ATIVAN INJECTION

Active substance: LORAZEPAM

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Ativan® Injection

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Ativan Injection contains the active ingredient lorazepam at a concentration of
4 mg/ml.
Lorazepam (INN, BAN) is chemically defined as 7-chloro-5-(o-chlorphenyl)1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one.

3

PHARMACEUTICAL FORM
Solution for injection
Clear, colourless solution supplied in clear glass ampoules containing 4 mg
lorazepam in 1 ml of solution.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Pre-operative medication or premedication for uncomfortable or prolonged
investigations e.g. bronchoscopy, arteriography, endoscopy.
The treatment of acute anxiety states, acute excitement or acute mania.
The control of status epilepticus.

4.2

Posology and method of administration

Dosage and duration of therapy should be individualised. The lowest effective dose should be
prescribed for the shortest time possible.
Treatment in all patients should be withdrawn gradually to minimise possible withdrawal
symptoms (See Special Warnings and Precautions for Use).

Route of administration
Ativan Injection can be given intravenously or intramuscularly. However, the intravenous
route is to be preferred. Care should be taken to avoid injection into small veins and
intra-arterial injection.
Absorption from the injection site is considerably slower if the intramuscular route is used and
as rapid an effect may be obtained by oral administration of lorazepam.
Ativan should not be used for long-term chronic treatment.
Preparation of the injection
Ativan Injection is slightly viscid when cool.
Intramuscular administration:
A 1:1 dilution of Ativan Injection with normal saline or Sterile Water for Injection BP is
recommended in order to facilitate intramuscular administration.
Intravenous administration:
For intravenous administration, Ativan Injection should always be diluted with saline or
Sterile Water for Injection BP as a 1:1 dilution.
Ativan Injection is presented as a 1ml solution in a 2ml ampoule to facilitate dilution.
Ativan Injection should not be mixed with other drugs in the same syringe.
Dosage:
1. Premedication:
Adults:

0.05mg/kg (3.5mg for an average 70kg man). By the intravenous route the
injection should be given 30-45 minutes before surgery when sedation will be
evident after 5-10 minutes and maximal loss of recall will occur after 30-45
minutes.
By the intramuscular route the injection should be given 1-11/2 hours before
surgery when sedation will be evident after 30-45 minutes and maximal loss
of recall will occur after 60-90 minutes.

Children:

Ativan Injection is not recommended in children under 12.

2. Acute Anxiety
Adults:

0.025-0.03mg/kg (1.75-2.1mg for an average 70kg man). Repeat 6 hourly.

Children:

Ativan Injection is not recommended in children under 12.

3. Status epilepticus
Adults:

4mg intravenously

Children:
Elderly:

2mg intravenously
The elderly may respond to lower doses and half the normal adult dose may
be sufficient.

Patients with Renal or Hepatic impairment:
Lower doses may be sufficient in these patients (See Special Warnings and Precautions for
Use). Use in patients with severe hepatic insufficiency is contraindicated.

4.3

Contraindications
• Acute pulmonary insufficiency.
• Hypersensitivity to benzodiazepines, including Ativan Injection or any of
the vehicle
constituents (polyethylene glycol, propylene glycol, benzyl
alcohol).
• Sleep apnoea syndrome
• Myasthenis gravis
• Severe hepatic insufficiency
• Ativan Injection contains benzyl alcohol and is contraindicated in infants or
young
children, up to 3 years old.
Ativan Injection is not recommended for out-patient use unless the patient is
accompanied.

