HALDOL AMPOULES

Israel - English - Ministry of Health

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Active ingredient:
HALOPERIDOL
Available from:
J-C HEALTH CARE LTD
ATC code:
N05AD01
Pharmaceutical form:
SOLUTION FOR INJECTION
Composition:
HALOPERIDOL 5 MG/ML
Administration route:
I.M
Prescription type:
Required
Manufactured by:
GLAXO SMITH KLINE MANUFACTURING SPA,ITALY
Therapeutic group:
HALOPERIDOL
Therapeutic area:
HALOPERIDOL
Therapeutic indications:
Psychomotor agitation encountered in different neuropsychotic affections, prophylaxis and therapy of acute and chronic vomiting.
Authorization number:
024 04 21146 00
Authorization date:
2012-02-28

Haldol amp PI Approved on 21/08/2013

1.

NAME OF THE MEDICINAL PRODUCT

HALDOL AMPOULES

(haloperidol)

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Contains 5 mg haloperidol per ml.

For excipients, see Section 6.1

3.

PHARMACEUTICAL FORM

Solution for injection.

Clear, colorless solution, free from visible foreign material containing 5mg

haloperidol per ml.

For excipients, see List of Excipients.

4.

CLINICAL PARTICULARS

4.1. Therapeutic Indications

Psychomotor agitation encountered in different neuropsychotic affections.

Prophylaxis and therapy of acute and chronic vomiting.

4.2. Posology and Method of Administration

There is considerable variation from patient to patient in the amount of

medication required for treatment. As with all antipsychotic drugs, dosage

should

individualized

according

needs

response

individual patient. When initiating treatment, consideration should be given

to the following factors: age of the patient, severity of the disease, history of

response to other antipsychotic drugs, concomitant medication or disease

state.

Haldol Injection is reserved for prompt control of the acutely agitated patient

with moderately severe to very severe symptoms.

Haldol Injection is recommended for IM administration only.

Haldol Injection should be substituted by Haldol Tablets as soon as feasible.

The usual dosage is 2-5 mg (0.4-1 ml of a Haldol ampoule) administered

intramuscularly.

Haldol amp PI Approved on 21/08/2013

Depending on the response of the patient, subsequent doses may be given,

administered as often as every hour, although 4- to 8-hour intervals may be

satisfactory.

Acute and Chronic Vomiting:

5 mg administered IM.

Treatment withdrawal

Gradual

withdrawal

haloperidol

advaisable

(see

Warnings

Precautions – Additional considerations)

4.3. Contraindications

Comatose state; CNS depression due to alcohol or other depressant drug;

Parkinson's disease; known hypersensitivity to Haldol; lesion of the basal

ganglia.

In common with other neuroleptics, haloperidol has the potential to cause

rare prolongation of the QT interval. Use of haloperidol is therefore contra-

indicated in patients with clinically significant cardiac disorders e.g. recent

acute

myocardial

infarction,

uncompensated

heart

failure,

arrhythmias

treated with class IA and III antiarrhythmic medicinal products, QTc interval

prolongation,

history

ventricular

arrhythmia

torsades

pointes

clinically significant bradycardia, second or third degree heart block and

uncorrected hypokalaemia. Haloperidol should not be used concomitantly

with other QT prolonging drugs (see section 4.5, Interactions)

4.4. Special Warnings and Special Precautions for Use

Increased

Mortality

in

Elderly

Patients

with

Dementia

Related

Psychosis

Rare

cases of

sudden

death have

been

reported in psychiatric patients

receiving antipsychotic drugs, including Haldol.

Elderly patients with dementia-related psychosis treated with antipsychotic

drugs are at an increased risk of death. Analyses of seventeen placebo-

controlled trials (modal duration of 10 weeks), largely in patients taking

atypical antipsychotic drugs, revealed a risk of death in drug-treated patients

of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over

the course of a typical 10 week controlled trial, the rate of death in drug-

treated patients was about 4.5%, compared to a rate of about 2.6% in the

Haldol amp PI Approved on 21/08/2013

placebo group. Although the causes of death were varied, most of the deaths

appeared to be either cardiovascular (e.g., heart failure, sudden death) or

infectious (e.g., pneumonia) in nature. Observational studies suggest that,

similar

atypical

antipsychotic

drugs,

treatment

with

conventional

antipsychotic drugs may increase mortality. The extent to which the findings

of increased mortality in observational studies may be attributed to the

antipsychotic drug as opposed to some characteristic(s) of the patients is not

clear.

