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NEW ZEALAND DATA SHEET
1. PRODUCT NAME
Arrow – Diazepam 2, tablets, 2 mg
Arrow – Diazepam 5, tablets, 5 mg
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 2 mg or 5 mg of diazepam.
Excipient with known effect: lactose
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Arrow - Diazepam 2: White, round, flat-bevel edged tablet embossed with ‘D2’ on one side and
breakline on the other side. Each tablet contains diazepam 2 mg.
Arrow - Diazepam 5: Yellow, round, flat-bevel edged tablet embossed with ‘D5’ on one side and
breakline on the other side. Each tablet contains diazepam 5 mg.
The tablet can be divided into equal doses.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Adults
Short-term (2 to 4 weeks) symptomatic treatment of anxiety that is severe, disabling or subjecting the
individual to unacceptable distress, occurring alone or in association with insomnia or short-term
psychosomatic, organic or psychotic illness.
Short-term (2 to 4 weeks) treatment of conditions where anxiety may be a precipitating or aggravating
factor, e.g. tension headaches or migraine attacks.
Symptomatic treatment of acute alcohol withdrawal.
Muscle spasm. As an adjunct to the control of muscle spasm in tetanus.
May be useful in the management of cerebral spasticity in selected cases.
As an adjunct to the management of some types of epilepsy, e.g. myoclonus.
Premedication.
Children
Night terrors and somnambulism.
May be useful in controlling tension and irritability in cerebral spasticity in selected cases.
As an adjunct to the control of muscle spasm in tetanus.
Premedication.
4.2 Dose and method of administration
This product may not be interchangeable with other products containing this ingredient in the New
Zealand's market.
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Anxiety states
Adults: Usual dose: 2 mg three times daily.
Maximum dose: Up to 30 mg daily in divided doses. Adjusted on an individual basis.
Insomnia associated with anxiety: 5 to 15 mg before retiring.
The lowest dose which can control symptoms should be used. Treatment should not be continued at
the full dose beyond four weeks. Long-term chronic use is not recommended. Treatment should
always be tapered off gradually. Patients who have taken benzodiazepines for a prolonged time may
require a longer period during which doses are reduced. Specialist help may be appropriate.
Symptomatic relief of acute alcohol withdrawal
Adults: 5 to 20 mg, repeated if necessary in 2 to 4 hours.
Night terrors and somnambulism
Children: 1 to 5 mg at bedtime.
Conditions associated with muscle spasm:
Adults:
Muscle spasm: 2 to 15 mg daily in divided doses.
Management of cerebral spasticity in selected cases: 2 to 60 mg daily in divided doses.
Adjunct to control of muscle spasm in tetanus: 3 to 10 mg/kg bodyweight daily by nasoduodenal tube.
The selected dose should relate to the severity of the case and in extremely severe cases higher doses
have been used.
Children:
Control of tension and irritability in cerebral spasticity in selected cases: 2 to 40 mg daily in divided
doses.
As an adjunct to the control of muscle spasm in tetanus: As for adults.
Adjunct to the management to some types of epilepsy:
Adults: 2 to 60 mg daily in divided doses
Premedication:
Adults: 5 to 20 mg
Children: 2 to 10 mg
Special populations
Elderly or debilitated patients: Doses should not exceed half those normally recommended.
4.3 Contraindications
Diazepam should not be given to patients with acute closed-angle glaucoma, or a predisposition to it,
myasthenia gravis, severe chronic obstructive pulmonary disease, hyperkinesis and children with
swallowing abnormalities.
Diazepam should also be avoided in psychotic patients with mental illness or suicidal tendencies
unless there is a marked component of anxiety.
Also avoid use in patients with hypersensitivity to diazepam.
Diazepam is also contraindicated in acute alcohol intoxication with depressed vital signs.
Diazepam should not be used as monotherapy in patients with depression or those with anxiety and
depression, as suicide may be precipitated in such patients (see Section 4.4. Special warnings and
precautions for use).
