Diazepam 5 mg Tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Diazepam 5 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 5 mg tablets of diazepam.

Excipient with known effect: 158.20 mg lactose monohydrate per tablet

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

Pale yellow colored, circular, flat face bevelled edge approximately 8.8mm, uncoated tablet debossed with “D” and “5” separated by break line on one side and plain on the other side.

The tablet can be divided into equal halves.

4.1 Therapeutic indications

Diazepam has potent anxiolytic, anticonvulsant and central muscle-relaxing properties; these effects are probably mediated through special areas in the CNS. It also has uses in preoperative medication and is used in the treatment of skeletal-muscle spasm, and the associated pain.

The main uses are:

Adults:

1. 1) The short-term relief (2 to 4 weeks) only of anxiety which 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.

The use of benzodiazepines to treat short-term anxiety is considered to be inappropriate.

1. 2) The management of cerebral palsy spasticity in selected cases.
2. 3) Muscle spasm; as an adjunct to the control of muscle spasm in tetanus.
3. 4) As an adjunct to the management of certain types of epilepsy (e.g. myoclonus).
4. 5) Symptomatic treatment of acute alcohol withdrawal.
5. 6) As oral premedication for the nervous dental patient.
6. 7) For premedication before surgery.

Paediatric population:

1. 1) Night terrors and somnambulism.
2. 2) As an adjunct to the control of muscle spasms as in tetanus.
3. 3) Control of tension and irritability in cerebral spasticity in selected cases.
4. 4) Oral premedication.

Diazepam should be used to treat insomnia only when it is severe, disabling or subjecting the individual to extreme stress.

4.2 Posology and method of administration

Posology

Prior to starting treatment with diazepam, a discussion should be held with patients to put in place a strategy for ending treatment with diazepam in order to minimise the risk of dependence, addiction and drug withdrawal syndrome (see section 4.4).

Treatment should be given for the shortest possible duration. If this medicine is being used for the treatment of epilepsy this medicine should be used for as long as the prescriber considers it necessary.

As an anxiolytic, the lowest effective dose should be employed; dosage regimes should not exceed beyond 4 weeks, including tapering off. Patients who have received benzodiazepines for a long time may require an extended withdrawal period. Long-term chronic use is not recommended.

Adults:

Anxiety states, obsessive-compulsive neuroses, and other psychiatric disorders: 5-30mg daily in divided doses.

Insomnia associated with anxiety: 5mg to 15mg before retiring. Management of cerebral palsy spasticity in selected cases: 5mg to 60mg daily in divided doses.

Muscle spasm of varied aetiology, fibrositis, cervical spondylosis: 5mg to 15mg daily in divided doses.

In the control of muscle spasms as in tetanus: 3mg to 10mg/kg body weight daily.

The selected dose should relate to the severity of the case and in extremely severe cases higher doses have been used. Intravenous diazepam is recommended initially (see separate prescribing information).

Adjunct to the management of some types of epilepsy: 2mg to 60mg daily in divided doses. Symptomatic treatment of acute alcohol withdrawal: 5mg to 20mg, repeated if necessary in 2 to 4 hours.

Oral premedication in dental patients: 5mg the night before, 5mg on waking and 5mg two hours before the appointment.

Oral Premedication before surgery: 5mg to 20mg.

Paediatric population:

Alternative presentations of diazepam are recommended for paediatric usage in order to obtain suitable doses of less than 5mg.

Spastic children with minimal brain damage: 5-40mg daily in divided doses. Oral Premedication before surgery (see section 4.4): 2mg-10mg

Elderly and debilitated patients:

Doses should be half the above recommended adult doses.

Hepatic impairment

The use of diazepam in hepatic impairment may precipitate coma, therefore Patients with impaired hepatic function should be given a reduced dose.

Renal impairment

Patients with impaired renal function should be given a reduced dose.

Method of Administration

For oral administration.

