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Serenace – Product information
PRODUCT INFORMATION

NAME OF THE DRUG
SERENACE Tablets, Liquid and Ampoules contain Haloperidol.
Haloperidol (CAS- 52 – 86 – 8) has the following chemical structure:

DESCRIPTION
.
Haloperidol is a psychotropic drug of the butyrophenone series and is not related chemically to
phenothiazines. Haloperidol is chemically described as 4-[4-(4-Chlorophenyl)-4-hydroxy-1-
piperidinyl]-1-(4-fluorophenyl)-1-butanone. Its molecular formula is C21H23ClFNO2 and the
molecular weight is 375.90.
Haloperidol presents as an odourless, tasteless, white to faintly yellowish amorphous or
microcrystalline powder. It is insoluble in water but sparingly soluble in alcohol. Solutions are
affected by light and can become discoloured after a few hours exposure; the discolouration is
prevented by storage in brown glass containers.

Excipients:

SERENACE tablets contain the following excipients: lactose, starch – maize, acacia,
magnesium stearate, calcium hydrogen phosphate. SERENACE 0.5 mg tablets also contain
quinoline yellow CI47005 and green s CI44090. SERENACE 5 mg tablets also contain brilliant
scarlet 4R CI16255.
SERENACE liquid contains the following excipients: lactic acid, water, methyl
hydroxybenzoate and propyl hydroxybenzoate as preservatives.

SERENACE ampoules contain the following excipients: (S)-lactic acid (5 mg/mL ampoules),
lactic acid ( 10 mg/mL & 20 mg/2mL ampoules) sodium hydroxide and water for injections.
PHARMACOLOGY
Actions
Although the complex mechanism of the therapeutic effect of haloperidol is not clearly
established, it is known that it produces a selective effect on the central nervous system by
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competitive blockade of postsynaptic dopamine (D2) receptors in the mesolimbic dopaminergic
system, and an increased turnover of brain dopamine to produce its tranquillising effects. With
subchronic therapy, depolarisation blockade, or diminished firing rate of the dopamine neurone
(decreased release) along with D2 postsynaptic blockade results in the antipsychotic action.
Blockade of dopamine receptors in the nigrostriatal dopamine pathway produces extrapyramidal
motor reactions; blockade of dopamine receptors in the tuberoinfundibular system decreases
growth hormone release and increases prolactin release by the pituitary. There is also some
blockade of alpha-adrenergic receptors of the autonomic system.
Pharmacokinetics
Absorption: Haloperidol is rapidly absorbed from the gastrointestinal tract following oral
administration but appears to undergo first-pass metabolism in the liver. Peak plasma levels of
haloperidol occur within two to six hours of oral dosing and about twenty minutes after
intramuscular administration.
Distribution: Haloperidol is approximately 92% bound to plasma proteins. The distribution of
haloperidol into the human body tissues and fluids has not been fully determined. In animal
studies, the drug is mainly distributed into the liver, with lower concentrations being distributed
into the brain, lungs, kidneys, spleen and heart. Haloperidol is also distributed into breast milk.

Metabolism: Metabolism of haloperidol occurs in the liver. Haloperidol is metabolised by
oxidative N-dealkylation of the piperidine nitrogen to form flurophenylcarbonic acids and
piperidine metabolites which appeared to be inactive, and by reduction of the butyrophenone
carbonyl to the carbinol, forming the alcohol hydroxyhaloperidol. Limited data suggest that
reduced metabolite, hydroxyhaloperidol, has some pharmacological activity, although its
activity appears to be less than that of haloperidol. There is evidence of enterohepatic recycling
and due to the influence of the first-pass effect of metabolism in the liver, plasma concentrations
following oral administration are lower than those following intramuscular administration.
Haloperidol and its metabolites are excreted in the urine, via the bile and in the faeces. The
plasma half-life of haloperidol after oral administration ranges from 12 to 38 hours. Studies have
shown that CYP3A4 and/or CYP2D6 are involved in the metabolic biotransformation of
haloperidol.

Excretion: The mean plasma half-life (terminal elimination) has been determined as 20.7 ± 4.6
(SD) hours, and although excretion begins rapidly, only 24 to 60% of ingested radioactive drug
is excreted (mainly as metabolites in urine; some in faeces) by the end of the first week, and
very small but detectable levels of radioactivity persist in the blood and are excreted for several
weeks after dosing. In humans, haloperidol glucuronide is a major metabolite excreted in the
urine. About 1% of the ingested dose is recovered unchanged in the urine. The slow excretion
may be related to a high degree of plasma protein binding. Haloperidol is highly lipid-soluble
and may remain in fatty tissue for some weeks.
INDICATIONS

