may be
masked.
It has been reported that fine vermicular movements of the tongue may be an
early sign of the syndrome and if the medication is stopped at that time the
syndrome may not develop.
ADVERSE BEHAVIORAL EFFECTS--Psychotic symptoms and catatonic-like states have
been reported rarely.
OTHER CNS EFFECTS--Neuroleptic Malignant Syndrome (NMS) has been reported in
association with antipsychotic drugs (see WARNINGS.)
Cerebral edema has been reported.
Convulsive seizures (Petit Mal and Grand Mal) have been reported, particularly
in patients with EEG abnormalities or history of such disorders.
Abnormality of the cerebrospinal fluid proteins has also been reported.
ALLERGIC REACTIONS of a mild urticarial type or photosensitivity are seen. Avoid
undue exposure to sun. More severe reactions, including exfoliative dermatitis,
have been reported occasionally.
Contact dermatitis has been reported in nursing personnel; accordingly, the use
of rubber gloves when administering Megatil liquid or injectable is
recommended.
In addition, asthma, laryngeal edema, angioneurotic edema and anaphylactoid
reactions have been reported.
ENDOCRINE DISORDERS: Lactation and moderate breast engorgement may occur in
females on large doses. If persistent, lower dosage or withdraw drug. False-
positive pregnancy tests have been reported, but are less likely to occur when a
serum test is used. Amenorrhea and gynecomastia have also been reported.
Hyperglycemia, hypoglycemia and glycosuria have been reported.
AUTONOMIC REACTIONS: Occasional dry mouth; nasal congestion; nausea;
obstipation; constipation; adynamic ileus; urinary retention; priapism; miosis
and mydriasis, atonic colon, ejaculatory disorders/impotence.
SPECIAL CONSIDERATIONS IN LONG-TERM THERAPY: Skin pigmentation and ocular
changes have occurred in some patients taking substantial doses of Megatil
(chlorpromazine) for prolonged periods.
SKIN PIGMENTATION--Rare instances of skin pigmentation have been observed in
hospitalized mental patients, primarily females who have received the drug
usually for 3 years or more in dosages ranging from 500 mg to 1500 mg daily. The
pigmentary changes, restricted to exposed areas of the body, range from an
almost imperceptible darkening of the skin to a slate gray color, sometimes with
a violet hue. Histological examination reveals a pigment, chiefly in the dermis,
which is probably a melanin-like complex. The pigmentation may fade following
discontinuance of the drug.
OCULAR CHANGES--Ocular changes have occurred more frequently than skin
pigmentation and have been observed both in pigmented and nonpigmented patients
receiving Megatil (chlorpromazine) usually for 2 years or more in dosages of
300 mg daily and higher. Eye changes are characterized by deposition of fine
particulate matter in the lens and cornea. In more advanced cases, star- shaped
opacities have also been observed in the anterior portion of the lens. The
nature of the eye deposits has not yet been determined. A small number of
patients with more severe ocular changes have had some visual impairment. In
addition to these corneal and lenticular changes, epithelial keratopathy and
pigmentary retinopathy have been reported. Reports suggest that the eye lesions
may regress after withdrawal of the drug.
Since the occurrence of eye changes seems to be related to dosage levels and/or
duration of therapy, it is suggested that long-term patients on moderate to high
dosage levels have periodic ocular examinations.
ETIOLOGY--The etiology of both of these reactions is not clear, but exposure to
light, along with dosage/duration of therapy, appears to be the most significant
factor. If either of these reactions is observed, the physician should weigh the
benefits of continued therapy against the possible risks and, on the merits of
the individual case, determine whether or not to continue present therapy, lower
the dosage, or withdraw the drug.
OTHER ADVERSE REACTIONS: Mild fever may occur after large I.M. doses.
Hyperpyrexia has been reported. Increases in appetite and weight sometimes
occur. Peripheral edema and a systemic lupus erythematosus-like syndrome have
been reported.
Note: There have been occasional reports of sudden death in patients receiving
phenothiazines. In some cases, the cause appeared to be cardiac arrest or
asphyxia due to failure of the cough reflex.
Flupenthixol is less likely to cause sedation, but extrapyramidal disor-
ders are more frequent.
Sudden death. A report of sudden death in 3 patients who
had received depot injections of flupenthixol decanoate.
Flupenthixol is not recommended in states of excite-
ment or overactivity, including mania.
Porphyria. Flupenthixol was considered to be unsafe in pa-
tients with acute porphyria because it has been shown to be
porphyrinogenic in animals or in-vitro systems.