4.3 Contraindications

Diazepam is contra-indicated for patients with:

• Hypersensitivity to diazepam, benzodiazepines or any of the excipients listed in section 6.1.
• Phobic or obsessional states; chronic psychosis, hyperkinesis (paradoxical reactions may occur).
• Acute pulmonary insufficiency; respiratory depression, acute or chronic severe

respiratory insufficiency (ventilatory failure may be exacerbated).

• Myasthenia gravis (condition may be exacerbated).
• Sleep apnoea (condition may be exacerbated).
• Severe hepatic insufficiency (elimination half-life of diazepam may be prolonged).
• Acute porphyria.
• 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.
• Planning a pregnancy (see section 4.6).
• Pregnancy (unless there are compelling reasons – see section 4.6).

4.4 Special warnings and precautions for use

Warnings

• 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 possibly including severe sedation, clinically relevant respiratory and/or cardio-vascular depression (see section 4.5).
• Duration of Treatment - The duration of treatment should be as short as possible depending on the indication. The patient must be evaluated after a period of no more than 4 weeks and then regularly thereafter in order to assess the need for continued treatment, especially if the patient is free of symptoms. In general, treatment must not last any longer than 8-12 weeks, including the tapering off process. Extension beyond these periods should not take place without re-evaluation of the situation. It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage will be progressively decreased. Moreover it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur while diazepam is being discontinued. 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.
• Diazepam should be used with caution in patients with a history of alcohol or drug abuse as these are patients predisposed to habituation and dependence.

• Drug dependence, tolerance and potential for abuse

  Drug addiction comprises behavioural, cognitive and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use and possible tolerance or physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, which manifests as withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Addiction and dependence are related but distinct presentations and in discussing these themes, terminology that apportion blame to the individual should be avoided.

  For all patients, prolonged use of this product may lead to drug dependence and addiction but can occur with short-term use at recommended therapeutic doses. The risks are increased with the dose and duration of treatment, and in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression). Additional support and monitoring may be necessary when prescribing for patients at risk of drug misuse. Routine repeat prescriptions should be avoided and treatment should be withdrawn gradually.

  A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained online, and past and present medical and psychiatric conditions. Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of symptom control as initially experienced. Patients may also supplement their treatment with additional medications to achieve the same effect. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

  Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else. Patients should be closely monitored for signs of misuse, abuse, or addiction. The clinical need for treatment with diazepam should be reviewed regularly, with frequent assessments of patients being undertaken during the course of their treatment.

  As sudden discontinuation of benzodiazepines may result in convulsions, particular care should be taken in patients with epilepsy, other patients who have had a history of seizures or in alcohol or drug dependence.

• Limits of tolerance in patients with organic cerebral changes (particularly arteriosclerosis) or cardio-respiratory insufficiency may be very wide; care must be taken in adapting the dosage with such patients.

  Some loss of efficacy to the hypnotic effects of diazepam may develop after repeated use for a few weeks.

• Drug withdrawal syndrome - Prior to starting treatment with diazepam, a discussion should be held with patients to explain the risk of dependence, addiction, and drug withdrawal syndrome. A withdrawal strategy for ending treatment with diazepam should also be put in place with the patient before starting treatment (there may be exceptions to this in specific clinical situations such as symptom management in end of life palliative care, and for use in epilepsy).

  Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take in excess of weeks or months. Patients should be informed of this when the medication is first prescribed.

  The reduction schedule for a patient should be tailored to the individual and should be modified to allow intolerable withdrawal symptoms to improve before making the next reduction. If using a published withdrawal schedule, apply it flexibly to accommodate the person’s preferences, changes to their circumstances and the response to dose reductions.

  Suggest a slow stepwise rate of reduction proportionate to the existing dose, so that decrements become smaller as the dose is lowered, unless clinical risk is such that rapid withdrawal is needed.

  If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level.

  If women take this drug during pregnancy, there is a risk that their new born infants will experience neonatal withdrawal syndrome.