Chronic Therapy:
The management of manifestations of psychotic disorders such as schizophrenia, psychosis due to organic brain damage or mental deficiency, senile psychosis, the manic phase of manic depressive illness, Gilles de la Tourette syndrome. Serenace – Product information


Short Term Therapy:
The treatment of acute alcoholism for the relief of delusions, hallucinations and confused states,
and for the control of accompanying tremulousness and aggressive behaviour.
In the treatment of intractable nausea and vomiting associated with radiation or malignancy and
not responding to other therapy. Neuroleptanalgesia.
CONTRAINDICATIONS
Comatose states; in the presence of central nervous system depression due to alcohol and other
depressant drugs; severe depressive states; previous spastic diseases; senile patients with pre-
existing parkinsonian symptoms; Parkinson's disease; known hypersensitivity to haloperidol; in
patients with manifest occult lesions of the basal ganglia; and in patients with prolactin
dependent tumours. Serenace is also contraindicated in patients who are sensitive to haloperidol
or other ingredients in the dosage form (See DESCRIPTION).
PRECAUTIONS

Neuroleptic Malignant Syndrome (NMS):
A potentially fatal syndrome known as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of this syndrome are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and autonomic instability (irregular pulse or blood pressure). Additional signs may include elevated creatine phosphokinase (CPK), myoglobinuria and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. The management of NMS should include immediate discontinuation of antipsychotic drugs, intensive symptomatic treatment and monitoring, and treatment of any serious medical problems for which specific treatments are available. Dantrolene and bromocriptine have been used for the treatment of NMS. The reintroduction of antipsychotic therapy after recovery from NMS should be carefully considered since recurrences of NMS have been reported. Haloperidol should be used cautiously in patients exposed to high temperatures. Hyperpyrexia and heat stroke have been reported to be associated with haloperidol, not associated with other manifestations of NMS (See ADVERSE REACTIONS). Tardive Dyskinesia:
A syndrome consisting of potentially irreversible, involuntary dyskinetic movements may develop in patients treated with antipsychotic drugs (See ADVERSE REACTIONS). Although the dyskinetic syndrome may remit partially or completely if the medication is withdrawn, it is irreversible in some patients. The prevalence of this syndrome appears to be highest among the elderly, particulary elderly women. At the present time, it is uncertain whether neuroleptic drugs differ in their potential to cause tardive dyskinesia. Since there is a significant prevalence of this syndrome associated with the use of neuroleptic drugs, and since there is no known effective treatment, chronic use of these drugs should generally be restricted to patients for whom there is no alternative therapy available with better risk acceptability. The risk of developing irreversible tardive dyskinesias Serenace – Product information
increases the duration of treatment and total cumulative doses, although in some instances, tardive dyskinesia may develop after relatively short periods of treatment at low doses. The risk of developing tardive dyskinesia may therefore be minimised by reducing the dose of the neuroleptic drug used and its duration of administration, consistent with the effective management of the patient’s condition. There is no known effective treatment. If manifestations of tardive dyskinesia are noted, the neuroleptic drug should be discontinued. QT Prolongation & Torsades de Pointe:
Higher doses and intravenous administration of haloperidol appear to be associated with a higher risk of QT prolongation and Torsades de Pointes. Rare cases of sudden death have been reported even in the absence of predisposing factors. It is advisable to be particular cautious in treating patients using haloperidol who: • have other QT-prolonging conditions, including electrolyte imbalance (particularly hypokalaemia, hypocalcaemia or hypomagnesaemia), • have underlying cardiac abnormalities, hypothyroidism, familial long QT syndrome, or patients with risk factors for ventricular arrhythmias such as cardiac disease, subarachnoid haemorrhage, starvation and alcohol abuse, • are taking drugs which are known to prolong the QT interval ( see INTERACTIONS) Because of this risk of Torsades de Pointes and QT prolongation, ECG monitoring is
recommended if haloperidol is given intravenously.
Alcoholism, active:
CNS depression may be potentiated and risk of stroke may be increased. Increased hypotensive
effects and the potential for alcohol intoxication may also occur.

Severe Cardiovascular diseases:
Haloperidol in therapeutic doses does not usually affect blood pressure significantly but care
should be exercised in patients with severe cardiovascular disorders or being treated with
antihypertensive drugs because of the possibility of unexpected hypotension, and/or
precipitation of angina. Severe or prolonged hypotension may require vasopressors. Adrenaline
should not be used since haloperidol may block its vasopressor activity and cause further
decrease in blood pressure. Therefore, noradrenaline or metaraminol should be used instead.
Anginal pain may be provoked in patients with ischaemic heart disease.
Caution should be observed in patients with arteriosclerosis who may have occult lesions of the
basal ganglia (See CONTRAINDICATIONS).