Pharmacokinetics
Flupenthixol is readily absorbed from the gastro-in-
testinal tract and is probably subject to first-pass me-
tabolism in the gut wall. It is also extensively
metabolised in the liver and is excreted in the urine
and faeces in the form of numerous metabolites;
there is evidence of enterohepatic recycling. Owing
to the first-pass effect, plasma concentrations fol-
lowing oral administration are much lower than
those following estimated equivalent doses of the in-
tramuscular depot preparation. Moreover, there is
very wide intersubject variation in plasma concen-
trations of flupenthixol, but in practice, no simple
correlation has been found between plasma concen-
trations of flupenthixol and its metabolites. and the
therapeutic effect. Paths of metabolism of flupen-
thixol include sulphoxidation, side-chain N-
dealkylalion. and glucuronic acid conjugation. It is
widely distributed in the body, and crosses the
blood-brain barrier. Flupenthixol passes the placen-
tal barrier and small amounts have been detected in
breast milk.
The decanoate ester of flupenthixol is very slowly
absorbed from the site of intramuscular injection
and is therefore suitable for depot injection. It is
gradually released into the blood stream where it is
rapidly hydrolysed to flupenthixol.
Uses and Administration
Flupenthixol is a thioxanthene antipsychotic with
general properties similar to those of the phenothi-
azine, chlorpromazine. It has a piperazine
side-chain. Flupenthixol is used mainly in the treat-
ment of schizophrenia and other psychoses.
Unlike chlorpromazine. a certain activating effect
has been ascribed to flupenthixol and, accordingly,
it is not indicated in overactive, including manic. pa-
tients, Flupenthixol has also been used for its antide-
pressant properties.
Flupenthixol is administered as the hydrochloride
by mouth or as the longer-acting decanoate ester by
deep intramuscular injection.
The usual initial dose of the hydrochloride for the
treatment of psychoses is the equivalent of 3 to 9 mg
of flupenthixol twice daily adjusted according to the
response: the maximum recommended dose is a to-
tal of 18 mg daily. The initial dose in elderly and de-
bilitated patients may need to be reduced to a quarter
or a half of the normal starting dose. The long-acting
decanoate preparation available in the UK contains
flupenthixol as the cis(Z)-isomer (see Action, be-
low) and doses are expressed in terms of the amount
of cis(Z)-flupenthixol decanoate. It should be given
by deep intramuscular injection in an initial test
dose of 20 mg, as I mL of a 2%oily solution. Then
after at least 7 days and according .to the patient's
response, this may be followed by doses of 20 to
40 mg at intervals of 2 to 4 weeks. Shorter dosage
intervals or greater amounts may be required ac-
cording to the patient's response. The initial dose in
elderly and debilitated patients may need to be re-
duced to a quarter or a half of the normal starting
dose. If doses greater than 40 mg are considered.
necessary they should be divided between 2 separate
injection sites. Another means of reducing the vol-
ume of fluid to be injected in patients requiring high-
dose therapy with flupenthixol decanoate is to give
an injection containing 100 or 200 mg of the de-
canoate per mL (10 or 20%). The usual maintenance
dose is between 50 mg every 4 weeks and 300 mg
every 2 weeks but doses of up to 400 mg weekly
have been given in severe or resistant conditions.
Flupenthixol has also been given as the hydrochlo-
ride by mouth, for the treatment of mild to moderate
depression, with or without anxiety. The usual ini-
tial dose, expressed in terms of the equivalent
amount of flupenthixol. is I mg (0.5 mg in the eld-
erly) daily, increased after I week to 2 mg (I mg in
the elderly) and then to a maximum of 3 mg (2 mg
in the elderly) daily in divided doses. The last dose
of the day should be given no later than 4 p.m. and
if no effect has been noted within I week of admin-
istration of the maximum dose, the treatment should
be withdrawn.
Action. Patients with acute schizophrenic illnesses taking
alpha-flupenthixol ((Z)-flupenthixol or cis-flupenthixol]
improved more after 3 weeks than patients who were taking equal
doses of U-flupenthixol ((E)-flupenthixol or trans-
flupenthixol] or a placebo. The alpha-isomer had more effect on
the positive symptoms of the disease: this difference was less
apparent for the
negative symptoms. The difference in activity between the
isomers was attributed lo the greater dopamine-receptor
blocking activity of the n-isomer rather than to differences in
distribution.
Cocaine withdrawal. Depot flupenthixol decanoate has
produced some promising results as an aid in reducing co-
caine usage.
Depression. Flupenthixol is not one of the drugs usually
considered for first-line treatment of depression but there are
some small studies claiming favourable antidepressant efficacy
for flupenthixol compared with other drugs.
FLUPENTHIXOL TABLETS
A potent non-sedating neuroleptic
Composition
Each coated tablet contains flupenthixol
dihydrochloride corresponding to 3 mg
flupenthixol.
The tablets contain lactose. Colour: Yellow
iron oxide.
Pharmacological Information
Pharmacological effects and mode of
action
Fluanxol is a thioxanthene derivative with
pronounced antipsychotic, alerting and
anxiolytic effects.
The antipsychotic effect of neuroleptics is
normally related to their dopamine
receptor blocking effect, which seems to
release a chain reaction as other
transmitter systems are influenced as well.