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4.4 Special warnings and precautions for use
An underlying cause for insomnia should be sought before deciding upon the use of benzodiazepines
for symptomatic relief. In patients with chronic pulmonary insufficiency, and in patients with chronic
renal or hepatic disease, dosage may need to be reduced.
In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.
Abnormal psychological reactions to benzodiazepines have been reported. Rare behavioural effects
include paradoxical aggressive outbursts, excitement, confusion, and the uncovering of depression
with suicidal tendencies.
Disinhibiting effects may be manifested in various ways. Suicide may be precipitated in patients who
are depressed, and aggressive behaviour towards self and others may be precipitated. Extreme caution
should therefore be used in prescribing benzodiazepines to patients with personality disorders.
In patients with myasthenia gravis, who are prescribed diazepam, care should be taken on account of
pre-existing muscle weakness.
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Treatment should be kept to a minimum and given only under close medical supervision. Little is
known regarding the efficacy or safety of benzodiazepines in long-term use.
Duration of Treatment
For patients with anxiety and/or insomnia the duration of treatment should not exceed 4 weeks
(including the tapering off process).
Continuous long term treatment is not recommended, but intermittent use may be appropriate.
Where long-term therapy is considered essential, the patient should be regularly reviewed.
Tolerance
Tolerance to benzodiazepines may develop from continued therapy. There is evidence that tolerance
develops to the sedative effects of benzodiazepines.
Dependence and Withdrawal
Use of benzodiazepines may lead to the development of physical and psychological dependence. The
risk of dependence increases with dose and duration of treatment. Development of dependence is
common after regular use of diazepam, particularly in patients with a history of drug or alcohol abuse
or marked personality disorders. Regular monitoring in such patients is essential, routine repeat
prescriptions should be avoided and treatment should be withdrawn gradually. Dependence can occur
even with therapeutic doses administered for short periods of time.
Abrupt discontinuation or rapid dosage reduction of diazepam therapy may result in withdrawal or
rebound phenomena. The likelihood and degree of severity of withdrawal symptoms is dependent on
the duration of treatment, dose level and degree of dependency.
Withdrawal from benzodiazepines may be associated with physiological and psychological symptoms
of withdrawal including depression. Symptoms of benzodiazepine withdrawal include anxiety,
depression, impaired concentration, insomnia, headache, dizziness, tinnitus, loss of appetite, tremor,
perspiration, irritability, perceptual disturbances such as hypersensitivity to physical, visual and
auditory stimuli and abnormal taste, nausea, vomiting, abdominal cramps, palpitations, mild systolic
hypertension, tachycardia and orthostatic hypertension.
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Withdrawal symptoms occur with benzodiazepines following normal therapeutic doses given for short
periods of time. Symptoms such as depression, nervousness, rebound insomnia, irritability, sweating
and diarrhoea have been reported following abrupt cessation of treatment in patients receiving even
normal therapeutic doses for short periods of time.
Rare and more serious symptoms include muscle twitching, confusional or paranoid psychosis,
convulsions, hallucinations and a state resembling delirium tremens. Broken sleep with vivid dreams
and increased REM sleep may persist for some weeks after withdrawal of benzodiazepines. More
serious manifestations of withdrawal are more common in patients who have received excessive doses
over a prolonged period, or in patients who have been dependent on alcohol or other narcotic drugs in
the past.
The diazepam dose should be tapered gradually to minimise the occurrence of withdrawal symptoms.
Patients should be advised to consult their physician before either increasing the dose or abruptly
discontinuing the medication. An individualised withdrawal timetable needs to be planned for each
patient in whom dependence is known or suspected.
A sudden discontinuation of benzodiazepines may result in convulsion. Particular care should be
taken in patients with epilepsy, and other patients who have had a history of seizures, alcohol or drug
dependence.