Haldol Ampoules is not approved for treatment of patients with Dementia-

related psychosis.

Cardiovascular effects

Very rare reports of QT prolongation and/or ventricular arrhythmias, in

addition to rare reports of sudden death, have been reported with haloperidol.

They

occur

more

frequently

with

high

doses

predisposed

patients.

As QT-prolongation has been observed during Haldol treatment, caution is

advised

in patients

with

QT-prolonging

conditions

(long

QT-syndrome,

hypokalaemia,

electrolyte

imbalance,

drugs

known

prolong

cardiovascular diseases, family history of QT prolongation), especially if

Haldol is given parenterally (see Section 4.5). The risk of QT prolongation

and/or ventricular arrhythmias may be increased with higher doses (see

Sections

4.9)

with

parenteral

use,

particularly

intravenous

administration. Continuous ECG monitoring should be performed for QT

interval prolongation and for serious cardiac dysrhythmias if Haldol is

administered intravenously.

Haldol Injection is recommended for IM administration only.

Tachycardia and hypotension have also been reported in occasional patients.

Neuroleptic malignant syndrome

In common with other antipsychotic drugs, Haldol

has been associated with

neuroleptic malignant syndrome: a rare idiosyncratic response characterized

by hyperthermia, generalised muscle rigidity, autonomic instability, and

altered consciousness. Hyperthermia is often an early sign of this syndrome

.

Antipsychotic treatment should be withdrawn immediately and appropriate

supportive therapy and careful monitoring instituted.

Haldol amp PI Approved on 21/08/2013

Tardive dyskinesia

As with all antipsychotic agents, tardive dyskinesia may appear in some

patients on long-term therapy or after drug discontinuation. The syndrome is

mainly characterized by rhythmic involuntary movements of the tongue,

face, mouth or jaw. The manifestations may be permanent in some patients.

The syndrome may be masked when treatment is reinstituted, when the

dosage is increased or when a switch is made to a different antipsychotic

drug. Treatment should be discontinued as soon as possible

.

Extrapyramidal symptoms

In common with all antipsychotics, extrapyramidal symptoms may occur,

e.g. tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia.

Antiparkinson

drugs

anticholinergic

type

prescribed

required, but should not be prescribed routinely as a preventive measure. If

concomitant

antiparkinson

medication

required,

have

continued after stopping Haldol if its excretion is faster than that of Haldol in

order to avoid the development or aggravation of extrapyramidal symptoms.

The physician should keep in mind the possible increase in intraocular

pressure when anticholinergic drugs, including antiparkinson agents, are

administered concomitantly with Haldol.

Seizures/ convulsions

It has been reported that seizures can be triggered by Haldol. Caution is

advised in patients suffering from epilepsy and in

conditions predisposing to

convulsions (e.g., alcohol withdrawal and brain damage).

Hepatobiliary concerns

As Haldol

is metabolized by the liver, caution is advised in patients with

liver disease. Isolated cases of liver function abnormalities or hepatitis, most

often cholestatic, have been reported.

Endocrine system concerns

Thyroxin may facilitate Haldol

toxicity. Antipsychotic therapy in patients

with hyperthyroidism should be used only with great caution and must

always be accompanied by therapy to achieve a euthyroid state.

Hormonal effects of antipsychotic drugs include hyperprolactinaemia, which

may cause galactorrhoea, gynaecomastia and oligo- or amenorrhoea. Very

rare

cases

hypoglycaemia

Syndrome

Inappropriate

Secretion have been reported.

