Oral dosage forms
Symptomatic treatment of anxiety, agitation, and psychic tension resulting from
psychoneurotic conditions and temporary situational disturbances. As an adjuvant in the
treatment of mental and organic disorders with an anxiety component. Anxiety can
manifest itself as an obviously anxious mood, as worried behaviour, and/or via functional
autonomic or motor symptoms (palpitations, sweating, sleep disturbance, tremor, nervous
restlessness, etc.).
All dosage forms
As adjuvant therapy to relieve reflex muscle spasms associated with local trauma
(wounds, inflammation) and to combat spasticity associated with damage to spinal and
supraspinal interneurons; such changes can occur, for example, in spasms of cerebral
origin, paraplegia, athetosis, and the stiff-man syndrome.

In order to obtain the greatest possible benefit from the product, the dose should be
carefully adjusted on an individual basis. The standard daily doses indicated below are
appropriate to the needs of most patients, although higher doses may be required in
certain cases.

Oral administration
Standard dosage with oral administration in adults: Initial dose: 5–10 mg. Depending on
symptom severity, the standard daily dose is 5–20 mg. Individual oral doses should
generally not exceed 10 mg. Time of ingestion is determined by patients’ individual
needs, with evening dosing being most appropriate in most cases.
Special dosage instructions
Oral dosage forms
Dosage in children: 0.1–0.3 mg per kg body weight per day.
The tablets can be divided to facilitate dosage. In hepatic impairment particular attention
must be paid to individualised dose adjustment.
All dosage forms
Elderly patients and patients with hepatic impairment should receive a lower dose. These
patients should be checked regularly at the start of treatment so that if necessary the dose
can be reduced and/or the dosage interval prolonged in order to avoid overdosage as a
result of product accumulation.
After about one week of treatment consideration should be given to reducing the dose.
Duration of treatment
The duration of treatment should be as short as possible. The patient should be reassessed
at regular intervals and the need for continued treatment determined, especially if the
patient no longer has any symptoms. The duration of treatment – the tapering-off period
included – should not exceed two to three months. More prolonged treatment should be
contemplated only after a reassessment of the situation. At the start of treatment it may be
useful to inform the patient that the duration of treatment will be limited and to explain in
detail how the dose will be tapered off.
It is also important to inform the patient of the possibility of rebound phenomena so that
he/she will not be too worried should these occur. There is evidence that with short-acting
benzodiazepines withdrawal phenomena can occur even within the dose interval,
especially with high doses. When long-acting benzodiazepines such as diazepam are used
it is mandatory to warn the patient against switching to a short-acting benzodiazepine, as
this can result in withdrawal phenomena.

Known hypersensitivity to benzodiazepines or to any excipient listed under Composition. Severe respiratory failure, severe liver failure, sleep apnea syndrome and myasthenia gravis. Benzodiazepines are not recommended for the primary treatment of psychotic disorders. Benzodiazepines should not be used for the treatment of depression or anxiety states related to depression, as such patients are at risk of suicide.

Simultaneous use of alcohol/central nervous system depressants
Simultaneous use of Valium and alcohol or other central nervous system depressants
should be avoided. Such simultaneous use may potentiate the clinical effect of Valium.
This may have certain repercussions such as severe sedation or clinically relevant
depression of respiratory and/or cardiovascular function (see Interactions).
History of alcohol or prescription drug abuse
Valium should only be used with extreme caution in patients with a history of alcoholism,
prescription drug abuse or drug addiction. Use of Valium should be avoided in patients
dependent on central nervous system depressants, including alcohol.
The exception to the above is the management of acute withdrawal symptoms. The
patient should be warned against simultaneous consumption of alcohol as such a
combination can potentiate the undesirable effects of both substances.
Lower doses should be used in elderly or debilitated patients. Particular caution is
essential when injecting Valium intravenously. Cases of apnea and cardiac arrest in
particular have been reported in elderly and seriously ill patients and in patients with heart
or respiratory failure.
The benzyl alcohol contained in Valium ampoules may produce irreversible lesions in
neonates and in particular in premature neonates. For this reason, ampoules should only
be used in these patients if there is no other alternative treatment.
Caution is required in known cardiorespiratory failure as sedatives such as Valium can
exacerbate preexisting respiratory depression. On the other hand, the sedative effect can
be beneficial in some patients in that it reduces the effort required for breathing.
Very small veins should not be used for injection. In particular, intra-arterial injection and
extravasation should be avoided at all costs, as rapid intravenous injection in particular
can lead to venous thrombosis, phlebitis, local inflammation, swelling, and in rare cases
vascular changes.
In patients with impaired renal or hepatic function the standard precautionary measures
should be observed.
Valium tablets contain lactose. Patients with rare congenital galactose intolerance, lactase
deficiency or glucose-galactose malabsorption should not take Valium tablets.
Rebound anxiety
Rebound anxiety refers to a transient syndrome in which the symptoms that led to
treatment with Valium in the first place recur with increased intensity. This can occur on
discontinuation of treatment. This syndrome can also be accompanied by other reactions
such as mood changes, anxiety, and restlessness.
As the risk for withdrawal phenomena and rebound phenomena is greater after abrupt
discontinuation of treatment, it is recommended that the dose be reduced gradually.