In some cases, patients taking benzodiazepines have developed protracted withdrawal syndrome with
withdrawal symptoms lasting weeks to more than 12 months.
Amnesia
Benzodiazepines may induce anterograde amnesia. Anterograde amnesia may occur even if
benzodiazepines are used within the normal dose range, though this is seen in particular at high dose
levels. The condition occurs most often several hours after ingesting the product. Therefore to reduce
the risk, patients should ensure that they will be able to have an uninterrupted sleep of 7-8 hours.
Amnestic effects may be associated with inappropriate behaviour.
Psychiatric and/or paradoxical reactions
Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rages,
nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects
have been reported during the use of benzodiazepines. These reactions are more likely to occur in
children and elderly patients. Should these reactions occur, treatment with diazepam should be
discontinued.
As with other benzodiazepines and CNS active drugs, three idiosyncratic symptom clusters which
may overlap have been described.
• Amnestic symptoms: anterograde amnesia with appropriate or inappropriate behaviour
• Confusional states: disorientation, derealisation, depersonalisation and/or clouding of
consciousness
• Agitational states: sleep disturbances restlessness, irritability, aggression and excitation.
Depression
Depression has been reported with therapeutic use and withdrawal of benzodiazepine therapy. The
disinhibiting effects of benzodiazepines may also play a role in the precipitation of suicide attempts or
completed suicides. Therefore, benzodiazepines should be used with caution and the prescription size
should be limited in patients with signs and symptoms of a depressive disorder or suicidal tendencies.
Use in the elderly
Benzodiazepines should be used with caution in elderly patients due to a greater susceptibility to
adverse effects such as dizziness, ataxia and confusion which may increase the risk of falls and
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consequent injury. Lower doses should be used in elderly patients (see Section 4.2 Dose and method
of administration.
Paediatric population
Benzodiazepines should not be given to children without careful assessment. The duration of
treatment must be kept to a minimum. Safety and effectiveness of diazepam in paediatric patients
below the age of 6 months have not been established.
Abuse
Abuse of benzodiazepines has been reported. Before prescribing and throughout treatment, assess
each patient’s risk for abuse, misuse and addiction. Because of a risk of abuse, repeat prescriptions
should not be given without medical review.
Benzodiazepines should be used in caution in patients with a history of alcohol or drug abuse,
dependence on CNS depressants, those known to be addiction prone or those whose history suggests
they may increase the dosage on their own initiative. Use of benzodiazepines, particularly patients at
elevated risk, necessitates counselling about the risks and proper use.
Concomitant use with alcohol/CNS depressants
The concomitant use of diazepam with alcohol and/or CNS depressants should be avoided. Such
concomitant use has the potential to increase the clinical effects of diazepam which may include
severe sedation, clinically relevant respiratory and/or cardiovascular depression (see Section 4.5
Interactions with medicines and other forms of interaction).
Risks from Concomitant Use with Opioids
Concomitant use of benzodiazepines, including diazepam, and opioids may result in profound
sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant
prescribing of benzodiazepines and opioids for use in patients for whom alternative treatment options
are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and
benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a
decision is made to prescribe diazepam concomitantly with opioids, prescribe the lowest effective
dosages and minimum durations of concomitant use, and follow patients closely for signs and
symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks
of respiratory depression and sedation when diazepam is used with opioids (see Section 4.5
Interactions with other medicines and other forms of interaction).
4.5 Interaction with other medicines and other forms of interaction
Alcohol
Concomitant intake with alcohol is not recommended. The sedative effect may be enhanced when the
product is used in combination with alcohol. This affects the ability to drive or use machines.
Other CNS depressant medicinal products
If diazepam is given concomitantly with centrally-acting drugs such as neuroleptics, tranquillisers,
antidepressants, hypnotics, analgesics and anaesthetics, the sedative effects are likely to be intensified.
The elderly require special supervision.
