The injectable forms of Valium are indicated for:
Conscious sedation: diagnostic and therapeutic interventions such as cardioversion,
cardiac catheterization, endoscopy, radiological procedures, minor surgical interventions,
reduction of dislocations and fractures, biopsies, dressing of burns, etc. in order to relieve
apprehension, anxiety, acute stress and to diminish recollections of such procedures.
Premedication and induction of anaesthesia: allaying anxiety and tension prior to
surgical procedures.

Excitation: In psychiatry, Valium is used in the treatment of excitation states associated
with psychiatric disorders including acute anxiety and panic, as well as in motor unrest
and delirium tremens.
Anticonvulsant effect: the treatment of status epilepticus and other convulsive states
Gynaecology and obstetrics: second line treatment of eclampsia (if magnesium sulphate
is unavailable or if seizures continue despite administration of magnesium sulphate).
Muscle relaxation: an adjunct for the relief of reflex muscle spasm (including tetanus)
due to local trauma. It is indicated for combating spasticity arising from damage to spinal
and supraspinal interneurons such as cerebral palsy and paraplegia, as well as in athetosis
and stiff-man syndrome.

Standard dosage
For optimal effect, the dosage should be carefully individualized. The usual daily doses
given below will meet the needs of most patients, though there will be cases requiring
higher doses.
In adults and juveniles, a parenteral dose 2-20 mg i.m. or i.v. is generally recommended,
depending on bodyweight, indication and severity of symptoms. In some indications (e.g.
tetanus) higher doses may occasionally be required. Elderly patients and those with
impaired hepatic function should be given a reduced dose (see section 4.2 Special Dosage
Instructions). These patients should be checked regularly at the start of treatment in order
to minimize the dosage and/or the frequency of administration to prevent overdose due to
accumulation.
I.V. injection of Valium should always be slow (approximately 0.5-1 ml per minute), as
excessively rapid administration can lead to apnoea; resuscitation apparatus must be kept
ready at all times.
Anaesthesiology
Premedication and induction of anaesthesia: For premedication: 10-20 mg i.m.; children
0.1-0.2 mg/kg bodyweight, 1 hour before induction of anaesthesia. For induction of
anaesthesia: 0.2-0.5 mg/kg bodyweight i.v.
Conscious sedation before stressful therapeutic interventions: 10-20 mg i.v. and in
particularly heavy patients 30 mg i.v.; children 0.1-0.2 mg/kg bodyweight. Adapting the
dose to the patient’s individual needs consists of an initial injection of 5 mg (1 ml), or 0.1
mg/kg bodyweight in children, followed every 30 seconds by increments of 50% of the
initial dose.Gynaecology and obstetrics
Eclampsia: For actual or threatened convulsions where magnesium sulphate is
unavailable: 10-20 mg i.v.; additional doses, as required, either i.v. or by continuous
infusion (up to 100 mg in 24 hours). If seizures continue despite the administration of
magnesium sulphate, Valium can be administered at a dose of 5-10 mg i.v .
Tetanus
0.1-0.3 mg/kg bodyweight should be given i.v. in intervals at 1-4 hours. Alternatively by
continuous infusion or gastric tube (3-4 mg/kg bodyweight in 24 hours).
Status epilepticus
Anticonvulsant effect in status epilepticus: 0.15-0.25 mg/kg bodyweight should be given
i.v., repeated as necessary after 10-15 minutes or by continuous infusion. Maximum dose:
3 mg/kg bodyweight in 24 hours.
Excitation states
Excitation in acute anxiety states, motor unrest or delirium tremens: Initially 0.1-0.2
mg/kg bodyweight i.v., repeated at 8-hourly intervals until acute symptoms subside, then
continue with oral treatment.
Special dosage instructions
There is evidence that diazepam can be adsorbed within plastic infusion bags and
infusion sets especially those containing PVC and leading to a reduction in diazepam
concentration by 50% or more, especially where prepared bags are stored for 24 hours or
more, in warm ambient conditions, or where long tubing sets or slow rates of infusion are
used. If possible PVC-containing bags and infusion sets should be avoided when infusing
diazepam. When infusing diazepam caution should be exercised when switching between
PVC and non-PVC-containing bags and infusion sets
Geriatric use
Dosage for elderly patients: The lowest possible dose should be used in the elderly (see
5.2 Use in Special Populations; Geriatric Use). These patients should be checked
regularly at the start of treatment in order to minimize the dosage and/or the frequency of
administration to prevent overdose due to accumulation (see 5.2 Pharmacokinetics in
Special Populations).
Pediatric use
Children’s dosage: 0.1-0.3 mg/kg bodyweight daily. Benzodiazepines should not be given
to children without careful assessment of the indication; the duration of treatment must be
kept to a minimum.Hepatic Impairment
Patients with severe hepatic impairment should not be treated with Valium tablets (see
section 4.3 Contraindications). In patients with mild or moderate hepatic impairment, the
lowest dose possible should be given.