4.4

Special warnings and precautions for use
Prior to use, Ativan Injection may be diluted for IM administration and
should always be diluted for IV administration with equal amounts of
compatible diluent (see Posology and Method of Administration). Intravenous
injection should be administered slowly except in the control of status
epilepticus where rapid injection is required.
The possibility that respiratory arrest may occur or that the patient may have
partial airway obstruction should be considered. Therefore, equipment
necessary to maintain a patent airway and to support respiration/ventilation
should be available and used where necessary.
The use of benzodiazepines, including lorazepam, may lead to physical and
psychological dependence.
Severe anaphylactic/anaphylactoid reactions have been reported with the use
of benzodiazepines. Cases of angioedema involving the tongue, glottis or
larynx have been reported in patients after taking the first or subsequent
doses of benzodiazepines. Some patients taking benzodiazepines have had
additional symptoms such as dyspnoea, throat closing, or nausea and
vomiting. Some patients have required medical therapy in the emergency
department. If angioedema involves the tongue, glottis or larynx, airway

obstruction may occur and be fatal. Patients who develop angioedema after
treatment with a benzodiazepine should not be rechallenged with the drug.
It is recommended that patients receiving Ativan Injection should remain
under observation for at least eight hours and preferably overnight. When
Ativan Injection is used for short procedures on an outpatient basis, the
patient should be accompanied when discharged.
Patients should be advised that their tolerance for alcohol and other CNS
depressants will be diminished in the presence of Ativan Injection. Alcoholic
beverages should not be consumed for at least 24 to 48 hours after receiving
Ativan Injection.
Use of benzodiazepines, including lorazepam, may lead to potentially fatal
respiratory depression. Extreme care must be taken in administering Ativan
Injection to elderly or very ill patients and to those with limited pulmonary
reserve or compromised respiratory function (eg, chronic obstructive
pulmonary disease [COPD]), because of the possibility that apnoea and/or
cardiac arrest may occur. Care should also be exercised when administering
Ativan Injection to a patient with status epilepticus, especially when the
patient has received other central nervous system depressants.
There is no evidence to support the use of Ativan Injection in coma or shock.
Ativan is not intended for the primary treatment of psychotic illness or
depressive disorders, and should not be used alone to treat depressed
patients. The use of benzodiazepines may have a disinhibiting effect and
may release suicidal tendencies in depressed patients.
Pre-existing depression may emerge during benzodiazepine use.
There are no clinical data available for Ativan Injection with regard to abuse
or dependence. However, based upon experience with oral benzodiazepines,
doctors should be aware that repeated doses of Ativan Injection over a
prolonged period of time may lead to physical and psychological
dependence. The risk of dependence on Ativan is low when used at the
recommended dose and duration, but increases with higher doses and longer
term use. The risk of dependence is further increased in patients with a
history of alcoholism or drug abuse, or in patients with significant
personality disorders. Therefore, use in individuals with a history of
alcoholism or drug abuse should be avoided.
Dependence may lead to withdrawal symptoms, especially if treatment is
discontinued abruptly. Therefore, the drug should always be discontinued
gradually - using the oral preparation if necessary.
Symptoms reported following discontinuation of oral benzodiazepines include
headaches, muscle pain, anxiety, tension, depression, insomnia, restlessness,
confusion, irritability, sweating, and the occurrence of "rebound" phenomena
whereby the symptoms that led to treatment with benzodiazepines recur in an