The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression
because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines
interact at GABA
A sites, and opioids interact primarily at mu receptors. When benzodiazepines and
opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related
respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and
opioids, and follow patients closely for respiratory depression and sedation.
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Pharmacokinetic studies on potential interactions between diazepam and anti-epileptic drugs have
produced conflicting results. Both depression and elevation of drug levels, as well as no change, have
been reported.
When diazepam is used in conjunction with anti-epileptic drugs, side-effects and toxicity may be
more evident, particularly with hydantoins or barbiturates or combinations including them. This
requires extra care in adjusting dosage in the initial stages of treatment.
Phenobarbital
Phenobarbital increases the risk of sedation and respiratory depression when co-administered with
diazepam due to the additive CNS-depressant effects.
Also, phenobarbital is a known CYP3A4 inducer and increases the hepatic metabolism of diazepam,
thus decreasing its effects.
Clozapine
When taken concomitantly with diazepam, treatment with clozapine may lead to severe hypotension,
respiratory depression, unconsciousness and potentially fatal respiratory and/or cardiac arrest due to
synergistic CNS depressant effects. Therefore, concomitant use of diazepam and clozapine is not
recommended and should be avoided.
Opioids
The concomitant use of sedative medicines such as benzodiazepines or related drugs with opioids
increases the risk of sedation, respiratory depression, coma and death because of additive CNS
depressant effect. The dosage and duration of concomitant use should be limited (see Section 4.4
Special warnings and precautions for use).
Theophylline
When this medicinal product is concomitantly administered with theophylline, inhibition of the
pharmacodynamic effects of diazepam may occur, e.g. reduction of sedation and psychomotor effects.
This possibly occurs due to competitive binding of theophylline to adenosine receptors in the brain.
Muscle relaxants (suxamethonium, tubocurarin)
Modified intensity of neuromuscular blockage may occur.
Hepatic metabolism
Diazepam is mainly metabolised to the pharmacologically active metabolites N-desmethyldiazepam,
temazepam and oxazepam. The oxidative metabolism of diazepam is mediated by CYP3A4 and
CYP2C19 isoenzymes. Oxazepam and temazepam are further conjugated to glucuronic acid.
Inhibitors of CYP3A4 and/or CYP2C19 can give rise to increased concentrations of diazepam while
enzyme inducing drugs can result in substantially decreased plasma concentrations of diazepam.
CYP3A4 and CYP2C19 inducers
Medicinal products that are known inducers of CYP3A4 can substantially increase the hepatic
metabolism and clearance of diazepam. Concomitant administration of CYP inducers and diazepam
can lead to significantly decreased effects of diazepam. Therefore, concomitant use of diazepam is not
recommended with rifampicin, carbamazepine, phenytoin, phenobarbital, etc.
When diazepam is co-administered with corticosteroids, it may lead to increased metabolism of
diazepam due to induction of CYP3A4 enzyme, or enzymes responsible for glucuronidation of
diazepam.
CYP3A4 and CYP2C19 inhibitors
Antiviral agents (atazanavir, ritonavir, delavirdine, efavirenz, indinavir, nelfinavir, saquinavir)
Antiviral agents may inhibit the CYP3A4 metabolic pathway for diazepam.
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Increased risk of sedation and respiratory depression may occur when these medicinal products are
concomitantly used with diazepam. Therefore, concomitant use should be avoided.
Azoles (fluconazole, itraconazole, ketoconazole, voriconazole)
Co-administration of azole antifungals may lead to increased plasma concentration of
benzodiazepines, due to inhibition of the CYP3A4 and/or CYP2C19 metabolic pathway.
When these medicinal products are concomitantly used, increased risk of undesired effects and
toxicity of diazepam may occur. Concomitant use should be avoided or the dose of diazepam reduced.