Epilepsy:
Haloperidol may be given to epileptics but adequate anticonvulsant therapy should be
maintained as haloperidol may decrease the seizure threshold. It has been reported that
haloperidol can trigger seizures in known epileptics that were previously controlled. Caution is
therefore advised in patients receiving anticonvulsants, with a history of seizures, or with EEG
abnormalities and in conditions predisposing to convulsions (e.g. alcohol withdrawal and brain
damage).
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Glaucoma:
Glaucoma or a predisposition to glaucoma may be triggered because of the secondary
anticholinergic affects of haloperidol.

Hepatic function:
Impairment of hepatic function may alter metabolism of haloperidol.

Hyperthyroidism or Thyrotoxicosis:
Severe neurotoxicity such as rigidity and inability to walk or talk may result when these patients
are treated with antipsychotics. Thyrotoxic patients may be more prone to develop
extrapyramidal symptoms. Antipsychotic treatment in these patients should always be
accompanied by appropriate monitoring and therapy.

Pulmonary Insufficiency:
A number of cases of bronchopneumonia, sometimes fatal, have been reported following the use
of antipsychotic drugs. Haloperidol should be used with caution in patients with pulmonary
insufficiency such as asthma, emphysema or acute pulmonary infections. Haloperidol may cause
potentiation of breathing impairment and may possibly lead to ‘silent pneumonia’.
Renal Function Impairment:
Renal function impairment is mostly a concern at higher dosage since renal clearance of
unchanged drug is relatively low.

Urinary retention:
Urinary retention may be potentiated due to secondary anticholinergic effects.

Elderly or debilitated patients:
Elderly or debilitated patients receiving haloperidol should be observed for evidence of over-
sedation which, unless alleviated, could result in complications such as terminal stasis
pneumonia.

Bipolar mood disorders:
When haloperidol is used to control mania in cyclic disorders, a rapid mood swing to depression
may occur. As with all antipsychotic agents, haloperidol should not be used alone where
depression is predominant. It may be combined with antidepressants to treat those conditions in
which depression and psychosis coexist. However, it should be noted that haloperidol may
impair the metabolism of tricyclic antidepressants (See Interactions with other Drugs).

Dental:
Patients should be instructed in proper oral hygiene, including caution in use of regular
toothbrushes, dental floss and toothpicks as the leukopenic and thrombocytopenic effects of
haloperidol 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. The peripheral anticholinergic effects of haloperidol
may decrease or inhibit salivary flow, especially in middle-aged or elderly patients, thus
contributing to the development of caries, periodontal disease, oral candiasis and discomfort.

Other Precautions:
It should be borne in mind that the antiemetic action of haloperidol may relieve nausea and
vomiting, and so obscure the diagnosis of an underlying organic disorder which was causing
these symptoms.
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Ocular or cutaneous changes and decreases in serum cholesterol have occurred following
administration of a butyrophenone structurally related to haloperidol. In the same study which
reported these changes, haloperidol was shown to be free of these side effects–however, it is
advisable to carefully observe patients who receive haloperidol for a prolonged period in order
to identify any changes in the skin or eyes.

Haloperidol should be used with caution in patients with known allergies or with a history of
allergic reactions to drugs.
Caution is advised in patients receiving anticoagulants since an isolated instance of interference
occurred with the effects of one anticoagulant (phenindione).
If concomitant antiparkinson medication is required, it may have to be continued after
haloperidol is discontinued, because of the different excretion rates, Extrapyramidal symptoms
may occur if both haloperidol and the antiparkinson agent are discontinued simultaneously. The
physician should keep in mind the possible anticholinergic effects associated with antiparkinson
agents.

Caution is advised in patients with phaeochromocytoma.
In schizophrenia, the response to antipsychotic drug treatment may be delayed. If drugs are
withdrawn, recurrence of symptoms may not become apparent for several weeks or months.
With parenteral haloperidol in the acute situation, the use of a prophylactic anticholinergic agent
(e.g. benztropine) is recommended to cover the period of parenteral administration and for
several days afterwards.

There is considerable variation from patient to patient in the amount of medication required for
therapy. Close observation is required during dosage titration in order to minimise the risk of
overdosage or emergence of psychotic manifestations prior to the next dose. This is particularly
important in patients with impaired liver or renal function.