enhanced form. These symptoms may be difficult to distinguish from the
original symptoms for which the drug was prescribed.
In severe cases the following symptoms may occur: derealisation;
depersonalisation; hyperacusis; tinnitus; numbness and tingling of the
extremities; hypersensitivity to light, noise, and physical contact; involuntary
movements; vomiting; hallucinations; convulsions. Convulsions may be more
common in patients with pre-existing seizure disorders or who are taking other
drugs that lower the convulsive threshold, such as antidepressants.
It may be useful to inform the patient that treatment will be of limited duration
and that it will be discontinued gradually. The patient should also be made
aware of the possibility of "rebound" phenomena to minimise anxiety should
they occur.
Withdrawal symptoms (eg, rebound insomnia) can appear following cessation
of recommended doses after as little as one week of therapy.
There are indications that, in the case of benzodiazepines with a short duration
of action, withdrawal phenomena can become manifest within the dosage
interval, especially when the dosage is high.
When benzodiazepines with a long duration of action are being used, it is
important to warn against changing to a benzodiazepine with a short duration
of action, as withdrawal symptoms may develop.
Abuse of benzodiazepines has been reported.
Anxiety or insomnia may be a symptom of several other disorders. The
possibility should be considered that the complaint may be related to an
underlying physical or psychiatric disorder for which there is more specific
treatment.
Caution should be used in the treatment of patients with acute narrow-angle
glaucoma.
As with all benzodiazepines, the use of lorazepam may worsen hepatic
encephalopathy.
Patients with impaired renal or hepatic function should be monitored frequently
and have their dosage adjusted carefully according to patient response. Lower
doses may be sufficient in these patients. The same precautions apply to
elderly or debilitated patients and patients with chronic respiratory
insufficiency.
As with all CNS-depressants, the use of benzodiazepines may precipitate
encephalopathy in patients with severe hepatic insufficiency. Therefore, use in
these patients is contraindicated.
Some patients taking benzodiazepines have developed a blood dyscrasia, and
some have had elevations in liver enzymes. Periodic haematologic and liver-

function assessments are recommended where repeated courses of treatment are
considered clinically necessary.
Transient anterograde amnesia or memory impairment has been reported in
association with the use of benzodiazepines. This effect may be
advantageous when Ativan is used as a premedicant.
Paradoxical reactions have been occasionally reported during
benzodiazepine use (see Undesirable effects). Such reactions may be more
likely to occur in children and the elderly. Should these occur, use of the
drug should be discontinued.
Although hypotension has occurred only rarely, benzodiazepines should be
administered with caution to patients in whom a drop in blood pressure might
lead to cardiovascular or cerebrovascular complications. This is particularly
important in elderly patients.
Ativan Injection contains the excipients polyethylene glycol and propylene
glycol. There have been reports of propylene glycol toxicity (e.g. lactic
acidosis, hyperosmolality, hypotension) and polyethylene glycol toxicity
(e.g. acute tubular necrosis) during administration of Ativan Injection,
including at higher than recommended doses. Central nervous system
toxicity, including seizures, as well as unresponsiveness, tachypnoea,
tachycardia and diaphoresis have also been associated with propylene glycol
toxicity. Those prone to propylene glycol accumulation and its potential
adverse effects include patients with impaired alcohol and aldehyde
dehydrogenase enzyme systems, those with renal or hepatic disease; and
paediatric patients.

4.5

Interaction with other medicinal products and other forms of interaction
Not recommended: Concomitant intake with alcohol
The sedative effects may be enhanced when the product is used in
combination with alcohol. This affects the ability to drive or use machines.
The benzodiazepines, including Ativan Injection, produce additive CNS
depressant effects when co-administered with other medications which
themselves produce CNS depression, e.g. barbiturates, antipsychotics,
sedatives/hypnotics, anxiolytics, antidepressants, narcotic analgesics,
sedative antihistamines, anticonvulsants and anaesthetics.
Concurrent administration of lorazepam with sodium valproate may result in
reduced clearance (20 to 40%) and increased concentrations of lorazepam.
Therefore clinical monitoring is advised and lorazepam dosage should be
reduced when appropriate.

Concurrent administration of lorazepam with probenecid may result in
reduced clearance, increased elimination half-life and increased
concentrations of lorazepam. Therefore clinical monitoring is advised and
lorazepam dosage should be reduced when appropriate.
An enhancement of the euphoria induced by narcotic analgesics may occur
with benzodiazepine use, leading to an increase in psychic dependence.
Compounds which inhibit certain hepatic enzymes (particularly cytochrome
P450) may enhance the activity of benzodiazepines. To a lesser degree this
also applies to benzodiazepines which are metabolised only by conjugation.
The addition of scopolamine to Ativan Injection is not recommended, since
their combination has been observed to cause an increased incidence of
sedation, hallucination and irrational behaviour.
Concomitant use of clozapine and lorazepam may produce marked sedation,
excessive salivation, and ataxia.
Administration of theophylline or aminophylline may reduce the sedative
effects of benzodiazepines, including lorazepam.
There have been reports of apnoea, coma, bradycardia, heart arrest and death
with the concomitant use of lorazepam injection solution and haloperidol.