  Rebound insomnia and anxiety: a transient syndrome whereby the symptoms that led to treatment with diazepam may recur in an enhanced form on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.

• Alcohol should be avoided during treatment with diazepam (additive CNS depression).
• Amnesia - diazepam may induce anterograde amnesia. The condition occurs most often several hours after ingesting the product and therefore to reduce the risk patients should ensure that they will be able to have uninterrupted sleep of 7-8 hours. Anterograde amnesia may occur using therapeutic doses, the risk increases with higher doses.
• In cases of loss of bereavement, psychological adjustment may be inhibited by benzodiazepines.
• Hypo-albuminaemia may predispose patient to higher incidence of sedative side effects.
• Extreme caution should be used in prescribing diazepam to patients with personality disorders.
• Benzodiazepines should not be used in patients with severe hepatic insufficiency as they may precipitate encephalopathy. In patients with chronic hepatic disease dosage may need to be reduced.
• Cerebral sensitivity is increased in severe renal failure; therefore lower doses should be used (see section 4.2).
• Hypnotics should be avoided in the elderly who are at risk of becoming ataxic and confused and so liable to fall and injure themselves. If, based on clinical need, a decision to treat is nevertheless taken, treatment should be initiated a lower dose (see section 4.2).
• Caution should be exercised when using diazepam peri-operatively in children, as effects and timing of response may be unreliable and paradoxical effects may occur.

• Risk from concomitant use of opioids:

  Concomitant use of diazepam and opioids may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of sedative medicines such as benzodiazepines or related drugs such as diazepam with opioids should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe diazepam concomitantly with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2).

  The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers (where applicable) to be aware of these symptoms (see section 4.5).

• Psychiatric and 'paradoxical' reactions:

  Paradoxical reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. Should this occur, use of the drug should be discontinued. They are more likely to occur in children and the elderly.

• Elderly and debilitated patients should be given a reduced dose (see section

  4.2). Due to the myorelaxant effect there is a risk of falls and consequently hip fractures in the elderly.

• A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression.
• The usual precautions in treating patients with impaired renal function should be observed. In renal failure, the half-life of diazepam is not clinically significantly changed, and dose adjustment is usually not necessary.
• Benzodiazepines are not recommended for the primary treatment of psychotic illness.
• Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients).

• Potentially suicidal individuals should not have access to large amounts of diazepam due to the risk of overdosing.

  Paediatric population

  Benzodiazepines should not be given to children without careful assessment of the need to do so; 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.

  Lactose monohydrate:

  Diazepam Tablets contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Not recommended

Alcohol

Diazepam should not be used together with alcohol (CNS inhibition enhanced sedative

effects: impaired ability to drive/ operate machinery).

Sodium oxybate

Avoid concomitant use (enhanced effects of sodium oxybate).

HIV-protease inhibitors

Avoid concomitant use (increased risk of prolonged sedation) – see below for zidovudine

Take into account

Pharmacodynamic interactions

If diazepam is used with other centrally acting agents, careful consideration has to be given to the pharmacology of the agents employed, particularly with compounds that may potentiate or be potentiated by the action of diazepam, such as neuroleptics, anxiolytics/sedatives, hypnotics, antidepressants, anticonvulsants, sedating antihistamines, antipsychotics, anaesthetics for general anaesthesia and narcotic analgesics. Such concomitant use may increase sedative effects and cause depression of respiratory and cardiovascular functions. Concomitant use of narcotic analgesics may promote psychic dependency due to enhancement of euphorigenic effects.

Opioids:

The concomitant use of sedative medicines such as benzodiazepines or related drugs such as diazepam 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).