Fluvoxamine
Fluvoxamine inhibits both CYP3A4 and CYP2C19 which leads to inhibition of the oxidative
metabolism of diazepam. Co-administration with fluvoxamine results in an increased half-life of
diazepam.When fluvoxamine is co-administered with diazepam, drowsiness, reduced psychomotor
performance and memory may occur. Preferably, benzodiazepines that are metabolised via a non-
oxidative pathway should be used instead.
Cimetidine
Cimetidine inhibits the hepatic metabolism of diazepam, reducing its clearance and prolonging its
half-life. This interaction leads to increased effects of diazepam and increased risk of drowsiness.
Reduction of the diazepam dose may be necessary.
Omeprazole, esomeprazole
Omeprazole and esomeprazole inhibit the CYP2C19 metabolic pathway for diazepam, resulting in an
increased half-life and concentrations of diazepam. This leads to increased effects of diazepam.
Reduction of the diazepam dose may be necessary.
Isoniazid
Isoniazid inhibits the CYP2C19 and CYP3A4 metabolic pathway for diazepam. This leads to
increased effects of diazepam.
Fluoxetine
Fluoxetine inhibits the metabolism of diazepam via CYP2C19 and other pathways, resulting in
elevated plasma concentrations and decreased clearance of diazepam. This can lead to increased effect
of diazepam. Concomitant use should be monitored closely.
Disulfiram
Reduced metabolism of diazepam leading to prolonged half-life and increased plasma concentration
of diazepam. The elimination of the N-desmethyl metabolites of diazepam is slowed down which can
give rise to marked sedative effects.
Oral contraceptives
Effect on diazepam: Inhibition of oxidative metabolism of diazepam.
Effect on oral contraceptives: Co-administration of diazepam and combined oral contraceptives has
been known to cause breakthrough bleeding. The mechanism of this reaction is unknown.
Grapefruit juice
Grapefruit juice is believed to inhibit CYP3A4 and increases the plasma concentration of diazepam.
This may lead to increased effects of diazepam.
Other
Cisapride
When administered concomitantly with diazepam, cisapride may cause accelerated absorption of
diazepam. This may result in temporary increase of the sedative effects of orally administered
diazepam.
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Levodopa
Concomitant use with diazepam may result in reduced effects of levodopa.
Valproic acid
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. This
can lead to increased serum concentrations of diazepam.
Ketamine
Due to similar oxidative processes, diazepam competitively inhibits ketamine metabolism. Pre-
medication with diazepam leads to prolonged half-life of ketamine with enhanced effect as a result.
4.6 Fertility, pregnancy and lactation
Use in pregnancy
Category C
If the product is prescribed to a woman of childbearing potential, she should be warned to contact her
physician regarding discontinuance of the product if she intends to become or suspects that she is
pregnant.
There are limited amount of data from the use of diazepam in pregnant women. Studies in animals
have shown reproductive toxicity.
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.
Moreover, infants born to mothers who took benzodiazepines chronically during the latter stages of
pregnancy may have developed physical dependence and may be at some risk for developing
withdrawal symptoms in the postnatal period.
Use in lactation
Since benzodiazepines are found in breast milk, benzodiazepines should not be given to breast feeding
mothers.
Fertility
Studies in animals have shown a decrease in pregnancy rate and reduced number of surviving
offspring in rats at high doses. There are no human data.
4.7 Effects on ability to drive and use machines
Diazepam has a significant influence on the ability to drive and to operate machines.
During treatment with diazepam, undesirable effects such as impaired motor skills, tremor,
somnolence, amnesia, impaired concentration and tiredness may occur.
The effect can be observed immediately after the start of treatment and can last for several days
following discontinuation due to the long half-life of diazepam.
If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased (see
Section 4.5 Interactions with other medicines and other forms of interaction).
Patients should be advised that, like all medicaments of this type, diazepam may modify patients'
performance at skilled tasks (driving, operating machinery, etc) to a varying degree depending on
dosage, administration and individual susceptibility. Patients should further be advised that alcohol
may intensify any impairment and should, therefore be avoided during treatment.