4.6

Pregnancy and lactation
Ativan Injection should not be used during pregnancy, especially during the
first and last trimesters, unless in the judgement of the physician such
administration is clinically justifiable. Benzodiazepines may cause foetal
damage when administered to pregnant women.
If the drug is prescribed to a woman of childbearing potential, she should be
warned to contact her physician about stopping the drug if she intends to
become, or suspects that she is, pregnant.
Use of Ativan Injection during the late phase of pregnancy may require
ventilation of the infant at birth.
If, for compelling medical reasons, the product is administered during the late
phase of pregnancy, or during labour at high doses, effects on the neonate,
such as hypothermia, hypotonia and moderate respiratory depression, can be
expected, due to the pharmacological action of the compound.
Infants of mothers who ingested benzodiazepines for several weeks or more
preceding delivery have been reported to have withdrawal symptoms during
the postnatal period.

Symptoms such as hypotonia, hypothermia, respiratory depression, apnoea,
feeding problems, and impaired metabolic response to cold stress have been
reported in neonates born of mothers who have received benzodiazepines
during the late phase of pregnancy or at delivery.
There are insufficient data regarding obstetrical safety of parenteral Ativan,
including use in cesarean section. Such use, therefore, is not recommended.
Since benzodiazepines are found in breast milk, Ativan Injection should not be
given to breast feeding mothers unless the expected benefit to the woman
outweighs the potential risk to the infant.

4.7

Effects on ability to drive and use machines
Sedation, amnesia, impaired concentration and impaired muscular function
may adversely affect the ability to drive or use machines. Therefore, patients
should not drive or operate machinery within 24-48 hours of administration of
Ativan Injection and should be advised not to take alcohol (see also
interactions).

4.8

Undesirable effects
Adverse reactions are listed in the table in CIOMS frequency categories:
Very common:
Common:
Uncommon:
Rare:
Very rare:
Undetermined:

≥ 10%
≥ 1% and < 10%
≥ 0.1% and < 1%
≥ 0.01% and < 0.1%
< 0.01%
Insufficient data to calculate significant frequencies.

System Organ Class
Adverse Reaction
and Frequency
Blood and lymphatic system disorders
Undetermined:

Thrombocytopenia, agranulocytosis,
pancytopenia.

Immune system disorders
Undetermined:

Hypersensitivity reactions, anaphylactic/oid
reactions, angioedema.

Endocrine disorders
Undetermined:

Syndrome of Inappropriate Antidiuretic Hormone
secretion (SIADH)

Metabolism and nutrition disorders
Undetermined:

Hyponatremia.

Psychiatric disorders
Common:
Undetermined:

Confusion, depression, unmasking of depression.
Disinhibition, euphoria, suicidal ideation/attempt.
Paradoxical reactions, including anxiety,
agitation, excitation, hostility, aggression, rage,
sleep disturbances/insomnia, sexual arousal, and
hallucinations.

Nervous system disorders*
Very common:
Common:
Undetermined:

Sedation, drowsiness.
Ataxia, dizziness.
Extrapyramidal symptoms, tremor, vertigo, visual
disturbances (including diplopia and blurred
vision), dysarthria/slurred speech, headache,
convulsions/seizures, amnesia, coma.
* Benzodiazepine effects on the CNS are dose dependent, with more severe
CNS depression occurring with higher doses.
Vascular disorders
Undetermined:

Hypotension

System Organ Class
Adverse Reaction
and Frequency
Respiratory, thoracic and mediastinal disorders†
Undetermined:

Respiratory depression, apnoea, worsening of
sleep
Worsening of obstructive pulmonary disease.