Concomitant use of alcohol / CNS depressants
The concomitant use of Valium with alcohol or/and CNS depressants should be avoided.
Such concomitant use has the potential to increase the clinical effects of Valium possibly
including severe sedation that could result in coma or death, clinically relevant respiratory
and/or cardio-vascular depression (see 4.5 Interactions with other Medicinal Products and
other Forms of Interactions and 4.9 Overdose).

Medical history of alcohol or drug abuse
Valium should be used with extreme caution in patients with a history of alcohol or drug
abuse.
Valium should be avoided in patients with dependence on CNS depressants including
alcohol.
An exception to the latter is the management of acute withdrawal reactions.

Hepatic impairment
Benzodiazepines may have a contributory role in precipitating episodes of hepatic
encephalopathy in severe hepatic impairment. Special caution should be exercised when
administering Valium to patients with mild to moderate hepatic impairment (see 4.3
Contraindications).
Psychiatric and 'paradoxical' reactions
Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, anxiety,
delusion, anger, nightmares, hallucinations, psychoses, inappropriate behaviour and other
adverse behavioural effects are known to occur when using benzodiazepines. Should this

August 2015 Saudi Arabia – Summary of Product Characteristic (SPC)
Ref CDS 9.0 7/2017 Valium ampoules

July 2017 SPC
occur, the use of the drug should be discontinued. They are more likely to occur in
children and in the elderly.

Amnesia
It should be borne in mind that benzodiazepines may induce anterograde amnesia.
Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher
dosages. Amnestic effects may be associated with inappropriate behavior.
Tolerance
Some loss of response to the effects of benzodiazepines may develop after repeated use of
Valium for a prolonged time.
Pediatric use
Since the safety and effectiveness in paediatric patients below the age of 6 months have
not been established, Valium should be used in this age group with extreme caution and
only when other therapeutic alternatives are not available.
Geriatric use
Lower doses should be used for elderly and debilitated patients.
Respiratory Insufficiency
A lower dose is recommended for patients with chronic respiratory insufficiency, due to
the risk of respiratory depression.
As with any substance with CNS depressant and/or muscle-relaxant properties, particular
care should be taken when administering Valium to a patient with myasthenia gravis,
owing to pre-existing muscle weakness.
Care must be used in administering injectable Valium, particularly by the i.v. route, to the
elderly, to very ill patients and to those with limited pulmonary reserve because of the
possibility that apnoea and/or cardiac arrest may occur.
The benzyl alcohol contained in Valium ampoules may lead to irreversible damage in the
newborn, especially in the premature. Therefore, for these patients the ampoules should
only be used if no therapeutic alternative is available.
Very small veins should not be selected for injection. In particular, intra-arterial injection
or extravasation must be strictly avoided because venous thrombosis, phlebitis, local
irritation, swelling or - less frequently - vascular changes may occur, particularly after
rapid i.v. injection.
Valium ampoules should be used with caution in patients with sleep apnoea due to
possible additive effects on respiratory depression.

August 2015 Saudi Arabia – Summary of Product Characteristic (SPC)
Ref CDS 9.0 7/2017 Valium ampoules