Carcinogenicity and Mutagenicity:
There was no evidence of carcinogenicity in Wistar rats following oral administration of
haloperidol for 24 months at doses up to 5 mg/kg/day (about five folds the maximum
recommended human dose based on body surface area). In female mice, there was a statistically
significant increase in mammary gland neoplasia and total tumour incidence following oral
administration of haloperidol at doses of 1.25 and 5 mg/kg/day (less than, and about twice, the
maximum recommended human dose based on body surface area), and a statistically significant
increase in pituitary gland neoplasia at 5 mg/kg/day. In male mice, there were no carcinogenic
effects, Haloperidol increases prolactin levels, which may affect human breast cancers, one-third
of which are prolactin dependent in vitro. Although clinical studies have not shown a clear
association between chronic administration of antipyschotic drugs (including haloperidol) and
an increase in the incidence of breast cancers, it may be a factor of importance when prescribing
haloperidol for patients in which breast cancer was previously detected.
Impairment of Fertility:
The animal data falls into three broad areas: female fertility, male fertility and effects in
offspring.
There are no human data on the effects of haloperidol on male or female fertility. In female rats,
administration of haloperidol induced oestrus cycle disruptions. In female mice, delays in the
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implantation, cleavages, and blastocele formation followed subcutaneous administration of
haloperidol prior to ovulation. In male rats, oral administration of haloperidol prior to mating
reduced fertility, increased pre-implantation loss, and induced histopathological changes in the
reproductive organs. Following intraperitoneal administration of haloperidol to female rats from
early pregnancy to weaning, the frequency of ejaculation in offspring was reduced.
Various dose levels were used in the above animal studies and in some studies a no effect level
was not established. The relationship between the effects at the given dose levels in mice and
rats and potential toxicity in humans is unknown.
Use in Pregnancy: Category C
The Australian categorisation definition of:
Category C: Drugs which, owing to their pharmacological effects, have caused or may be
suspected of causing, harmful effects on the human fetus or neonate without causing
malformations. These effects may be reversible. Accompanying texts should be consulted for
further details.
When given in high doses during late pregnancy, butyrophenones may cause prolonged
neurological disturbances in the newborn infant. In pregnant mice, rats and hamsters,
administration of haloperidol during the period of organogenesis has produced a range of
adverse effects, including embryolethality, gross malformations such as cleft palate and
neuronal tube defects, and reduced brain and body weight and behavioural effects in offspring.
The significance of these findings for human exposure to therapeutic doses of haloperidol is
unknown.
Non-teratogenic class effect: Neonates exposed to antipsychotic drugs (including Haloperidol)
during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological
disturbances and/or withdrawal symptoms following delivery. There have been post-market
reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding
disorder in these neonates. These complications have varied in severity; while in some cases
symptoms have been self-limited, in other cases neonates required additional medical treatment
or monitoring.
Haloperidol should be used during pregnancy only if the anticipated benefit outweighs the risk.
The administered dose and duration of treatment should be as low, and as short as possible.
Use in Lactation:
Haloperidol is distributed into breast milk. Safe use of haloperidol by nursing mothers has not
been established; therefore its use is not recommended. The frequency of ejaculation in
offspring was reduced following intraperitoneal administration of haloperidol to female rats
from early pregnancy to weaning (See Impairment of Fertility).

Use in Paediatrics:
As the safety and effectiveness of haloperidol has not been generally established in children, the
drug is not recommended for use in the paediatric age group except in severely aggressive and
hostile children or for the treatment of the rare Gilles de la Tourette syndrome. Haloperidol
should not be used in children under 3 years of age. Children are highly susceptible to the
extrapyramidal side effects of haloperidol, especially dystonias.

Use in the Elderly:
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Elderly patients tend to develop higher plasma concentrations of haloperidol 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. These patients usually require lower initial dosage and a
more gradual titration of dose (See DOSAGE AND ADMINISTRATION). Elderly patients
exhibit an increased sensitivity to the anticholinergic, sedative and extrapyramidal side effects of
haloperidol. Careful observation during haloperidol therapy for early signs of tardive dyskinesia
and reduction of dosage or discontinuation of medication may prevent a more severe
manifestation of the syndrome.

Driving and Operating Machinery:
Haloperidol may impair the mental and/or physical abilities required for the performance of
hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient
should be warned accordingly.

Interactions with other Drugs:

Pharmacokinetic Interactions
There is evidence to suggest that haloperidol is a substrate of CYP3A4 and CYP2D6, and
inhibitor, as well as a stimulator of CYP2D6. Studies also suggested that reduced haloperidol,
one of the metabolites of haloperidol, is a substrate of CYP3A4 and an inhibitor of CYP2D6.
Involvement of these isoforms in the biotransformation of haloperidol may explain some of the
drug interactions observed.
Haloperidol inhibits the metabolism of tricyclic antidepressants, increasing the blood levels of
these drugs. This may result in increased tricyclic antidepressant toxicity as well as increased
anticholinergic effects. It is thought that inhibition of CYP2D6 by haloperidol or reduced
haloperidol is responsible for this inhibitory effect. On the other hand, it is not known whether
the metabolism of haloperidol is affected when tricyclic antidepressants is co-administered.
In pharmacokinetic studies, mild to moderately increased haloperidol levels have been reported
when haloperidol was given concomitantly with quinidine, buspirone or fluoxetine. It may be
necessary to reduce the dosage of haloperidol when any of these drugs are used concomitantly
with haloperidol. The exact mechanism responsible for the interactions is not known but may be
secondary to inhibition of CYP2D6 by quinidine, competition with CYP3A4 by buspirone and
inhibition of CYP2D6 and CYP3A4 by fluoxetine. It is not known whether haloperidol affects
the levels of quinidine or buspirone whereas fluoxetine levels appear to be unaffected when used
concomitantly with haloperidol. Antidepressants such as fluvoxamine, nefazodone, paroxetine
and venlafaxine may increase haloperidol concentrations by possibly inhibiting CYP2D6
mediated metabolism of haloperidol similarly to that seen with fluoxetine.
Due to competitive inhibition of CYP2D6-mediated haloperidol metabolism and increased
dopamine2 blockade, co-administration of haloperidol and olanzapine may result in an increased
risk of Parkinsonism.
A significant fall in haloperidol plasma levels occurs when prolonged treatment with enzyme
inducing drugs such as carbamazepine, phenobarbitone, phenytoin or rifampicin is added to
haloperidol therapy. This is thought to be the result of the ability of these drugs to induce
CYP3A4, thereby accelerating the metabolism of haloperidol; serum concentrations of
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haloperidol may be significantly reduced. Therefore, during therapy with this combination, the
dosage of haloperidol may need to be increased. Conversely, after stopping therapy with such
drugs, it may be necessary to reduce the dosage of haloperidol. Haloperidol does not appear to
influence the pharmacokinetics of carbamazepine and phenobarbitone. Whether or not
haloperidol affects the plasma level of rifampicin is at present unclear.
The clearance of haloperidol is greater in tobacco smokers as compared with non-smokers, and
serum concentrations of haloperidol are lower in smoking patients. It is suggested that plasma
concentrations of haloperidol be monitored in patients who either start or stop smoking.
Pharmacodynamic Interactions
Haloperidol may block the vasopressor activity of adrenaline and related sympathomimetic
agents, and cause a paradoxical further lowering of blood pressure in hypotensive patients.
Haloperidol may also reverse the blood pressure lowering effects of adrenergic blocking agents
such as guanethidine. Concomitant use of propranolol and haloperidol therapy has been reported
to result in hypotension and cardiopulmonary arrest. This is due to alpha-receptor binding and
intrinsic relaxant effects on peripheral blood vessels by haloperidol and relaxant effects on
peripheral vessels by propranolol.
Drugs known to prolong the QT interval may affect haloperidol therapy (See PRECAUTIONS-
QT Prolongation & Torsades de Pointe). Concurrent use of haloperidol with antiarrythmic
agents may result in additive cardiac effects (See PRECAUTIONS- QT Prolongation &
Torsades de Pointe).
High doses of haloperidol may potentiate the action of methyldopa. This combination has
reportedly resulted in dementia and enhanced CNS effects (e.g. disorientation, memory loss,
slowed or difficult thought, aggression, irritability, and mental retardation) in several patients.
Haloperidol blocks dopamine receptors. Haloperidol may therefore interfere with the anti-
Parkinsonian effects of levodopa. Cabergoline, a long-acting dopamine-2 receptor agonist,
should not be used concurrently with haloperidol, a dopamine-2 antagonist, due to the
antagonistic pharmacologic effects and therefore, decreased therapeutic effect of both drugs.
Parkinsonian syndrome has been reported with concomitant use of tacrine and haloperidol due
to increased acetylcholine activity in striatal region of the brain.
Alcohol may potentiate the sedative effect of haloperidol thereby impairing the ability of
patients to perform activities requiring mental alertness. Concurrent use of alcohol and
haloperidol may cause hypotension and increase alcohol intoxication (See PRECAUTIONS).
Haloperidol will potentiate the action of other central nervous system depressants (e.g.
anaesthetics, opiates, barbiturates and alcohol).
The combination of lithium with an antipyschotic agent such as haloperidol, has occasionally
produced an acute encephalopathic syndrome characterised by weakness, lethargy, fever,
tremulousness and confusion, extrapyramidal symptoms, leucocytosis, elevated serum enzymes
and serum urea and followed by irreversible brain damage. Although a casual relationship has
not been established, patients receiving such combined therapy should be monitored closely for
early evidence of neurological toxicity, and treatment discontinued should such signs appear.
Dextromethorphan is metabolised by CYP2D6. Concomitant use of dextromethorphan and
haloperidol, an inhibitor of this isoenzyme, may result in elevated concentrations of
dextromethorphan and increased adverse effects (CNS excitement, mental confusion, respiratory
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depression, nervousness, tremors, insomnia, and diarrhoea). A reduction of dextromethorphan
doses may reduce or resolve adverse effects.
Haloperidol has been reported to antagonise the anticoagulant activity of phenindione and
coumarin anticoagulants.
Increases in intraocular pressure may occur in patients receiving anticholinergic agents,
including anti-Parkinsonian agents, concurrently with haloperidol.
Concurrent use of amphetamines and haloperidol may decrease both the stimulant effects of
amphetamines as well as the antipsychotic effects of haloperidol.
The anticholinergic effects of other drugs may be intensified when used concurrently with
haloperidol e.g. anticholinergic agents, antihistamines, tricyclic antidepressants, MAO inhibitors
and antidyskinetic agents.
Concurrent use of anticonvulsants with haloperidol may cause a change in the pattern and/or
frequency of seizures; dosage adjustments of anticonvulsants may be necessary. Tramadol may
increase the seizure risk in patients taking other medications that lower the seizure threshold,
such as haloperidol.
Haloperidol may interfere with the effects of bromocriptine; concurrent use may increase serum
prolactin levels and dosage adjustment of bromocriptine may be necessary.
ADVERSE REACTIONS