Amnesia
It is important to bear in mind that benzodiazepines can cause anterograde amnesia. This
form of amnesia can also occur at therapeutic doses, the risk increasing with increasing
dose. The amnesic effects can be accompanied by odd behaviour.
Psychiatric and “paradoxical” reactions
It is known that benzodiazepine administration can cause paradoxical reactions such as
agitation, irritability, aggressiveness, delusions, outbursts of rage, nightmares,
hallucinations, psychoses, odd behaviour, and other behavioural disturbances. In such
cases administration of the drug should be discontinued. Such reactions are more
common in children and elderly.
Habituation
Response to the effect of benzodiazepines may weaken after repeated Valium use over a
prolonged period.
Children and neonates
The safety and efficacy of Valium have not been studied in children under 6 months of
age. Valium should be used in this age group only with the greatest caution and in the
absence of alternative treatments.
Dependence
Use of benzodiazepines can lead to physical and psychological dependence. This risk is
increased by prolonged use and high doses and in patients with known alcoholism and/or
prescription drug abuse or drug addiction. Withdrawal phenomena occur especially after
abrupt treatment discontinuation and are limited in milder cases to tremor, agitation, sleep
disturbance, anxiety, headache, and impairment of concentration. However, other
symptoms and in rare cases delirium and convulsions may occur.
Depending on the duration of action of the substance, withdrawal phenomena appear a
few hours to a week or even more after discontinuation of treatment.
In order to minimise the risk of dependence, benzodiazepines should be prescribed only
after a careful consideration of the indication and should be taken for as short a period as
possible (generally no longer than four weeks when used as a hypnotic, for example). The
need for continuation of treatment should be reviewed regularly. The risk-benefit
relationship of more prolonged treatment is less clear, hence it is indicated only in certain
patients (e.g. those with panic attacks).
In order to avoid withdrawal symptoms, treatment should be discontinued by tapering the
dose in all patients. Should withdrawal symptoms occur nonetheless, close medical
monitoring and support of the patient are required.

Interaction with other medicinal products and other forms of interaction
Pharmacokinetic interactions (drug-drug interactions [DDI])
Oxidative metabolism of diazepam leading to the formation of N-desmethyldiazepam,
3-hydroxydiazepam (temazepam) and oxazepam depends on the CYP2C19 and CYP3A
isoenzymes of cytochrome P450. In-vitro studies have shown that the CYP3A isoform is
mainly responsible for hydroxylation while both CYP3A and CYP2C19 are responsible
for N-demethylation. The results of in-vivo studies conducted in volunteers have
confirmed the in-vitro results. Substrates modulating CYP3A and/or CYP2C19 may in
some circumstances influence the pharmacokinetics of diazepam. Inhibitors of CYP3A
and CYP2C19 such as cimetidine, ketoconazole, fluvoxamine, topiramate, fluoxetine and
omeprazole may produce more potent and longer sedation. In addition, according to some
reports, diazepam modifies the metabolic elimination of phenytoin.
Tablets
Cisapride can cause a temporary increase in the sedative effects of orally administered
benzodiazepines, as it accelerates their absorption.
Pharmacodynamic interactions (DDI)
The effects on sedation, respiration and hemodynamics may be potentiated when taking
Valium with central depressants such as neuroleptics, anxiolytics/sedatives,
antidepressants, hypnotics, anticonvulsants, opioids, anesthetics and sedative
antihistamines, and similarly when Valium is taken together with alcohol.
Patients receiving Valium should avoid taking alcohol (see Warnings and precautions).
For other remarks on other central depressants, including alcohol, see Overdosage.
Theophylline may inhibit the action of diazepam.
On the other hand, no interactions with commonly used antidiabetic agents,
anticoagulants or diuretics are known.
Rifampicin is a potent hepatic enzyme inducer. This may accelerate diazepam metabolism
in the liver.
When Valium is given in combination with opiates that cause respiratory depression, the
possibility of potentiation of the respiratory depressant effect should be borne in mind.