Haldol amp PI Approved on 21/08/2013

Venous thromboembolism

Cases

venous

thromboembolism

(VTE)

have

been

reported

with

antipsychotic drugs. Since patients treated with antipsychotics often present

with acquired risk factors for VTE, all possible risk factors for VTE should

identified

before

during

treatment

with

Haldol

preventive

measures undertaken.

Additional considerations

schizophrenia,

response

antipsychotic

drug

treatment

delayed. Also, if drugs are withdrawn, recurrence of symptoms may not

become apparent for several weeks or months. Acute withdrawal symptoms

including nausea, vomiting and insomnia have very rarely been described

after abrupt cessation of high doses of antipsychotic drugs. Relapse may also

occur and gradual withdrawal is advisable.

As with all antipsychotic agents, Haldol

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.

4.5. Interactions with Other Medicinal Products and Other

Forms of Interaction

with

other

antipsychotics,

caution

advised

when

prescribing

haloperidol with medications known to prolong the QT interval.

Haloperidol is metabolized by several routes, including glucuronidation and

the cytochrome P450 enzyme system (particularly CYP 3A4 or CYP 2D6).

Inhibition of these routes of metabolism by another drug or a decrease in

CYP 2D6 enzyme activity may result in increased haloperidol concentrations

and an increased risk of adverse events, including QT-prolongation. In

pharmacokinetic

studies,

mild

moderately

increased

haloperidol

concentrations

have

been

reported

when

haloperidol

given

concomitantly with drugs characterized as substrates or inhibitors of CYP

3A4 or CYP 2D6 isozymes, such as, itraconazole, nefazodone, buspirone,

venlafaxine,

alprazolam,

fluvoxamine,

quinidine,

fluoxetine,

sertraline,

chlorpromazine, and promethazine. A decrease in CYP2D6 enzyme activity

may result in increased haloperidol concentrations. Increases in QTc have

been observed when haloperidol was given with a combination of the

metabolic inhibitors ketoconazole

(400 mg/day) and paroxetine (20 mg/day).

It may be necessary to reduce the haloperidol dosage.

Caution is advised when used in combination with drugs known to cause

electrolyte imbalance.

Haldol amp PI Approved on 21/08/2013

Effect of Other Drugs on Haloperidol

When

prolonged

treatment

with

enzyme-inducing

drugs

such

carbamazepine, phenobarbital, rifampicine is added to Haldol

therapy, this

results in a significant reduction of haloperidol plasma levels. Therefore,

during combination treatment, the Haldol

dose should be adjusted, when

necessary. After stopping such drugs, it may be necessary to reduce the

dosage of Haldol.

Sodium valproate, a drug known to inhibit glucuronidation, does not affect

haloperidol plasma concentrations.

Effect of Haloperidol on Other Drugs

In common with all antipsychotics, Haldol

can increase the central nervous

system

depression

produced

other

CNS-depressant

drugs,

including

alcohol, hypnotics, sedatives or strong analgesics. An enhanced CNS effect,

when combined with methyldopa, has also been reported.

Haldol

may antagonise the action of adrenaline and other sympathomimetic

agents

reverse

blood-pressure-lowering

effects

adrenergic-

blocking agents such as guanethidine.

Haldol

may impair the antiparkinson effects of levodopa.

Haloperidol is an inhibitor of CYP 2D6. Haldol

inhibits the metabolization

of tricyclic antidepressants, thereby increasing plasma levels of these drugs.

Other Forms of Interaction

In rare cases the following symptoms were reported during the concomitant

use of lithium and haloperidol: encephalopathy, extrapyramidal symptoms,

tardive dyskinesia, neuroleptic malignant syndrome, brain stem disorder,

acute brain syndrome and coma. Most of these symptoms were reversible. It

remains unclear whether this represents a distinct clinical entity.

Nonetheless, it is advised that in patients, who are treated concomitantly

with lithium and Haldol, therapy should be stopped immediately if such

symptoms occur.

Antagonism of the effect of the anticoagulant phenindione has been reported.