Anti-epileptic drugs

Pharmacokinetic studies on potential interactions between diazepam and antiepileptic drugs have produced conflicting results. Both depression and elevation of drug levels, as well as no change, have been reported. Phenobarbital taken concomitantly may result in an additive CNS effect. Increased risk of sedation and respiratory depression. Phenobarbital is a known inducer

of CYP3A4 and increases hepatic metabolism of diazepam. Reduced effect of diazepam.

Special care should be taken in adjusting the dose in the initial stages of treatment. Side effects may be more evident with hydantoins or barbiturates. Diazepam has been reported to be displaced from protein-binding sites by sodium valproate (increased serum levels:

increased risk of drowsiness).

Narcotic analgesics

Enhancement of the euphoria may lead to increased psychological dependence.

Other drugs enhancing the sedative effect of diazepam

Cisapride, lofexidine, nabilone, disulfiram and the muscle-relaxants – baclofen, tizanidine, suxamethonium and tubocurarin.

Compounds that affect hepatic enzymes (particularly cytochrome P450):

• Inhibitors (eg cimetidine: isoniazid: erythromycin: omeprazole: esomeprazole) reduce clearance and may potentiate the action of benzodiazepines. Itraconazole, ketoconazole, and to a lesser extent fluconazole and voriconazole are potent inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may increase plasma levels of benzodiazepines. The effects of benzodiazepines may be increased and prolonged by concomitant use. A dose reduction of the benzodiazepine may be required.

Rifamycins (rifampicin)

Rifampicin is a potent inducer of CYP3A4 and substantially increases the hepatic metabolism and clearance of diazepam. In a study with healthy subjects administered 600 mg or 1.2 g rifampicin daily for 7 days, the clearance of diazepam was increased by about fourfold. Co-administration with rifampicin gives rise to substantially decreased concentrations of diazepam. Reduced effect of diazepam. The concomitant use of rifampicin and diazepam should be avoided.

Antihypertensives, vasodilators& diuretics: Enhanced hypotensive effect with ACEinhibitors, alpha-blockers, angiotensin–II receptor antagonists, calcium channel blockers adrenergic neurone blockers, beta-blockers, moxonidine, nitrates, hydralazine, minoxidil, sodium nitroprusside and diuretics. Enhanced sedative effect with alpha-blockers or moxonidine.

Dopaminergics

Possible antagonism of the effect of levodopa.

Antacids

Concurrent use may delay absorption of diazepam.

Antiviral agents (atazanavir, ritonavir, delavirdine, efavirenz, indinavir, nelfinavir,

saquinavir)

Antiviral agents may inhibit the CYP3A4 metabolic pathway for diazepam. Increased risk of sedation and respiratory depression. Therefore, concomitant use should be avoided.

Zidovudine

Increased zidovudine clearance by diazepam.

Oral contraceptives

Inhibition of oxidative metabolism of diazepam. Increased effects of diazepam.

Co-administration of diazepam and combined oral contraceptives has been known to cause breakthrough bleeding. The mechanism of this reaction is unknown. Breakthrough bleeding, but no contraceptive failures have been reported.

Theophylline

A proposed mechanism is competitive binding of theophylline to adenosine receptors in the brain. Counteraction of the pharmacodynamic effects of diazepam, e.g. reduction of sedation and psychomotor effects.

Caffeine

Concurrent use may result in reduced sedative and anxiolytic effects of diazepam.

Grapefruit juice

Inhibition of CYP3A4 may increase the plasma concentration of diazepam (possible increased sedation and amnesia). Cmax is increased by 1.5 times and AUC by 3.2 times. Possible increased effect of diazepam.

This interaction may have little significance in healthy individuals, but it is not clear is if other factors such as old age or liver cirrhosis increase the risk of adverse effects with concurrent use.

Clozapine

Mechanism: Pharmacodynamic synergism.

Effect: Severe hypotension, respiratory depression, unconsciousness and potentially fatal respiratory and/or cardiac arrest. Therefore, concomitant use is not recommended and should be avoided.