Pregnancy
Valium should not be used during pregnancy unless it is clearly required.
Diazepam and its metabolites cross the placenta.
Prolonged administration of benzodiazepines during pregnancy can result in hypotension,
respiratory failure, and hypothermia in the neonate. With this category of drugs,
withdrawal phenomena have also been reported occasionally in neonates. Particular
caution is required when Valium is used during labour and delivery, as high individual
doses can cause irregularities of heart rate in the unborn child and hypotonia, poor
sucking, hypothermia, and moderately severe respiratory depression in the neonate
(floppy infant syndrome). It must be borne in mind that the enzyme system responsible for the degradation of diazepam is not yet fully developed in neonates (especially
premature neonates).
Lactation
Diazepam and its metabolites are excreted in breast milk. Where use of Valium is
absolutely essential during lactation, breast-feeding should be discontinued.

Valium has a pronounced influence on the ability to drive and use machines. Patients
taking Valium should be warned against performing activities that require full mental
alertness; these include the operation of dangerous machines and the driving of motor
vehicles. Patients taking Valium should also be warned against simultaneous
consumption of alcoholic beverages, as such a combination can potentiate the undesirable
effects of both types of substances.

The most frequently reported undesirable effects are fatigue, clouding of consciousness
and muscle weakness; these effects are normally dose-related. These reactions occur
mainly on starting treatment and generally resolve on prolonged use.
Tablets and ampoules
Blood and lymphatic system
Elevation of alkaline phosphatase blood levels during i.v. administration.
Psychiatric disorders
Based on the experience acquired, paradoxical reactions such as anxiety, agitation,
irritability, aggressiveness, delusions, anger, nightmares, hallucinations, psychoses, odd
behaviour and other undesirable behavioural effects can occur with use of
benzodiazepines. In such cases the drug should be discontinued. The probability of such
an effect developing is greater in children and the elderly.
Confusion, emotional impoverishment, decreased vigilance, depression, increase or
decrease in libido.
Chronic use (even at therapeutic doses) may lead to the development of physical
dependence. Discontinuation of the therapy may result in withdrawal or rebound
symptoms (see under Warning and precautions / History of alcohol or prescription drug
abuse and Dependence).
Abuse of benzodiazepines has been reported (see under Warnings and precautions/
Dependence).
Musculoskeletal system
Muscle weakness. There have been reports of falls and fractures in benzodiazepine users.
The risk is increased in those taking concomitant sedatives (including alcoholic
beverages) and in the elderly.Gastrointestinal disorders
Nausea, pelvic pain, diarrhea, dry mouth, constipation, hypersalivation and
gastrointestinal disorders.
Eyes
Diplopia, blurred vision.
Vascular disorders
Hypotension, circulatory depression.
Investigations
Irregular pulse, elevated transaminases in rare cases, elevated alkaline phosphatase.
Kidneys and urinary tract
Incontinence, urinary retention.
Skin
Rashes.
Ear
Dizziness.
Heart
Heart failure, including cardiac arrest.
Respiratory organs
Respiratory depression, including respiratory arrest.
Liver and biliary tract
Jaundice in rare cases.
Ampoules only
Systemic disorders and injection site reactions
Venous thrombosis, phlebitis, irritation at the injection site, local swelling and, less
frequently, vascular changes may occur, in particular after rapid i.v. injection.
Very small veins should not be used for injection; in particular intra-arterial injection and
extravasation should be strictly avoided.
Intramuscular injection may cause local irritation and erythema may occur at the injection
site in some cases. Tenderness is relatively common.
Heart and circulation / Respiration
Cardiorespiratory depression may occur after rectal diazepam administration.

Symptoms
In overdosage, benzodiazepines often lead to clouding of consciousness, ataxia,
dysarthria and nystagmus. Overdosage of Valium alone is rarely life-threatening but it can
cause areflexia, apnea, hypotension, cardiorespiratory depression and coma. If coma
occurs it generally lasts only a few hours but it may also be more protracted and cyclical,
in particular in elderly patients. Benzodiazepine-induced respiratory depression is more
serious in patients with respiratory tract disease.
Benzodiazepines potentiate the effect of other central depressants, including alcohol.
Treatment
Monitor the patient’s vital functions and institute the supportive measures indicated by
the patient’s clinical status. In particular symptomatic treatment of the cardiorespiratory
and central nervous system effects may prove necessary in such patients.
Additional absorption should be prevented using appropriate methods, e.g. treatment with
activated charcoal within 1–2 hours. If activated charcoal is used, airway protection is
mandatory in semi-comatose patients. Gastric lavage can be considered in cases of mixed
ingestion, but not as a routine measure.
If central nervous system depression is severe consider the use of flumazenil (Anexate®),
a benzodiazepine antagonist. However, this should only be administered under closely
monitored conditions since it has a short half-life (about one hour), therefore patients
administered flumazenil will require monitoring after its effects have worn off. Caution is
mandatory when using flumazenil in epileptics treated with benzodiazepines. Flumazenil
must be used with the greatest caution after the ingestion of drugs that reduce the seizure
threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for
flumazenil (Anexate®) for further information on the correct use of this drug.