4.6. Pregnancy and Breast-feeding

Neonates exposed to antipsychotic drugs (including haloperidol) during the

third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal

symptoms that may vary in severity following delivery. These symptoms in

Haldol amp PI Approved on 21/08/2013

neonates

include

agitation,

hypertonia,

hypotonia,

tremor,

somnolence, respiratory distress, or feeding disorder

.

Haldol

shown

significant

increase

fetal

anomalies

large

population studies. There have been isolated case reports of birth defects

following fetal exposure to Haldol, mostly

in combination with other drugs.

Animal studies have demonstrated a teratogenic effect of haloperidol (see

Non-Clinical Information)

Haldol

should be used during pregnancy only if

the anticipated benefit justifies the potential risk to the fetus.

Breast-feeding

Haldol

is excreted in breast milk. If the use of Haldol

is considered essential,

the benefits of breast-feeding should be balanced against its potential risks.

Extrapyramidal

symptoms

have

been

observed

breast

-

infants

Haldol treated women

.

4.7. Effects on Ability to Drive and Use Machines

Some degree of sedation or impairment of alertness may occur, particularly

with higher doses and at the start of treatment and may be potentiated by

alcohol or other CNS depressants. Patients should be advised not to drive or

operate machinery during treatment, until their susceptibility is known.

4.8. Adverse Reactions

Throughout this section, adverse reactions are presented. Adverse reactions are

adverse events that were considered to be reasonably associated with the use of

haloperidol based on the comprehensive assessment of the available adverse event

information. A causal relationship with haloperidol cannot be reliably established in

individual cases. Further, because clinical trials are conducted under widely varying

conditions, adverse reaction rates observed in the clinical trials of a drug cannot be

directly compared to rates in the clinical trials of another drug and may not reflect the

rates observed in clinical practice.

4.9. Clinical trial data

4.9.1.

Placebo-controlled double-blind data – adverse

reactions reported at

1% incidence

The safety of HALDOL (2-20 mg/day) was evaluated in 566 subjects (of

which 284 were treated with HALDOL, 282 were given placebo) who

participated in 3 placebo-controlled, double-blind clinical trials, two in the

treatment of schizophrenia and the third in the treatment of bipolar disorder.

Adverse reactions (ADRs) reported by

1% of HALDOL-treated subjects in

these trials are shown in Table 1.

Haldol amp PI Approved on 21/08/2013

Table 1.

Adverse Reactions Reported by

1% of HALDOL-treated Subjects in 3 Double-Blind

Parallel Placebo-Controlled Clinical Trials of HALDOL

System/Organ Class

Adverse Reaction

HALDOL

(n=284)

%

Placebo

(n=282)

%

Nervous System Disorders

Extrapyramidal disorder

34.2

Hyperkinesia

10.2

Tremor

Hypertonia

Dystonia

Somnolence

Bradykinesia

Eye Disorders

Visual disturbance

Gastrointestinal Disorders

Constipation

Dry mouth

Salivary hypersecretion

4.9.1.

Active comparator-controlled data – adverse

reactions reported at

1% incidence

Sixteen double-blind active comparator-controlled trials were selected to

determine

incidence

adverse

reactions.

these

studies,

1295 subjects were treated with 1-45 mg/day HALDOL, in the treatment of

schizophrenia.

Adverse reactions reported by

1% of HALDOL-treated subjects noted in the

active-comparator controlled clinical trials are shown in Table 2.

Table 2.

Adverse Reactions Reported by

1% of HALDOL-treated Subjects in 16 Double-

Blind Active Comparator Clinical Trials of HALDOL

System/Organ Class

Adverse Reaction

HALDOL

(n=1295)

%

Nervous System Disorder

Dizziness

Akathisia

Dyskinesia

Hypokinesia

Tardive dyskinesia

1.62

Eye Disorders

Oculogyric crisis

1.24

Vascular Disorders

Orthostatic hypotension

Hypotension

1.47

Reproductive system and breast Disorders

Erectile dysfunction

Investigations

Weight increased

4.9.1.