In low to moderate dosages (up to 25 mg
daily) Fluanxol is non-sedating, while an
unspecific sedative effect may be
anticipated when higher doses are
administered. Fluanxol has within the
whole dosage range a pronounced
anxiolytic effect.
The effect on hallucinations, paranoid
delusions and other psychotic symptoms
appears only when the drug is given in
dosages of 3 mg or more daily: the
antipsychotic effect increases with
increasing dosages. Fluanxol has
disinhibiting (antiautistic and activating)
and mood elevating properties making
apathetic, depressed, withdrawn and poorly
motivated patients more alert, more
co-operative and more actively seeking
social contact.
In the maintenance treatment of psychotic
patients especially when compliance with
oral medication is a problem it may be
the long-acting depot preparation, Fluanxol
Depot, which is administered
intramuscularly at intervals of 2 to 4 weeks.
Pharmacokinetics
The bioavailability after oral administration
of flupenthixol is about 40% and maximum
serum concentration is reached in about 4
hours. Flupenthixol in small amounts
crosses the placental barrier. Flupenthixol
is excreted in small amounts with the milk.
The metabolites are devoid of neuroleptic
activity.The excretion proceeds mainly with
feces but also to some degree with the
urine. The biological half-life is about 35
hours.
Clinical Information
Indications
Schizophrenia and allied psychosis,
especially with symptoms such as
hallucinations, paranoid delusions and
thought disturbances along with apathy,
anergy and withdrawal.
Contraindications
Acute alcohol, barbiturate, and opiate
intoxications, comatose states. Not
recommended for excitable or overactive
patients, since its activating effect may lead
to exaggeration of these characteristics.
Adverse effects
Neurological: Extrapyramidal symptoms
may occur, especially during the early phase
of treatment. In most cases these side
effects can be satisfactorily controlled by
reduction of dosage and/or anti
parkinsonian drugs. The routine
prophylactic use of antiparkinsonian
medication is not recommended. Tardive
dyskinesias may occur very occasionally in
patients on long-term therapy. Anti
parkinsonian drugs do not alleviate these
symptoms. Reduction in dosage, or, if
possible, discontinuation of therapy is
recommended. Psychic: Transient insomnia,
especially when the patient is switched over
from sedative neuroleptics.At high dosage
a sedative effect may occur in the
occasional patient. Autonomic and
cardiovascular:Very rare in the therapeutic
dosage range.
Liver: Transient slight alterations in liver
function tests may occur.
Precautions
Patients on long-term therapy should be
monitored carefully. Fluanxol should be
used with caution in patients with
convulsive disorders or advanced hepatic,
or cardiovascular disease. If previously the
patient has been treated with neuroleptics
with sedative effect, these should be
withdrawn gradually.
Use during pregnancy and lactation
Fluanxol should preferably not be given
during pregnancy and lactation.
Drug interactions
Fluanxol in high doses may enhance the
response to alcohol and the effects of
barbiturates and other CNS depressants.
Fluanxol should not be given concomitantly
with guanethidine or similar acting
compounds, since neuroleptics may block
the antihypertensive effect of these
compounds. Fluanxol may reduce the effect
of levodopa and adrenergic drug, and
concomitant use of metoclopramide and
piperazine increases the risk of
extrapyrarnidal symptoms.
Dosage regimen
Adults:
The dosage should be individually adjusted
according to the condition. Ingeneral, small
doses should be used initially and increased
to the optimal effective level as rapidly as
possible based on the therapeutic response.
Initially 3-15 mg/day orally divided in two
or three daily doses, increased, if necessary,
to 40 mp/dav
The maintenance dose, usually 5-20 rng/
day, can be given as a single morning dose.
Overdose
Symptoms: Somnolence, coma,
extrapyramidal symptoms, convulsions,
hypotension, shock, hyper- or hypothermia.
Treatment: Symptomatic and supportive.
Gastric lavage should be carried out as soon
as possible and activated charcoal may be
administered. Measures aimed at
supporting the respiratory and
cardiovascular systems should be instituted.
Epinephrine (adrenaline) should not be
used, as further lowering of blood pressure
may result. Convulsions may be treated
with diazepam and extrapyramidal
symptoms with biperiden.
Special warnings
The neuroleptic malignant syndrome
(NMS) is a rare but potentially fatal
complication of the use of neuroleptic
drugs. Core features of NMS are
hyperthermia, muscular rigidity and
fluctuating consciousness along with
autonomic dysfunction (labile blood
pressure, tachycardia, diaphoresis). Aside
from immediate cessation of t~e
neuroleptic medication the use of general
supportive measures and symptomatic
treatment are vital.
Effects on ability to drive or operate
machinery
Although Fluanxol is a non-sedating drug
the ability to drive or operate machinery
may be affected. Therefore caution should
be exercised initially until the individuals
rpartinn to treatment is known