July 2017 SPC
Dependence
Use of benzodiazepines and benzodiazepine-like agents may lead to the development of
physical and psychological dependence (see 4.8 Undesirable Effects). The risk of
dependence increases with dose and duration of treatment; it is also greater in
patients with a medical history of alcohol and/or drug abuse. Abuse has been
reported in poly-drug abusers . Valium should be used with extreme caution in
patients with a history of alcohol or drug abuse.
Withdrawal
Once physical dependence has developed, abrupt termination of treatment will be
accompanied by withdrawal symptoms. These may consist of headache, diarrhea,
muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In
severe cases, the following symptoms may occur: derealization, depersonalization,
hyperacusis, numbness and tingling of the extremities, hypersensitivity to light,
noise and physical contact, hallucinations or convulsions.
When benzodiazepines are used, withdrawal symptoms may develop when switching to a
benzodiazepine with a considerably shorter elimination half-life.
Rebound anxiety
A transient syndrome whereby the symptoms that led to treatment with Valium recurs in
an enhanced form. This may occur on withdrawal of treatment. It may be
accompanied by other reactions including mood changes, anxiety, sleep
disturbances, and restlessness.
Since the risk of withdrawal phenomena and rebound phenomena is greater after abrupt
discontinuation of treatment, it is recommended that the dosage be decreased
gradually.

The metabolism of diazepam and its main metabolite, DMDZ depends on the cytochrome
P450 isozymes CYP3A4 and CYP2C19. Modulators of these enzymes may lead to
changes in diazepam disposition and effects. Strong interactions are seen with compounds
which affect both of diazepam’s oxidative metabolic pathways simultaneously; moderate
effects only occur even with strong inhibitors if they affect only one of diazepam’s
metabolic pathways . Inhibitors of CYP3A4 and CYP2C19 decrease metabolic rate and
may led to higher than normal concentrations of diazepam and the desmethyl metabolite
and consequently to increased/ prolonged sedation and anxiolytic effects. Such changes
may exacerbate diazepam’s effects in patients with increased sensitivity, e.g. due to their
age, reduced liver function or treatment with other drugs that impair oxidation. Inducers
of CYP3A4 and CYP2C19 may lead to lower than expected concentrations and hence to
a lack of desired efficacy.

Effect of other drugs on the pharmacokinetics of diazepam:
Enzyme inhibitors
Grapefruit juice contains strong inhibitors of CYP3A4. Diazepam exposure was strongly
increased (AUC 3.2-fold; Cmax 1.5-fold) and time to reach maximum concentration was
delayed when diazepam was given with grapefruit juice instead of water [144].
Antimycotic azole derivatives inhibit CYP3A4 and CYP2C19 pathways and lead to
increased exposure to diazepam (diazepam AUC ratio fluconazole 2.5; voriconazole 2.2)
and prolonged elimination half-life of diazepam (with fluconazole from 31 h to 73 h; with
voriconazole from 31h to 61 h). The influence of the antimycotics on diazepam levels
was only seen at 4 hours after administration and beyond. Itraconazole has a more
moderate effect with no clinically significant interaction with diazepam as determined by
psychomotor performance tests.
The serotonin reuptake inhibitor fluvoxamine is also an inhibitor of both of diazepam’s
degradation pathways and increased not only exposure to diazepam by 180% and
prolonged its elimination half-life from 51 h to 118 h, but also increased exposure and
time to reach steady state of the desmethyl metabolite. Fluoxetine showed a more
moderate effect on diazepam AUC (approximately 50% increase) and did not affect

psychomotor response because combined concentrations of diazepam and desmethyl-
diazepam were similar with and without fluoxetine .

Combined hormonal contraceptives appear to reduce the clearance (by 67%) and prolong
elimination half-life (by 47%) of diazepam . Diazepam-induced psychomotor impairment
in women on contraceptives may be higher during the 7-day menstrual pause when off the
hormone preparation than when taking the contraceptive (159). There is some limited
evidence that benzodiazepines can increase the incidence of break-through bleeding in
women with hormonal contraceptives. A drug interaction causing pregnancy was not
observed.
The proton pump inhibitor omeprazole, a CYP2C19 and CYP3A4 inhibitor, administered
at a dose of 20 mg o.d. increased the diazepam AUC by 40% and the half-life by 36%, at
a dose of 40 mg o.d. omeprazole increased the diazepam AUC by 122% and the half-life
by 130%. The elimination of desmethyl-diazepam was reduced as well. The effect of
omeprazole was only seen in extensive but not slow metabolizers of CYP2C19.
Esomeprazole (but not lansoprazole or pantoprazole) has the potential to inhibit the
metabolism of diazepam to a similar degree as omeprazole.
The histamine H2-receptor antagonist cimetidine, an inhibitor of multiple CYP isozymes,

including CYP3A4 and CYP2C19, reduces the clearance of diazepam and of desmethyl-
diazepam by 40 to 50%. The effect is no different after one day or after chronic treatment