To reports any side effect(s):
• Saudi Arabia:
− The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-
2340.
o Toll free phone: 8002490000
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc

• Other GCC States:
− Please contact the relevant competent authority.

ATC code: N05BA01.
5.1 Mechanism of action/Pharmacodynamics
The active ingredient of Valium is a member of the benzodiazepine group of
tranquillisers, which possess anxiolytic, sedative, muscle-relaxant, and anticonvulsant
properties. These actions are now known to be due to potentiation of the effect of
γ-aminobutyric acid (GABA), the most important inhibitory neurotransmitter in the brain.

Absorption
The active ingredient of Valium is rapidly and completely absorbed from the digestive
tract, peak plasma concentrations being reached 30–90 minutes after oral administration.
Intramuscular injection is likewise followed by complete absorption, though not always
more rapidly than with oral administration.
Distribution
Diazepam and its metabolites are highly bound to plasma proteins (diazepam: 98%).
Diazepam and its metabolites cross the blood-brain barrier and the placenta. They are also
detectable in breast milk in concentrations approximately 10–20% (diazepam) and 10–
30% (nordiazepam) of those in maternal plasma. The steady-state volume of distribution
is 0.8–1.0 l/kg. The distribution half-life is up to 3 hours.
Metabolism
Diazepam is metabolised to the pharmacologically active substance nordiazepam (t1⁄2β =
96 hours), hydroxydiazepam and oxazepam.
Oxidative metabolism of diazepam depends on the CYP3A and CYP2C19 isoenzymes.
Oxazepam and temazepam are then conjugated to glucuronic acid.
Elimination
The elimination curve of diazepam is biphasic, consisting of an initial distribution phase
with a half-life of up to 3 hours and a terminal elimination phase with a half-life of up to
48 hours.
Elimination is mostly (about 70%) via the urine in the form of free or (mostly) conjugated
metabolites. The clearance of diazepam is 20–30 ml/min.
Pharmacokinetics in special patient populations
The elimination half-life can be prolonged in neonates, the elderly and patients with
hepatic dysfunction; it should therefore be borne in mind that plasma concentrations may,
in such patients, only reach steady state with a certain delay.
The half-life of diazepam is unaltered in renal failure.
Diazepam and its active metabolite nordiazepam accumulate after repeated
administration.
After about one week of treatment consideration should be given to reducing the dose.

Carcinogenicity
The carcinogenic potential of orally administered diazepam has been examined in various
rodent species. The incidence of hepatocellular carcinoma increased in male mice. No
significant increase was observed in the incidence of the tumours in female mice, rats,
hamsters or Mongolian gerbils.
Mutagenicity
A number of studies have provided weak evidence of mutagenic potential at high
concentrations which, however, were far above therapeutic doses in humans.
Impairment of fertility
Reproductive studies in rats showed decreases in the number of pregnancies and in the
number of surviving offspring following administration of oral doses of 100 mg/kg/day to
both males and females prior to and during mating and throughout gestation and lactation.
Teratogenicity
Diazepam was found to be teratogenic in mice at doses of 45–50 mg/kg/day, 100
mg/kg/day and 140 mg/kg/day, and in hamsters at a dose of 280 mg/kg. However, no
teratogenicity was observed when diazepam was administered to rats at doses of 80 and
300 mg/kg/day or to rabbits at doses of 20 and 50 mg/kg/day.

Valium ampoules can be diluted with the following solutions for infusion: 0.9% sodium
chloride, 5% glucose and 10% glucose.
Opened ampoules have been shown to be chemically and physically stable for 24 hours at
ambient temperature.
From a microbiological point of view, however, the product should be used immediately
unless the dilute solution is prepared under controlled and validated aseptic conditions.
Use of PVC-containing containers and infusion sets may result in decreased
concentrations of diazepam (see Special dosage instructions, Ampoules).

The medicine should not be used after the expiry date (EXP) shown on the pack. The
contents must not be used if cloudy.

Valium tablets, 2 mg, 5 mg and 10 mg: Do not store above 30 °C. Valium ampoules, 10 mg/2 ml: Store below 30 °C and protect from light.

At the end of treatment return unused or expired medication in its original pack to the
point of sale (physician or pharmacist) for appropriate disposal.

6.5 Packs
Valium 2 Roche
Tablets (scored, white), 2 mg 30, 100
Valium 5 Roche
Tablets (scored, yellow), 5 mg 25, 100
Valium 10 Roche
Tablets (scored, light blue), 10 mg 25, 100

At the end of treatment return unused or expired medication in its original pack to the
point of sale (physician or pharmacist) for appropriate disposal.