In the low dosage range (1-2 mg daily), adverse effects from haloperidol have been infrequent,
mild and transitory. In patients receiving higher doses, some adverse effects are seen more
frequently. Neurological effects are the most common.

Central Nervous System Effects:

Common (≥ 1% and < 10%)
-akathisia -dystonia -parkinsonian effects Uncommon (≥ 0.1% and < 1%)
-Hallucinations -Unusual tiredness or weakness -Persistent tardive dyskinesia Rare (≥ 0.01% and < 0.1%)
-Neuroleptic Malignant Syndrome (NMS)
-Tardive dystonia

Akathisia: may appear within the first 6 hours after dose; often indistinguishable from
psychotic agitation. Akathisia is best managed by a reduction in dosage in conjunction with the
temporary use of an oral antiparkinson drug.
Dystonias: appear most often in children and young adults and early in treatment; may subside
within 24 to 48 hours after discontinuation of haloperidol. Dystonias, which can produce
laryngeal spasm or bronchospasm may be controlled by intravenous or intramuscular
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administration of benztropine mesylate (1-2 mg IM or IV) or biperiden (2-10 mg IM or IV), or
intravenous diazepam (10 mg IV). A pseudo Parkinson rigidity syndrome may occur later
during the course of treatment and may respond to antiparkinson agents.
Parkinsonian effects: are characterised by difficulty in speaking or swallowing; loss of balance
control; mask-like face; shuffling gait; stiffness of arms or legs; trembling and shaking of hands
and fingers. Parkinsonian effects are more frequent in the elderly; symptoms may be seen in the
first few days of treatment or after prolonged treatment, and can recur after even a single dose.
They sometimes remit spontaneously as treatment continues, or can be relieved by a reduction in
dose or the temporary use of antiparkinson medication.
It has been reported that some extrapyramidal reactions may persist even after a reduction in
dosage and/or treatment with antiparkinson drugs. In such cases, the drug should be
discontinued.
Tardive dyskinesia: (lip smacking or puckering; puffing of cheeks; rapid or worm-like
movements of tongue; uncontrolled chewing movements; uncontrolled movements of the arms
and legs) is more frequent in elderly patients, women, and patients with brain damage. 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 the drug increases. Less
commonly, the syndrome can develop after relatively brief treatment periods at low doses. It
may persist after discontinuation of haloperidol.
The syndrome may become clinically recognisable either during treatment, upon dosage
reduction, or upon withdrawal of treatment. The dosage of antipsychotic drug should be reduced
periodically (if clinically possible) and the patient observed for signs of the disorder, since the
syndrome may be masked by a higher dose. In patients requiring long-term treatment, the
smallest dose and the shortest duration of treatment producing a satisfactory clinical response
should be prescribed. The need for continued treatment should be reassessed periodically.
There is no known effective treatment for tardive dyskinesia. Antiparkinson agents usually do
not alleviate the symptoms. It is suggested that antipsychotic agents be discontinued if
symptoms of tardive dyskinesia appear.
Neuroleptic Malignant Syndrome (NMS): characterised by difficult or unusually fast
breathing; fast heartbeat or irregular pulse; high fever; high or low blood pressure; increased
sweating; loss of bladder control; severe muscle stiffness; seizures; unusual tiredness or
weakness; unusually pale skin. Additional signs may include elevated creatinine phosphokinase,
rhabdomyolysis and acute renal failure. May occur at any time during neuroleptic therapy, but is
most commonly seen after start of therapy, or after patient has switched from one neuroleptic to
another, during combination therapy with other psychotropic medication, or after a dosage
increase.
The management of neuroleptic malignant syndrome should include immediate discontinuation
of antipsychotic drugs, intensive monitoring and treatment of symptoms, and treatment of any
associated medical problems (e.g. pneumonia, systemic infection).
Tardive dystonia: increased blinking or spasm of eyelid; unusual facial expressions or body
positions; uncontrolled twisting movements of neck, trunk, arms, or legs.
Other Central Nervous System Effects:

Drowsiness, depression, anxiety, euphoria, lethargy, agitation, insomnia, headache, confusion,
sedation, anorexia, vertigo, restlessness, apprehension, grand mal seizures. Toxic psychosis may
occur with overdose.

Cardiovascular Effects:
-Orthostatic hypotension -Tachycardia -Increased respiratory rate Serenace – Product information
-Ventricular arrythmias -Polymorphous configuration of torsade de pointes
Haematological Effects:
-Agranulocytosis (sore throat and fever; unusual bleeding or bruising) -Mild and usually transient leukopenia and leukocytosis -Minor decreases in red blood cell counts -Anaemia -Tendency toward lymphocytosis and monocytosis Hepatobiliary Effects:
-Impaired liver function and/or jaundice or Cholestatic hepatitis “No causal relationship has been established”
Respiratory Effects:
-Laryngospasm
-Bronchospasm
-Increased

Dermatological and Hypersensitivity Reactions:
-Local reactions as erythema, swelling or tender lumps
-Maculopapular and acneiform skin reactions and isolated
cases of photosensitivity and loss of hair, urticaria,
exfoliative dermatitis and erythema multiforme
Endocrine Effects:
-Hyperprolactinaemia -Gynaecomastia -Menstrual irregularities including oligo or amenorrhoea -Mastalgia -Breast engorgement -Impotence or increased libido -Lactation -Hyperglycaemia -Hypoglycaemia -Hyponatraemia -Inappropriate anti-diuretic hormone secretion (very rare)
Gastrointestinal Effects:
-Constipation
-Anorexia
-Nausea
-Vomiting
-Diarrhoea
-Dyspepsia
-Heartburn
-Hypersalivation
Serenace – Product information

Autonomic Effects:
-Blurred vision -Dryness of mouth -Urinary retention
Ocular Effects:
-Cataract -Retinopathy -Visual disturbances
Other Effects:
-Heat stroke (hot, dry skin; inability to sweat; muscle weakness; confusion) -Increased sensitivity of skin to sun -Weight gain -Peripheral oedema
DOSAGE AND ADMINISTRATION
Warning:
Higher doses and intravenous administration of haloperidol appear to be associated with a
higher risk of QT prolongation and Torsades de Pointes (See PRECAUTIONS and ADVERSE
REACTIONS).
Where rapid control of an acutely disturbed patient is required, or where heavier than usual
dosages are envisaged, or when parenteral administration, particularly repeated parenteral
administration, is required, then the patient should be transferred as soon as possible to a
situation where, ECG monitoring, parenteral antiparkinson medication and resuscitative
measures are available.
There is considerable variation from patient to patient in the amount of medication required for
therapy. As with all antipsychotic drugs, it is important to titrate the dose of Serenace in
accordance with the clinical effect and the severity of the disease. Monitoring of blood levels is
not a routine procedure. Children and debilitated or geriatric patients may be more sensitive to
Serenace, and the starting dose, maximum dose and maintenance doses are therefore generally
lower for these patients. In all age groups, titration of dosage should be as rapid as possible, and
when therapy is commenced with parenteral Serenace, a change to oral medication should be
made as soon as possible.
Sedation should not be used as a control parameter, nor should Serenace be used to achieve
sedation, since it may lead to gross overdose.
Once a satisfactory clinical response has been achieved by the titration method, the daily doses
should be reduced to the lowest effective level.
No pharmacokinetic data are available to enable special recommendations to be given for
patients with renal or hepatic impairment.
Also, no information on the effects of meals on drug absorption is available.
Parenteral Administration

Serenace – Product information

The solution should be inspected for discolouration or the presence of particulate matter prior to
administration. Each Serenace injection is a single dose used in only one patient, and any
remaining contents should be discarded.

Agitation and aggressiveness associated with acute psychosis: (eg. mania, hypomania, acute
schizophrenia, toxic confusional states including delirium tremens). 2-10 mg IM or IV initially.
The amount will depend on the patient's age, physical status, and severity of symptoms. The
initial dose may be given as a slow IV injection or as a bolus. Depending on the response of the
patient, subsequent doses may be given as often as half hourly for IV injections or hourly for IM
injections. The total daily dose administered should not exceed 100 mg.
This treatment approach is not without risk and high doses of antipsychotic drugs should only be
administered to the physically healthy adult.
Appropriate precautions should be taken in patients with a history or evidence of such
conditions as cardiovascular disorders or epilepsy.