with cimetidine and results in higher exposure to and a prolonged elimination half-life of
diazepam and its main metabolite after single dosing and to higher steady-state

concentrations after multiple dosing of diazepam. Enhanced sedation was seen with co-
administration of cimetidine. No such pharmacokinetic interaction was seen with the H2-

antagonists ranitidine and famotidine.Disulfiram inhibits the metabolism of diazepam (median decrease in clearance 41%,
increase in half-life 37%) and probably the further metabolism of diazepam’s active
metabolites. Enhanced sedative effects may result.
Antituberculosis therapy may change the disposition of diazepam. In presence of
isoniazid diazepam mean exposure (AUC) and half-life were increased (on average 33-
35%) with the largest changes seen in subjects with slow-acetylator phenotype.
The calcium channel blocker diltiazem, a substrate for the same CYP isozymes as
diazepam and an inhibitor of CYP3A4, increased AUC (by approximately25%) and
prolonged half-life (by 43% in extensive CYP2C19 metabolizers) of diazepam with little
differences between subjects with different CYP2C19 phenotypes. In the presence of
diltiazem exposure to desmethyl-diazepam also tended to increase .
The primary metabolite of idelalisib is a strong CYP3A4 inhibitor and increases the
serum concentrations of diazepam so that dose reduction may have to be considered.
The psychostimulants modafinil and armodafinil induce CYP3A4 and inhibit CYP2C19;
they may prolong the elimination of diazepam and cause excessive sedation .
Enzyme inducers
Rifampicin very potently induces CYP3A4 and has also a significant accelerating effect
on the CYP2C19 pathway. When dosed at 600 mg daily for 7 days, diazepam clearance
was increased 4.3-fold and AUC decreased by -77%. A significant reduction in exposure
to all diazepam metabolites was also observed. Doubling the daily rifampicin dose did not
further increase its effect.
Carbamazepine is a known inducer of CYP3A4 and accelerated elimination (increased
clearance, reduced half-life) of diazepam 3-fold while increasing concentrations of
desmethyl-diazepam.
Food and Antacids
Food and antacids may lower the rate but will not lower the extent of diazepam
absorption from the tablet; this may lead to attenuated effects after a single dose but not
influence steady-state concentrations during multiple-dose therapy.
Prokinetic drugs increase the rate of diazepam absorption.
Intravenous but not oral metoclopramide increases the rate of absorption of diazepam and
increases the maximum concentration achieved after oral dosing.
Narcotics (morphine, pethidine) decrease the absorption rate and lower peak
concentrations of orally administered diazepam.
Effect of diazepam on the pharmacokinetics of other drugs
Diazepam has not been found to induce or inhibit metabolizing enzymes. Nevertheless
some interactions with other drugs occur where diazepam is the precipitant.Phenytoin therapy was associated with higher concentrations and increased phenytoin
intoxication when combined with diazepam. However, some authors have found no
interaction or even lowered plasma concentrations of phenytoin when co-administered
with diazepam.
- Pharmacodynamic interactions (DDI)Alcohol should be avoided in patients receiving Valium (see 4.4 General (Warnings and
Precautions)).
See section 4.9 Overdose for warning of other central nervous system depressants
including alcohol.
Enhanced side effects such as sedation and cardio-respiratory depression may also occur
when Valium is co-administered with any centrally acting depressants including
alcohol.
There are several reports of severe hypotension, respiratory depression or loss of
consciousness in patients under combined treatment with clozapine and
benzodiazepines, including diazepam .
Additive CNS depressant effects can be expected when combining phenothiazines and
benzodiazepines; sedation, respiratory depression and airway obstruction has been
reported with the combined use of levopromazine and diazepam.
Additive effects of olanzapine and diazepam on sedation and hypotension occur in the
absence of a pharmacokinetic interaction. Concomitant parenteral use is not
recommended.
Diazepam boosts the subjective opioid effects of methadone. It increases methadone
effects on pupil diameter and sedation and also causes significantly greater
deterioration in reaction time when compared to methadone alone . No
pharmacokinetic interaction occurs between the two drugs .
Reversible loss of control of Parkinson’s disease has been seen in some patients treated
with combined levodopa and diazepam. This might be caused by decreased striatal
dopamine levels.
The xanthines theophylline and caffeine oppose the sedative and possibly anxiolytic
effects of diazepam partially through blocking of adenosine receptors.
Diazepam pretreatment changes the pharmacodynamics and pharmacokinetics of the
anaesthetic ketamine. Ketamine N-demethylation was inhibited leading to a
prolonged half-life and prolonged ketamine-induced sleeping time. In the presence
of diazepam, a reduced ketamine concentration is required to achieve adequate
anaesthesia.