Pharmacokinetic interactions

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 such as rifampicin, hypericum perforatum and certain antiepileptics can result in substantially decreased plasma concentrations of diazepam.

Carbamazepine

Carbamazepine is a known inducer of CYP3A4 and increases hepatic metabolism of

diazepam. This can result in up to three-fold greater plasma clearance and a shorter half-life of diazepam. Reduced effect of diazepam.

Phenytoin

Phenytoin is a known inducer of CYP3A4 and increases hepatic metabolism of diazepam.

Reduced effect of diazepam.

The metabolism of phenytoin may be increased or decreased or remain unaltered by diazepam in an unpredictable way. Increased or decreased serum concentration of phenytoin. Phenytoin concentrations should be monitored more closely when diazepam is added or discontinued.

Azoles (fluconazole, itraconazole, ketoconazole, voriconazole) Increased plasma concentration of benzodiazepines, due to inhibition of the CYP3A4 and/or CYP2C19 metabolic pathway.

Fluconazole: Co-administration with 400 mg fluconazole on the first day and 200 mg on the second day increased the AUC of a single 5 mg oral dose of diazepam 2.5-fold and prolonged the half-life from 31 hours to 73 hours.

Voriconazole: A study with healthy subjects found that 400 mg voriconazole twice daily on the first day and 200 mg twice daily on the second day increased the AUC of a single 5 mg oral dose of diazepam 2.2-fold and prolonged the half-life from 31 hours to 61 hours. Increased risk of undesired effects and toxicity of benzodiazepine. 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 and an approximately 190% increased plasma concentrations (AUC) of diazepam. Drowsiness, reduced psychomotor performance and memory. Preferably, benzodiazepines that are metabolised via a non-oxidative pathway should be used instead.

Corticosteroids

Chronic use of corticosteroids may cause increased metabolism of diazepam due to induction of cytochrome P450 isoenzyme CYP3A4, or of enzymes responsible for glucuronidation. Reduced effects of diazepam.

Cimetidine

Cimetidine inhibits the hepatic metabolism of diazepam, reducing its clearance and

prolonging its half-life. In one study where 300 mg cimetidine was administered four times daily for 2 weeks, the combined plasma level of diazepam and its active metabolite, desmethyldiazepam, was found to be increased by 57%, but reaction times and other motor and intellectual tests remained unaffected. Increased action of diazepam and increased risk of drowsiness. Reduction of the diazepam dose may be necessary.

Omeprazole

Omeprazole inhibits the CYP2C19 metabolic pathway for diazepam. Omeprazole prolongs the elimination half-life of diazepam and increases the plasma concentrations (AUC) of diazepam approximately between 30% - 120%. The effect is seen in CYP2C19 extensive metabolisers but not in slow metabolisers, with a low clearance of diazepam. Increased action of diazepam. Reduction of the diazepam dose may be necessary.

Esomeprazole

Esomeprazole inhibits the CYP2C19 metabolic pathway for diazepam. Co-administration with esomeprazole results in an extended half-life and an increase in plasma concentrations (AUC) of diazepam by approximately 80%. Increased effect of diazepam. Reduction of the diazepam dose may be necessary.

Isoniazid

Isoniazid inhibits the CYP2C19 and CYP3A4 metabolic pathway for diazepam.

Co-administration with 90 mg isoniazid twice daily for 3 days resulted in a prolonged

elimination half-life of diazepam and in a 35% increased plasma concentration (AUC) of diazepam. Increased effect of diazepam.

Itraconazole

Increased plasma concentration of diazepam due to inhibition of the CYP3A4 metabolic pathway. In a study with healthy subject given 200 mg itraconazole daily for 4 days increased the AUC of a single 5 mg oral dose of diazepam by about 15%, but there was no clinically significant interaction as determined by psychomotor performance tests. Possible increased effect of diazepam.

Fluoxetine

Fluoxetine inhibits the metabolism of diazepam via CYP2C19 and other pathways, resulting in elevated plasma concentrations and decreased clearance of diazepam. 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. Increased risk of CNS inhibition such as sedation.