Placebo- and active comparator-controlled data –

adverse reactions reported at <1% incidence

Additional adverse reactions that occurred in <1% of HALDOL-treated

subjects either of the above 2 clinical datasets are listed below in Table 3.

Haldol amp PI Approved on 21/08/2013

Table 3.

Adverse Reactions Reported by <1% of HALDOL-treated Subjects in Either the

Placebo- or Comparator-controlled Clinical Trials.

Endocrine Disorders

Hyperprolactinaemia

Psychiatric Disorders

Libido decreased

Loss of libido

Restlessness

Nervous System Disorders

Motor dysfunction

Muscle contractions involuntary

Neuroleptic malignant syndrome

Nystagmus

Parkinsonism

Sedation

Eye Disorders

Vision blurred

Cardiac Disorders

Tachycardia

Musculoskeletal and Connective Tissue Disorders

Trismus

Torticollis

Muscle rigidity

Muscle Spasms

Musculoskeletal stiffness

Muscle Twitching

Reproductive System and Breast Disorders

Amenorrhoea

Breast discomfort

Breast pain

Galactorrhoea

Dysmenorrhoea

Sexual dysfunction

Menstrual disorder

Menorrhagia

General Disorders and Administration Site Conditions

Gait disturbance

Postmarketing data

Adverse events first identified as adverse reactions during postmarketing

experience with haloperidol

are included in Tables 4. The postmarketing

review was based on review of all cases where there was a use of the active

moiety haloperidol (both HALDOL and HALDOL DECANOATE). In the

table, the frequencies are provided according to the following convention:

Very common

1/10

Common

1/100 to <1/10

Uncommon

1/1,000 to <1/100

Rare

1/10,000 to <1/1,000

Very rare

<1/10,000, including isolated reports

Haldol amp PI Approved on 21/08/2013

In Table 4,

adverse reactions

are presented by frequency category based on spontaneous

reporting rates.

Table 4:

Adverse Reactions Identified During Postmarketing Experience with Haloperidol (oral,

solution, or decanoate) by Frequency Category Estimated From Spontaneous Reporting Rates

Blood and Lymphatic System Disorders

Very rare

Agranulocytosis, Pancytopenia, Thrombocytopenia, Leukopenia,

Neutropenia

Immune System Disorders

Very rare

Anaphylactic reaction, Hypersensitivity

Endocrine Disorders

Very rare

Inappropriate antidiuretic hormone secretion

Metabolic and Nutritional Disorders

Very rare

Hypoglycaemia

Psychiatric Disorders

Very rare

Psychotic disorder, Agitation, Confusional state, Depression, Insomnia

Nervous System Disorders

Very rare

Convulsion, Headache

Cardiac Disorders

Very rare

Torsade de pointes, Ventricular fibrillation, Ventricular tachycardia,

Extrasystoles

Respiratory, thoracic and mediastinal disorders

Very rare

Bronchospasm, Laryngospasm, Laryngeal oedema, Dyspnoea

Gastrointestinal Disorders

Very rare

Vomiting, Nausea

Hepatobiliary Disorders

Very rare

Acute Hepatic Failure, Hepatitis, Cholestasis, Jaundice, Liver function test

abnormal

Skin and subcutaneous tissue disorders

Very rare

Leukocytoclastic vasculitis, Dermatitis exfoliative, Urticaria,

Photosensitivity reaction, Rash, Pruritis, Hyperhidrosis

Renal and Urinary Disorders

Very rare

Urinary retention

Reproductive System and Breast Disorders

Very rare

Priapism, Gynaecomastia

Pregnancy, Puerperium and Perinatal Conditions

Very rare

Drug withdrawal syndrome neonatal

General Disorders and Administration Site Conditions

Very rare

Sudden Death, Face oedema, Oedema, Hypothermia, Hyperthermia

Investigations

Very rare

Electrocardiogram QT prolonged, Weight decreased

Haldol amp PI Approved on 21/08/2013

4.10.