Pregnancy
The safety of Valium for use in human pregnancy has not been established. An increased
risk of congenital malformation associated with the use of benzodiazepines during the
first trimester of pregnancy has been suggested.

Review of spontaneously reported adverse drug events shows no greater incidence than
would be anticipated from a similar untreated population. Benzodiazepines should be
avoided during pregnancy unless there is no safer alternative. Before administering
Valium during pregnancy, especially during the first trimester, possible risks for the
foetus should - as with any other drug - be weighed against the expected therapeutic
benefit for the mother.
Continuous administration of benzodiazepines during pregnancy may give rise to
hypotension, reduced respiratory function and hypothermia in the newborn child (see 5.2
Pharmacokinetics in Special Populations). Withdrawal symptoms in newborn infants
have occasionally been reported with this class of drugs.

Lactation

Since diazepam passes into breast milk, Valium should not be administered to breast-
feeding mothers.

Sedation, amnesia, impaired concentration and impaired muscle function may adversely
affect the ability to drive or operate machinery. Prior to receiving Valium, the patient
should be warned not to drive a vehicle or operate a machine until completely recovered.
The physician should decide when these activities may be resumed.
If sleep duration is insufficient or alcohol is consumed, the likelihood of impaired
alertness may be increased. (see 4.9 Interactions with other Medicinal Products and other
Forms of Interaction).

General Disorders and Administration Site Conditions: Venous thrombosis, phlebitis,
injection site irritation, local swelling, or - less frequently – vascular changes may occur,
particularly after rapid i.v. injection.
Very small veins should not be selected for injection; in particular, intra-arterial injection
or extravasation must be strictly avoided.

I.m. injection can result in local pain, in some cases accompanied by injection site
erythema. Tenderness is relatively common.
Respiratory, Thoracic and Mediastinal Disorders: Cardiorespiratory depression may occur
if the Valium is administered rectally.
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.

Symptoms
Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus.
Overdose of Valium is seldom life-threatening if the drug is taken alone, but may
lead to areflexia, apnoea, hypotension, cardiorespiratory depression and coma.
Coma, if it occurs, usually lasts a few hours but it may be more protracted and
cyclical, particularly in elderly patients. Benzodiazepine respiratory depressant
effects are more serious in patients with respiratory disease.
Benzodiazepines increase the effects of other central nervous system depressants,
including alcohol .
Treatment
Monitor the patient’s vital signs and institute supportive measures as indicated by the
patient’s clinical state. In particular, patients may require symptomatic treatment for
cardiorespiratory effects or central nervous system effects.
Further absorption should be prevented using an appropriate method e.g. treatment within
1-2 hours with activated charcoal. If activated charcoal is used airway protection is
imperative for drowsy patients. In case of mixed ingestion gastric lavage may be
considered, however not as a routine measure
If CNS depression is severe consider the use of flumazenil (Anexate®), a benzodiazepine
antagonist. This should only be administered under closely monitored conditions. It
has a short half-life (about an hour), therefore patients administered flumazenil will
require monitoring after its effects have worn off. Flumazenil is to be used with
extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic
antidepressants). Refer to the prescribing information for flumazenil (Anexate®),
for further information on the correct use of this drug.

ATC code: N05BA01.
Mechanism of action and pharmacodynamics
Diazepam is a member of the group of benzodiazepine tranquilizers which exert
anxiolytic, sedative, muscle-relaxant, anticonvulsant and amnesic effects. Its action is
enhanced by generation of active metabolites (mainly desmethydiazepam). The central
actions of benzodiazepines are mediated through an enhancement of the GABAergic
neurotransmission at inhibitory synapses. In the presence of benzodiazepines, the affinity
of the GABA receptor for the neurotransmitter is enhanced through positive allosteric
modulation resulting in an increased action of released GABA on the postsynaptic
transmembrane chloride ion flux.