The extent of respiratory depression with benzodiazepines is dose dependent
with more severe depression occurring with high doses.

Gastrointestinal disorders
Uncommon:
Undetermined:

Nausea.
Constipation.

Hepatobiliary disorders
Undetermined:

Increase in bilirubin, increase in liver
transaminases, increase in alkaline phosphatase.

Skin and subcutaneous tissue disorders
Undetermined:

Allergic skin reactions, alopecia.

Reproductive system and breast disorders
Uncommon:

Change in libido, impotence, decreased orgasm.

General disorders and administration site conditions
Very common:
Common:

Fatigue.
Muscle weakness, asthenia.

Undetermined:

Hypothermia

Tolerance at the injection site is generally good although, rarely, pain and
redness have been reported after Ativan Injection.
Transient anterograde amnesia or memory impairment may occur using
therapeutic doses, the risk increasing at higher doses (see Special warnings
and precautions for use).
Paradoxical reactions may be more likely to occur in children and the elderly
(see Special warnings and precautions for use).

4.9

Overdose
In the management of overdosage with any drug, it should be borne in mind
that multiple agents may have been taken.
Overdosage of benzodiazepines is usually manifested by degrees of central
nervous system depression ranging from drowsiness to coma. In mild cases,
symptoms include drowsiness, mental confusion and lethargy. In more
serious cases, and especially when other CNS-depressant drugs or alcohol
are ingested, symptoms may include ataxia, hypotension, hypotonia,
respiratory depression, cardiovascular depression, coma and, very rarely,
death.
Propylene glycol toxicity and polyethylene glycol toxicity have been
reported following higher than recommended doses of Ativan Injection (See
Section 4.4 Special warnings and precautions for use).
Treatment of overdosage is mainly supportive including monitoring of vital
signs and close observation of the patient. An adequate airway should be
maintained and assisted respiration used as needed. Hypotension, though
unlikely, may be controlled with noradrenaline. Lorazepam is poorly
dialysable.
The benzodiazepine antagonist, flumazenil, may be useful in hospitalised
patients for the management of benzodiazepine overdosage. Flumazenil
product information should be consulted prior to use. The physician should be
aware of a risk of seizure in association with flumazenil treatment, particularly
in long-term benzodiazepine users and in tricyclic antidepressant overdose.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Ativan is a benzodiazepine with anxiolytic, sedative, hypnotic, anticonvulsant
and muscle relaxant properties.

5.2

Pharmacokinetic properties
Ativan Injection is readily absorbed when given intramuscularly.
Peak
plasma concentrations occur approximately 60-90 minutes following
intramuscular administration.
Ativan is metabolised by a simple one-step process to a pharmacologically
inactive glucuronide. There is minimal risk of accumulation after repeated
doses, giving a wide margin of safety.

There are no major active metabolites. The elimination half-life is about 12-16
hours when given intramuscularly or intravenously.

5.3

Preclinical safety data
Nothing of relevance to the prescriber.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Polyethylene glycol 400
Benzyl alcohol
Propylene glycol

6.2

Incompatibilities
None known.

6.3

Shelf life
12 months

6.4

Special precautions for storage
Store and transport refrigerated (2°C to 8°C).
Keep ampoule in the outer carton.

6.5

Nature and contents of container
1ml solution in 2ml ampoules (Type I glass) with a one-point-cut opening, position
marked by red spot in pack sizes of 10.

6.6

Special precautions for disposal
None

7

MARKETING AUTHORISATION HOLDER
Pfizer Limited
Ramsgate Road
Sandwich
Kent
CT13 9NJ
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 00057/1279

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
12/03/2009

10

DATE OF REVISION OF THE TEXT
01/08/2012

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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