Overdose

Symptoms

manifestations of

haloperidol

overdose are

exaggeration

known pharmacological effects and adverse reactions. The most prominent

symptoms are: severe extrapyramidal reactions, hypotension, sedation. An

extrapyramidal reaction is manifest by muscular rigidity and a generalised or

localised tremor. Hypertension rather than hypotension is also possible.

extreme

cases,

patient

would

appear

comatose

with

respiratory

depression and hypotension that could be severe enough to produce a shock-

like state. The risk of ventricular arrhythmias, possibly associated with QT-

prolongation, should be considered.

Treatment

There is no specific antidote. Treatment is largely supportive. Activated

charcoal may be administered.

For comatose patients, a patent airway should be established by use of an

oropharyngeal airway or endotracheal tube. Respiratory depression may

necessitate artificial respiration.

ECG and vital signs should be monitored and monitoring should continue

until

normal.

Severe

arrhythmias

should

treated

with

appropriate anti-arrhythmic measures.

Hypotension

circulatory

collapse

counteracted

intravenous fluids, plasma, or concentrated albumin and vasopressor agents

such as dopamine or noradrenaline. Adrenaline should not be used, since it

might cause profound hypotension in the presence of Haldol.

In cases of severe extrapyramidal reactions, antiparkinson medication (e.g.

benztropine

mesylate

should

administered

parenterally.

5.

PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties

Pharmacotherapeutic group: antipsychotics ATC code N05AD01

Mechanism of action

Haloperidol

antipsychotic,

belonging

group

butyrophenones.

Haloperidol

potent

central

dopamine

receptor

antagonist

and,

therefore,

classified

among

very

incisive

antipsychotics.

Haloperidol

antihistaminergic

anticholinergic

activity.

Haldol amp PI Approved on 21/08/2013

Pharmacodynamic effects

As a direct consequence of the central dopamine blocking effect, haloperidol

has an incisive activity on delusions and hallucinations (probably due to an

interaction in the mesocortical and limbic tissues) and an activity on the

basal

ganglia

(nigrostriatal

bundles).

Haloperidol

causes

efficient

psychomotor sedation, which explains the favourable effect on mania and

other agitation syndromes (see "Indications").

The activity on the basal ganglia probably underlies the extrapyramidal

motor side effects (dystonia, akathisia and parkinsonism).

The more peripheral antidopaminergic effects explain the activity against

nausea and vomiting (via the chemoreceptor-trigger zone), the relaxation of

the gastro-intestinal sphincters and the increased prolactin release (through

an inhibition of the activity of the prolactin inhibiting factor, PIF, at the level

of the adenohypophysis).

5.2. Pharmacokinetic Properties

Absorption

Following oral administration, the bioavailability of the drug is 60 to 70%.

Peak plasma levels of haloperidol occur within two to six hours of oral

dosing and about twenty minutes after intramuscular administration.

Distribution

Plasma protein binding is 92%. The volume of distribution at steady state

(VDss) is large (7.9 ± 2.5 L/kg). Haloperidol crosses the blood-brain barrier

easily.

Metabolism

Haloperidol is metabolized by several routes including the cytochrome P450

enzyme system (particularly CYP 3A4 or CYP 2D6) and glucuronidation.

Elimination

The mean plasma half-life (terminal elimination) is 24 hours (range 12 to 38

hours) after oral administration and 21 hours (range 13 to 36 hours) after

intramuscular administration. Excretion occurs with the faeces (60%) and the

urine (40%). About 1% of the ingested haloperidol is excreted unchanged

with the urine.

Haldol amp PI Approved on 21/08/2013

Therapeutic Concentrations

It has been suggested that a plasma haloperidol concentration range from 4

µg/L to an upper limit of 20 to 25 µg/L is required for a therapeutic

response.

5.3. NON-CLINICAL INFORMATION

Non-clinical

data

reveal

special

hazards

humans

based

conventional

studies

repeat

dose

toxicity,

genotoxicity

carcinogenicity. In rodents, haloperidol administration showed a decrease in

fertility, limited teratogenicity as well as embryo-toxic effects.