Cisapride

Accelerated absorption of diazepam. Temporary increase of the sedative effects of orally administered diazepam.

Levodopa

Concomitant use with diazepam resulted in reduced effects of levodopa in a small number of case reports.

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. Increased sedation.

4.6 Fertility, pregnancy and lactation

The safety of diazepam in human pregnancy has not been established. It should not be used in the first and third trimesters. There may be a small increase in the risk of congenital malformation, particularly oral cleft with the use of benzodiazepines in the first trimester but a causal relationship has not been established.

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.

Pregnancy

Numerous data from cohort studies did not show the occurrence of malformative effects during exposure to benzodiazepines during the first trimester of pregnancy. However, in some case-control epidemiological studies, an increase in the occurrence of cleft palates has been observed with benzodiazepines. According to these data, the incidence of cleft labio-palatins in newborns is less than 2/1000 after exposure to benzodiazepines during pregnancy, while the expected rate in the general population is 1/1000.

Intake of high doses of benzodiazepines in the second and/or third trimesters of pregnancy has resulted in decreased fetal active movements and variability in fetal heart rate. Treatment with benzodiazepines in the later stages of pregnancy, even with low doses, may be responsible for signs of exposure in the newborn such as axial hypotonia, or impaired suction leading to poor weight gain. These signs are reversible but can last 1 to 3 weeks depending on the benzodiazepine prescribed. In high doses, respiratory depression or apnea, and hypothermia may occur in the newborn. Neonatal withdrawal syndrome is possible, even in the absence of signs of exposure, characterized by hyperexcitability, agitation and tremors.

Given these data, as a precautionary measure, the use of diazepam is not recommended during pregnancy regardless of the term. If the product is prescribed to a woman of child bearing 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.

At the end of pregnancy, if it is really necessary to introduce diazepam treatment, avoid prescribing high doses and take into account, for the monitoring of the newborn, the effects previously described.

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 (“Floppy Infant Syndrome”), irregularities in the heart rate, poor suckling 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.

Studies in animals have shown reproductive toxicity (see section 5.3).

Breast-feeding

Benzodiazepines are found in the breast milk -Reports have demonstrated milk: plasma concentration ratios to vary between 0.2 and 2.7. There is therefore a risk of accumulation in the breastfeeding child. 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

Sedation, amnesia, impaired concentration, dizziness, blurred vision and impaired muscular function may adversely effect the ability to drive or to use machines. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased. see also Interactions). Impaired function and sedation may occur the following morning and for several days after. Patients should be warned that effects on the central nervous system may persist into the day after administration even after a single dose. Concurrent medication may increase these effects (see section 4.5).

This medicine can impair cognitive function and can affect a patient’s ability to drive safely.

This class of medicine is in the list of drugs included in regulations under 5a of the Road

Traffic Act 1988. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive

• Do not drive until you know how the medicine affects you

  It is an offence to drive while under the influence of this medicine

• However, you would not be committing an offence (called ‘statutory defence’) if:
• The medicine has been prescribed to treat a medical or dental problem and
• You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
• It was not affecting your ability to drive safely

4.8 Undesirable effects

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, in particular in children.

Amnesia 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).

Psychiatric disorders

Drug dependence (see section 4.4). Abuse of benzodiazepines has been reported.

General disorders and administration site conditions

Drug withdrawal symptoms (see 4.4 Special warnings and precautions). Symptoms reported following discontinuation of 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; hyperreflexia, tremor, nausea, vomiting; diarrhoea, abdominal cramps, loss of appetite, agitation, palpitations, tachycardia, panic attacks, vertigo, short-term memory loss, hallucinations/delirium; catatonia; hyperthermia, 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.

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).