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4.8 Undesirable effects
Summary of the safety profile
Drowsiness, numbed emotions, reduced alertness, confusion, fatigue, headache, dizziness, muscle
weakness, ataxia or double vision predominantly occur at the start of therapy but usually disappear
with repeated administration. Among elderly patients there may be confusion conditions at high dose
levels.
There is an increased risk of falls and associated fractures in elderly patients using benzodiazepines.
Increased salivary and bronchial secretion has been reported, particularly in children.
Amnesia
Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages.
Amnestic effects may be associated with inappropriate behaviour.
Dependence
Chronic use (even at therapeutic doses) may lead to the development of physical and psychic
dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena. Abuse
of benzodiazepines has been reported.
List of adverse reactions
The frequencies of adverse events are ranked according to the following: 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), not known (cannot be estimated from the available data).
Blood and lymphatic system disorders
Very rare: Leukopenia
Immune system disorders
Not known: Anaphylactic reaction
Metabolism and nutrition disorders
Rare: Increased appetite
Psychiatric disorders
Rare: Increased or decreased libido
Not known: Confusional state, psychiatric and paradoxical reactions, numbed emotions, depression
Nervous system disorders
Common: Ataxia
Uncommon: Balance disorders
Rare: Loss of consciousness, insomnia
Not known: Tremor, somnolence, impaired motor ability, anterograde amnesia, disturbance in
attention, dizziness, headache, dysarthria, depressed levels of consciousness
Eye disorders
Not known: Vision blurred, diplopia, nystagmus
Cardiac disorders
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Rare: Bradycardia
Not known: Cardiac failure, cardiac arrest
Vascular disorders
Rare: Hypotension, syncope
Respiratory, thoracic and mediastinal disorders
Not known: Respiratory depression, respiratory arrest, increased bronchial secretion
Gastrointestinal disorders
Not known: Salivary hypersecretion, nausea, vomiting, constipation, diarrhoea, dry mouth
Hepatobiliary disorders
Rare: Jaundice
Skin and subcutaneous tissue disorders
Uncommon: Pruritus, urticarial, rash
Musculoskeletal and connective tissue disorders
Not known: Muscular weakness
Renal and urinary disorders
Rare: Urinary retention
Not known: Urinary incontinence
Reproductive system and breast disorders
Rare: Gynaecomastia, impotence
General disorders and administration site conditions
Common: Fatigue, withdrawal syndrome
Investigations
Not known: Aspartate aminotransferase increased, alanine aminotransferase increased, blood alkaline
phosphatase increased.
Description of selected adverse reactions
Psychiatric and paradoxical reactions
Psychiatric and paradoxical reactions such as excitation, restlessness, agitation, irritability,
aggressiveness, delusion, rages, hallucinations, psychoses, memory loss, nightmares, inappropriate
behaviour and other adverse behavioural effects are known to occur when using benzodiazepines or
benzodiazepine-like agents. These reactions may be quite severe. They are more likely to occur in
children and the elderly. Diazepam should be discontinued if such symptoms occur (see Section 4.4
Special warnings and precautions for use).
Depression
Pre-existing depression may be unmasked during benzodiazepine use.
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Anterograde amnesia
May occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be
associated with inappropriate behaviour (see Section 4.4 Special warnings and precautions for use).
Withdrawal symptoms
Upon abrupt discontinuation of diazepam, withdrawal symptoms may occur (anxiety, panic,
palpitations, sweating, tremor, gastrointestinal disorders, irritability, aggression, disrupted sensory
perception, muscle spasms, general malaise, loss of appetite, paranoid psychosis, delirium and
epileptic attacks.) The likelihood and degree of severity of withdrawal symptoms is dependent on the
duration of treatment, dose level and degree of dependency.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows
continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked
to report any suspected adverse reactions (https://nzphvc.otago.ac.nz/reporting/).