Haloperidol has been shown to block the cardiac hERG channel in several

published

studies

in

vitro

. In

a number of

in

vivo

studies

intravenous

administration of haloperidol in some animal models has caused significant

QTc prolongation, at doses around 0.3 mg/kg i.v., giving C

plasma levels

3 to 7 times higher than the effective human plasma concentrations of 4 to

20ng/ml. These intravenous doses which prolonged QTc did not cause

arrhythmias. In some studies higher intravenous doses of 1 to 5 mg/kg

haloperidol i.v. caused QTc prolongation and/or ventricular arrhythmias at

plasma levels 19 to 68 times higher than the effective human plasma

concentrations.

Non-clinical evaluations testing haloperidol revealed no clinically relevant

toxic effects in rats or dogs following chronic toxicity studies up to 18

months in rats and 12 months in dogs. A no adverse effect level (NOAEL) of

about 2 mg/kg/day day (~2x Maximum Recommended Oral Chronic Human

Dose {MROCHD}) and a NOAEL / low adverse effect level (LOAEL) of

about 0.65 to 2 mg/kg/day (~.65-2x MROCHD), has been determined for

dogs and rats, respectively. Several in-vitro and in-vivo tests for mutagenesis

of haloperidol showed no relevant information on any mutagenic effect.

Short-term (6 to 12 month) alternative carcinogenicity studies in various

mouse models have shown no carcinogenic potential. Long-term (18 to 24

month) carcinogenicity studies in rats, up to 50 mg/kg/day (diet) (~50x

MROCHD) showed no increase in a tumor-generating potential, although in

female mice increases in mammary tumors and pituitary gland adenomas, as

well

overall

increases

neoplasia

were

observed

mid-

(6.3

mg/kg/day - diet) (~6.3x MROCHD) and high-dose (25 mg/kg/day - diet)

(~25x

MROCHD) groups.

Mammary

tumors

can be

a consequence

increased prolactin concentrations in the blood. Numerous antipsychotics

also

cause

hyperprolactinemia

humans.

rodents,

haloperidol

Haldol amp PI Approved on 21/08/2013

administration

showed

limited

teratogenic

effects

(cleft

palate

mg/kg/day)

(~5x

MROCHD),

changes

skeletal

ossification

(0.5

mg/kg/day) (~0.5x MROCHD), as well as embryo-toxicity (0.5 mg/kg/day)

(~0.5x

MROCHD).

After

administration

haloperidol,

fertility

female mice and rats was decreased, possibly due to the sedative effect of the

compound.

6.

PHARMACEUTICAL PARTICULARS

6.1. List of Excipients

Lactic acid

W

ater for injection.

6.2. Incompatibilities

None known.

6.3. Special Precautions for Storage

Store below 30°C.

Protect from light.

Keep out of the sight and reach of children.

6.4. Nature and Contents of Container

1 ml amber colored glass ampoules Type I.

6.5. Instructions for Use and Handling

Solution for injection – ampoules

Hold the ampoule between the thumb and

index finger, leaving the tip of the ampoule

free.

With

other

hand,

hold

ampoule putting the index finger against

the neck of ampoule, and the thumb on the

coloured

point

parallel

identification coloured ring(s).

Keeping the thumb on the point, sharply

break the tip of ampoule while holding

firmly the other part of the ampoule in the

Haldol amp PI Approved on 21/08/2013

hand.

Manufacturer: GlaxoSmithkline Manufacturing S.p.A Torrile, Italy

Registration holder: J-C Health Care Ltd., Kibbutz Shefayim 60990, Israel

לע העדוה ( הרמחה עדימ ל ןולעב )תוחיטב אפור

_____________________ ךיראת

25.07.2013

םושירה רפסמו תילגנאב רישכת םש

21146

HALDOL AMPOULES

םושירה לעב םש

J-C Health Care Ltd

ספוט

הז

דעוימ

טורפל

תורמחהה

דבלב

תושקובמה תורמחהה ןולעב קרפ יחכונ טסקט שדח טסקט

Posology and

Method of

Administration

There

considerable

variation

from

patient to patient in the amount of

medication required for treatment. As with

………………..