Parenteral total daily maintenance dose: Once continuous therapeutic control is achieved,
there is a need to determine maintenance dosage. As pharmacokinetic studies to date have not
addressed this problem, it is necessary to make an estimate by assuming plasma levels are to be
maintained, that the plasma half life of haloperidol is approximately 24 hours, and that the initial
control is attained within 24 hours. The maintenance dose may be calculated as half the total
daily dose that is used to achieve control. This dose can then be given in divided doses morning
and evening. To avoid excessive plasma levels, giving of the first maintenance dose should be
delayed if possible until 4-8 hours after the last controlling dose.

Oral total daily maintenance dose: May be calculated in the same manner if transferring
directly from parenteral controlling dose. A transfer from parenteral maintenance dose to oral
maintenance dose would use the same daily dose.

Oral Administration
Adults:
Moderate Symptomatology: 1-5 mg per day.
Severe Symptomatology: 5-15 mg per day. Daily oral dosages should be titrated against patient
response and may be increased up to 100 mg or occasionally even higher. Once a satisfactory
clinical response has been achieved by the titration method, the daily dose should be reduced to
the lowest effective level.

Geriatric or Debilitated Patients: 1-3 mg per day is usually sufficient.

Children: For severely aggressive or hostile children or for the rare Gilles de la Tourette
Syndrome, the initial dose should be 1-3 mg per day and Serenace liquid is recommended (10-
30 drops). Maintenance dose is usually 0.05 mg/kg body weight per day.
OVERDOSAGE
Symptoms and Findings: would be an exaggeration of the known pharmacological effects and
adverse reactions. The most prominent symptoms would be:
1. Severe extrapyramidal reactions
2. Hypotension
3. Sedation
Serenace – Product information

Sometimes coma with respiratory depression and hypotension, which could be severe enough to
produce a shock-like state, can occur. Extrapyramidal reactions may consist of muscular
weakness or rigidity and a generalised or localised tremor. Hypertension, rather than
hypotension, is also possible. Convulsions, QT prolongation and ventricular arrhythmias
including torsade de pointes may occur.

Treatment of overdose: There is no specific antidote. Treatment is largely symptomatic and
supportive. Activated charcoal may be administered to decrease drug absorption. Note: Dialysis
is NOT effective in removing excessive systemic haloperidol.
For comatose patients, establish a patent airway by use of an oropharyngeal airway or
endotracheal tube. Respiratory depression may necessitate artificial respiration.
Convulsions may be treated with IV diazepam, however respiratory status should be monitored
during its administration.
Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma,
or concentrated albumin and vasopressor agents such as dopamine or noradrenaline. Adrenaline
should not be used, since haloperidol may reverse its action and cause profound hypotension.
In cases of severe extrapyramidal reactions, antiparkinson medication (eg. benztropine mesylate
1-2 mg IM or IV) should be administered parenterally.
ECG and vital signs should be monitored. Hypothermia should be managed with external
warming.

PRESENTATION
Tablets: (oral)
Serenace 0.5 mg, green, scored, uncoated, stamped "SIGMA" on one side, in bottles of 100 and
500.
Serenace 1.5 mg, white, scored, uncoated, stamped "SIGMA" on one side, in bottles of 100.
Serenace 5 mg, red, scored, uncoated, stamped "SIGMA" on one side, in bottles of 50 and 500.
# Serenace 20 mg, blue, scored, uncoated, stamped "SEARLE" on one side, in bottles of 100
and 500.

Liquid: (oral)
Serenace 2 mg per mL clear, colourless liquid in 100 mL bottles. Dropper is included in carton
and delivers 20 drops per mL.

Parenteral Ampoules:
Serenace 5 mg per mL amber coloured ampoules of 1 mL in boxes of 10 and 25.
# Serenace 10 mg per mL amber coloured ampoules of 1 mL in boxes of 10.
# Serenace 20 mg per 2 mL amber coloured ampoules of 2 mL in boxes of 10.
# - Currently not marketed
STORAGE

Store below 30oC
POISONS SCHEDULE
Serenace – Product information

NAME AND ADDRESS OF SPONSOR
Aspen Pharma Pty Ltd
34–36 Chandos Street
St Leonards NSW 2065
Australia
Approved by Therapeutic Goods Administration on 5 June 2001.
TGA amendment approved 22 October 2007
Date of most recent amendment: 29 September 2011

Source: http://www.aspenpharma.com.au/product_info/pi/PI_Serenace.pdf