Absorption
Diazepam is rapidly and completely absorbed from the gastrointestinal tract, peak plasma
concentrations appearing 30-90 minutes after oral ingestion.
On i.m. injection the extent of absorption is complete, The rate of absorption is variable
and depends on site and depth of the injection.
Following daily dosing, diazepam levels reach a steady state within approximately 5 days;
it takes about twice as long before desmethyl-diazepam levels reach a steady-state.
Average steady-state levels of diazepam after once daily administration are approximately
twice as high as the peak levels of the drug after the first dose.
During treatment, the elimination half-life of diazepam may increase by 50% due to a

reduction in hepatic clearance. Reports on the evolution of plasma levels during long-
term treatment are conflicting. A strong decrease of diazepam levels during long-term

treatment, possibly due to metabolic auto-induction, has been found, but in other studies
plasma concentrations of both diazepam and its desmethyl metabolite were independent
of duration of therapy
Distribution
Diazepam is widely distributed into tissues despite high binding to plasma proteins (98-
99%, mainly albumin and to lesser extent α1-acid glycoprotein. After intravenous
administration, a pronounced distribution phase is seen in plasma concentrations with a
half-life of distribution of up to 3 hours. The volume of distribution at steady state
averages between 0.88 and 1.1l/kg when derived from plasma concentration
measurements. Both protein binding and volume of distribution of desmethyl-diazepam
are similar to those of diazepam.
The high protein binding limits the extent of diazepam uptake into the cerebrospinal fluid
(CSF). CSF levels in man following single and multiple doses approximate closely the

free drug concentration in plasma. Upon multiple dosing desmethyl-diazepam, but not
diazepam, may significantly accumulate in CSF. Diazepam has very rapid uptake into and
equilibration with brain tissue, with equilibrium concentrations in brain exceeding those

in plasma. The overall time-course of receptor occupancy was consistent with the time-
course of the sum of brain concentrations of diazepam plus metabolites

Metabolism
Diazepam is mainly metabolized to pharmacologically active metabolites such as
desmethyldiazepam, a pathway accounting for 50-60% of total diazepam clearance; 3-
hydroxylation (27% of total diazepam clearance) is slow, leading to only low plasma
levels of the oxidation products temazepam and oxazepam. Oxazepam and temazepam
are further conjugated to glucuronides. After multiple doses of diazepam plasma
concentration ratios of desmethyl-diazepam/ diazepam were 1.1 ± 0.2, temazepam/
diazepam 0.11 ± 0.05, and oxazepam/ diazepam 0.09 ± 0.03 [103].
Oxidation of diazepam is mediated by cytochrome P450 isozymes; formation of
desmethyl-diazepam mainly by CYP2C19 and CYP3A and 3-hydroxy-diazepam
(temazepam) and oxazepam by CYP3A, Because CYP2C19 is polymorphic, extensive
metabolizers (EMs), and poor metabolizers (PMs) of diazepam can be distinguished. PMs
of diazepam showed significantly lower clearance (12 vs 26 mL/min) and longer
elimination half-life (88 vs 41 h) of diazepam than EMs after a single oral dose. Also,

PMs had lower clearance, higher AUC and longer elimination half-life of desmethyl-
diazepam. There appear to be inter-ethnic differences in this polymorphism.

Elimination
The plasma concentration-time decline of diazepam after administration is biphasic, an
initial rapid and extensive distribution phase being followed by a prolonged terminal
elimination phase. Typical elimination half-life values are in the range of 24-48 hours for
diazepam and 40-100 hours for the active metabolite desmethyldiazepam. The clearance
of diazepam is 20-40 ml/min.
Only insignificant amounts of unchanged diazepam are eliminated indicating that the
drug is almost completely metabolized before leaving the body;. Oxazepam-glucuronide
is the main drug-related product in urine.
Pharmacokinetics in special patient populations
Geriatric Population
The unbound fraction of diazepam correlates positively with age and was higher in

elderly than in young subjects. Age decreases the capacity of the liver for N-
demethylation and 3-hydroxylation of diazepam. An age-dependent decrease in clearance