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). a Pre-existing depression may be unmasked during benzodiazepine use. b May occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour (see section 4.4).

c Symptoms reported following discontinuation of 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; hyperreflexia, tremor, nausea, vomiting; diarrhoea, abdominal cramps, loss of appetite, agitation, palpitations, tachycardia, panic attacks, vertigo, short-term memory loss, hallucinations/delirium; catatonia; hyperthermia, 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.

d 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 medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in Google Play or Apple App Store.

4.9 Overdose

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

Features

The symptoms of diazepam overdose are mainly an intensification of the therapeutic effects (ataxia, drowsiness, dysarthria, sedation, muscle weakness, profound sleep, hypotension, bradycardia, nystagmus) or paradoxical excitation. In most cases only observation of vital functions is required. Extreme overdosage may lead to coma, areflexia, cardiorespiratory depression and apnoea, requiring appropriate countermeasures (ventilation, cardiovascular support). Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease. Severe effects in overdose also include rhabdomyolysis and hypothermia.

Coma usually lasts only a few hours but in elderly people it may be more protracted and cyclical.

Management

Maintain a clear airway and adequate ventilation.

Monitor the patient's vital signs and introduce support measures based on the patient's clinical condition. In particular, patients may need symptomatic treatment of central cardiorespiratory and neurological effects. Consider activated charcoal (50g for an adult, 1g/kg for a child) in adults who have taken more than 100mg or children who have taken more than 1mg/kg within one hour, provided they are not too drowsy.

Gastric lavage is unnecessary if these drugs have been taken alone. Patients who are

asymptomatic at four hours are unlikely to develop symptoms. In case of severe CNS depression, consider the use of flumazenil a benzodiazepine antagonist.

It should only be administered under close supervision. Since flumazenil has a short half-life (about an hour), patients will need to be monitored after its effects have disappeared. Flumazenil should be used with extreme caution in the presence of medications that reduce the epileptogenic threshold (e.g. tricyclic antidepressants). See the prescription information for flumazenil for more information on the proper use of this medication.

Monitoring level of consciousness, respiratory rate, pulse oximetry and blood pressure in symptomatic patients.

Consider arterial blood gas analysis in patients who have a reduced level of consciousness (GCS < 8; AVPU scale P or U) or have reduced oxygen saturations on pulse oximetry.

Correct hypotension by raising the foot of the bed and by giving an appropriate fluid challenge. Where hypotension is thought mainly due to decreased systemic vascular resistance, drugs with alpha-adrenergic activity such as noradrenaline or high dose dopamine (10-30 micrograms/kg/min) may be beneficial. The dose of inotrope should be titrated against blood pressure. If severe hypotension persists despite the above measures, then central venous pressure monitoring should be considered.

Supportive measures are indicated depending on the patient’s clinical state. Benzodiazepines are not significantly removed from the body by dialysis. Flumazenil, a benzodiazepine antagonist, is not advised as a routine diagnostic test in patients with reduced conscious level. It may sometimes be used as an alternative to ventilation in children who are naive to benzodiazepines, or in patients with COPD to avoid the need for ventilation. It is not necessary or appropriate in cases of poisoning to fully reverse the benzodiazepine effect. Flumazenil has a short half-life (about an hour) and in this situation an infusion may therefore be required. Flumazenil is contraindicated when patients have ingested multiple medicines, especially after co-ingestion of a benzodiazepine and a tricyclic antidepressant or any other drug that causes seizures. This is because the benzodiazepine may be suppressing seizures induced by the second drug; its antagonism by flumazenil can reveal severe status epilepticus that is very difficult to control.

Contraindications to the use of flumazenil include features suggestive of a tricyclic antidepressant ingestion including a wide QRS, or large pupils. Use in patients post-cardiac arrest is also contraindicated.

It should be used with caution in patients with a history of seizures, head injury, or chronic benzodiazepine use.

Occasionally a respirator may be required but generally few problems are encountered, although behavioural changes are likely in children. If excitation occurs, barbiturates should not be used.