4.9 Overdose
Symptoms
In every case of overdose with diazepam, the presence of multiple drug intoxication must be
considered.
In overdose with diazepam, symptoms such as confusion, somnolence, ataxia, dysarthria, hypotension
and muscular weakness may occur. In case of severe overdose, central nervous system depression
and respiratory depression can occur. This may lead to cyanosis, unconsciousness, coma and cardiac
arrest. Therefore, the patient must be placed under continuous monitoring.
In recovery phase from an overdose with diazepam, agitation has been reported.
Symptoms of overdose can be more pronounced under the concomitant influence of alcohol or other
CNS depressants.
Treatment
In early stage of intoxication, gastrointestinal absorption should be reduced by administering activated
charcoal.
A clear airway and adequate ventilation must be maintained, especially in unconscious patients.
Further treatment should be symptomatic and supportive. In intensive care unit, special attention
should be given to monitoring of cardiovascular and respiratory functions. Patient’s heart rate, blood
pressure and body temperature should also be closely monitored.
Flumazenil, a benzodiazepine antagonist, may be administered for the reversal of central depressant
effects of diazepam. Flumazenil may only be administered under close supervision.
Due to its high level of binding to plasma proteins, and its large volume of distribution, diazepam is
poorly removed by forced diuresis or dialysis.
For advice on the management of overdose please contact the National Poisons Centre on 0800
POISON (0800 764766).
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anxiolytics, benzodiazepine derivatives, ATC code: N05BA01
Diazepam is a benzodiazepine tranquilliser that is believed to act by facilitating the synaptic actions of
gamma aminobutyric acid (GABA). GABA is one of the major inhibitory neurotransmittors of the
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CNS. Diazepam does not act at the same site as GABA, but at a presumably allosterically-linked site,
called the benzodiazepine receptor. It is through this site that the anticonvulsant, sedative, skeletal
muscle relaxant and amnestic properties of diazepam are mediated.
5.2 Pharmacokinetic properties
Diazepam is readily and completely absorbed from the gastrointestinal tract. Peak plasma
concentrations occur in 30 to 60 minutes after administration, but may be further delayed in elderly
patients. Diazepam has a biphasic elimination curve, the terminal half-life being 1-2 days. It is
extensively protein-bound.
Diazepam is metabolised in the liver and the following active metabolites are produced:
desmethyldiazepam, methyloxazepam, oxazepam and temazepam. The metabolites are then
eliminated by the kidneys in either their free or conjugated form. The half-life of diazepam is
prolonged in patients with kidney or liver disease. Diazepam and its active metabolites show
significant accumulation during multiple dosage regimens. Steady state plasma concentrations are
attained in 5 days to 2 weeks, as some of its metabolites take several days to weeks to be eliminated.
5.3 Preclinical safety data
None.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose, magnesium stearate, maize starch, quinolone yellow (5 mg only).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
24 months
6.4 Special precautions for storage
Store below 30°C. Protect from light.
6.5 Nature and contents of container
PVC/Aluminium foil blister strips: 50 tablets
High density polyethylene bottles: Pack size of 200 and 500 tablets.
Not all pack types or pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements for disposal.
7. MEDICINE SCHEDULE
Controlled Drug C5
8. SPONSOR
Teva Pharma (New Zealand) Limited
PO Box 128 244
Remuera
Auckland 1541
Telephone: 0800 800 097
9. DATE OF FIRST APPROVAL
14 May 2009
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10. DATE OF REVISION OF THE TEXT
11 May 2022
SUMMARY TABLE OF CHANGES
Section changed
Summary of new information
4.3, 4.4
Additional information to more adequately describe the risks
of misuse, abuse, addiction, dependence and withdrawal
reactions, as requested by Medsafe.
4.5, 4.6, 4.7, 4.8, 4.9
Updated to fully align with Teva Company Core Safety
Information (CCSI).