of unbound drug occurs and is responsible for the observed 2-4 fold increase in
elimination half-life in the elderly, with a stronger effect seen in males than females.
Hence the extent of accumulation of unbound pharmacologically active diazepam in
elderly persons during multiple dosing will be greater than in younger adults.
The elimination of desmethyl-diazepam is slower in elderly males, but not in females.Hepatic impairment
Disposition of both diazepam and desmethyl-diazepam is altered in liver disease. In acute
viral hepatitis, the half-life of diazepam is increased by about 2-fold but returns slowly to
normal on recovery. A more marked (2- to 5-fold) increase in the elimination half-life is
seen in patients with alcoholic cirrhosis. These changes are primarily due to impaired
hepatic metabolism; altered distribution due to changes in protein binding may be
contributory. The reduced clearance of diazepam and desmethyl-diazepam leads to their
increased accumulation during long-term dosing. This in turn is associated with increased
sedation.
Renal impairment
In chronic renal failure, elimination of diazepam, as indicated by clearance of unbound
drug, was similar to that in healthy volunteers; thus steady-state concentrations of
unbound diazepam at any given daily dose on the average should not be different between
patients with renal insufficiency and healthy individuals. Due to changes in plasma
protein binding and tissue distribution of diazepam its elimination half-life was shortened
in renal disease from (mean ±S.E.) 92 ±23 h in control to 37 ±7 h in renal failure subjects.
Pregnancy
Diazepam and desmethyl-diazepam readily cross the placental barrier. The fetus can also
carry out N-demethylation of diazepam. Long-term treatment leads to accumulation of
both compounds in the fetus with high levels in the fetal heart, lungs and brain.
Plasma protein binding of diazepam is decreased during pregnancy, particularly during
the last trimester, partly due to the fall in serum albumin concentration. Increased
pharmacological effects may result after acute dosing. (see 4.6 Pregnancy)
Pediatric Population
During the first day of life, the free fractions of diazepam and desmethyl-diazepam
increased sharply to twice the values at birth and subsequently declined slowly to reach
near control values at one week of age. These changes parallel those of free fatty acid
concentrations.
Newborns and premature infants metabolize diazepam more slowly than older children
and adults leading to a prolonged half-life (very pronounced in premature newborns)
unless there was exposure to inducing agents before or immediately after birth. The
newborn's capacity to carry out metabolic processes involved in the biotransformation of
diazepam, including hydroxylation, demethylation, and glucuronide conjugation, remains
limited before 5 months of age; after this time hepatic enzymes develop to or even exceed
adult capacity.
Diazepam and its metabolites are excreted in breast milk. Concentrations of diazepam in
milk are only 10% of those in maternal blood. Normalized for body weight,
approximately 5% of the mother’s dose reaches the baby. After multiple administrations
of more than 10 mg daily doses the amounts transferred may be large enough to show
effects in the baby. (see 4.6 Lactation).

Carcinogenicity
The carcinogenic potential of oral diazepam has been studied in several rodent species.
An increase in the incidence of hepatocellular tumours occurred in male mice. No
significant increase in the incidence of tumours was observed in female mice, rats,
hamsters or gerbils.
Genotoxicity
A number of studies have provided weak evidence of a mutagenic potential at high
concentrations which are, however, far above therapeutic doses in humans.
Impaired 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
prior to and during mating and throughout gestation and lactation.
Reproductive toxicity
Diazepam was found to be teratogenic in mice at dose levels of 45-50 mg/kg 100 mg/kg,
and 140 mg/kg/day as well as in hamsters at 280 mg/kg. In contrast, this drug was
shown to be non teratogenic at 80 and 300 mg/kg/day in rats and at 20 and 50
mg/kg/day in rabbits (see 4.6 Pregnancy).

Valium Ampoules, 10 mg/2 ml: preservative: 95 mg sodium benzoate (E211); 5 mg
benzoic acid (E210); benzyl alcohol, propylene glycol; ethyl alcohol; 2 ml water for
injections.

Valium Ampoules can be diluted with the following infusion solutions: Sodium Chloride
0.9%, Dextrose 5.5% or Dextrose 10%.
Chemically and physically in use stability has been demonstrated for 24 hours at room
temperature.
From a microbiological point of view the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility
of the user.
Use of PVC-containing infusion sets
Use of PVC-containing containers and infusion sets may result in decreased
concentrations of diazepam.
Disposal of unused/expired medicines

Valium ampoules, 10 mg/2 ml: Store below 30°C and protect from light.

Clear injection solution containing 10 mg diazepam per 2 ml in 1 vial pack.

The release of pharmaceuticals in the environment should be minimized. Medicines
should not be disposed of via wastewater and disposal through household waste should be
avoided. Use established “collection systems”, if available in your location.

Medicine: keep out of reach of children