Haldol Injection is reserved for prompt

control of the acutely agitated patient with

moderately

severe

very

severe

symptoms……….

Acute and Chronic Vomiting:

5 mg administered IM.

There is considerable variation from patient to

patient in the amount of medication required

for treatment. As with all antipsychotic drugs,

dosage should be individualized according to

the needs and response of the individual

patient……….intramuscularly.

Acute and Chronic Vomiting:

5 mg administered IM.

Treatment withdrawal

Gradual

withdrawal

haloperidol

advaisable )see Warnings and Precautions –

Additional considerations(

Special Warnings

and Special

Precautions for Use

Additional considerations

In schizophrenia, ……….

As with all antipsychotic agents, Haldol

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.

Caution is advised in patients with renal failure and

phaeochromocytoma

Haldol

Ampoules

approved

treatment of patients with Dementia-related

psychosis.

Additional considerations

In schizophrenia, ……….

As with all antipsychotic agents, Haldol

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.

Caution is advised in patients with renal failure and

phaeochromocytoma

Undesirable

Effects

Adverse

Reactions

Throughout this section, adverse reactions are presented.

Adverse reactions are adverse events that were considered

to be reasonably associated with the use of haloperidol

based on the comprehensive assessment of the available

adverse event information. A causal relationship with

haloperidol cannot be reliably established in individual

cases. Further, because clinical trials are conducted under

widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared to

rates in the clinical trials of another drug and may not

reflect the rates observed in clinical practice.

Overdose

Treatment

There is no specific antidote. Treatment is

largely supportive. but gastric lavage or

induction of emesis is advised )unless the

patients

obtunded,

comatose

convulsing(, followed by administration of

activated charcoal.

……..

cases

severe

extrapyramidal

reactions, antiparkinson medication )e.g.

benztropine mesylate 1 to 2 mg IM or IV(

should be administered parenterally.

Treatment

There is no specific antidote. Treatment is

largely supportive. Activated charcoal may be

administered. but gastric lavage or induction

of emesis is advised )unless the patients is

obtunded, comatose or convulsing(, followed

by administration of activated charcoal.

………………..

In cases of severe extrapyramidal reactions,

antiparkinson medication )e.g. benztropine

mesylate 1 to 2 mg IM or IV( should be

administered parenterally.

PHARMACOLOGICAL

PROPERTIES

Pharmacodynamic effects

As a direct consequence of the central

dopamine blocking effect, haloperidol

has an

incisive

activity

delusions

hallucinations )probably due to an interaction

in the mesocortical and limbic tissues( and an

activity on the basal ganglia )nigrostriatal

bundles(. …….

On the basis of its limbic activity, haloperidol

exerts a neuroleptic sedative activity and has

been shown to be useful as an adjuvant in the

treatment of chronic pain

……..

The more peripheral antidopaminergic effects

explain

activity

against

nausea

vomiting )via the chemoreceptor-trigger zone(,

relaxation

gastro-intestinal

sphincters and the increased prolactin release

)through an inhibition of the activity of the

prolactin inhibiting factor, PIF, at the level of

the adenohypophysis(.

Pharmacodynamic effects

As a direct consequence of the central dopamine

blocking effect, haloperidol

has an incisive

activity on delusions and hallucinations )probably

due to an interaction in the mesocortical and

limbic tissues( and an activity on the basal ganglia

)nigrostriatal bundles(. …

On the basis of its limbic activity, haloperidol

exerts a neuroleptic sedative activity and has been

shown to be useful as an adjuvant in the treatment

of chronic pain.

…….

The more peripheral antidopaminergic effects

explain the activity against nausea and vomiting

)via

chemoreceptor-trigger

zone(,

relaxation of the gastro-intestinal sphincters and

increased

prolactin

release

)through

inhibition of the activity of the prolactin inhibiting

factor, PIF, at the level of the adenohypophysis(.

Special Precautions

for Storage

Keep out of reach of children

Keep out of the sight and reach of children

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