Effects of overdose are more severe when taken with centrally-acting drugs, especially alcohol, and in the absence of supportive measures, may prove fatal.

5.1 Pharmacodynamic properties

ATC code: N05B A01

Pharmacotherapeutic group: Anxiolytics, Psycholeptics, benzodiazepine derivative.

Diazepam belongs to the class of 1-4 benzodiazepines and has a pharmacodynamic activity qualitatively similar to that of other compounds in this class: muscle relaxant, anxiolytic, sedative, hypnotic, anticonvulsant and amnesiac.

Benzodiazepines, such as diazepam, bind to receptors in various regions of the brain and spinal cord. This binding increases the inhibitory effects of gamma-aminobutyric acid (GABA). GABAs functions include CNS involvement in sleep induction. Also involved in the control of hypnosis, memory, anxiety, epilepsy and neuronal excitability.

These effects are related to a specific agonist action on a central receptor that is part of the "GABA-OMEGA macromolecular receptors" complex, also known as BZ1 and BZ2 and modulating the opening of the chlorine channel.

5.2 Pharmacokinetic properties

Absorption

The absorption of diazepam is rapid: the t max is between 30-90 minutes of oral administration, a steady plasma concentration is reached after 5-6 days and is directly related to dose. Bioavailability is high and ranges from 80% to 100%.

Distribution

The distribution volume varies from 1 to 2 L/kg. The total plasma clearance of diazepam, calculated after intravenous administration, is 30 ml/min. It tends to decrease in multiple administrations. Protein binding is important, averaging 95-98%.

The plasma elimination half-life of diazepam is between 32 and 47 hours. The state of

equilibrium of plasma concentrations is reached after a minimum of one week. A concentration-effect relationship could not be established for this class of products, due to the intensity of their metabolism and the development of a tolerance.

Benzodiazepines pass through the blood-brain barrier as well as into the placenta and breast milk. For diazepam, the milk/plasma ratio is equal to 2.

Biotransformation and elimination

The liver plays a major role in the process of metabolizing benzodiazepines, which explains the negligible percentage (0.1%) unchanged product found in the urinary tract. The main metabolite of diazepam is desmethyldiazepam, also active, whose half-life is longer than that of the mother molecule (between 30 and 150 hours). The hydroxylation of this molecule is mediated by the isoenzymes CYP3A and CYP2C13 and gives rise to two other active metabolites, oxazepam and temazepam. Inactivation is by

glucuronoconjugation, resulting in water-soluble substances eliminated in the urine.

Pharmacokinetic interactions:

The oxidative metabolism of diazepam, leading to the formation of N-demethyldiazepam, 3 hydroxydiazepam (temazepam) and oxazepam, is mediated by CYP2C19 and CYP3A isoenzymes of cytochrome P450. As one in vitro study has shown, the hydroxylation reaction is performed primarily by the CYP3A isoform while N-demethylation is mediated by both CYP3A and CYP2C19. The results of in vivo studies in human volunteers confirmed in vitro observations. As a result, substrates that are modulators of CYP3A and CYP2C19, can potentially alter diazepam pharmacokinetics.

Populations at risk

Elderly subject: liver metabolism decreases as well as total clearance with increased half-life, free fraction, and concentrations at steady state. Doses should be reduced accordingly.

Liver failure: there is an increase in the free fraction (and therefore the volume of

distribution) as well as the half-life. Pregnant women: the distribution volume and half-life of diazepam are increased

5.3 Preclinical safety data

The carcinogenic potential of diazepam was studied in mice and rats treated orally at a dose of 75 mg/kg/day for 80 and 104 weeks respectively. An increase in the incidence of hepatocellular tumours was observed in male mice. No significant increase in tumor incidence was observed in female mice or rats. Diazepam has been shown to have teratogenic potential in mice at doses of 45 mg/kg/day (3.6 times the maximum recommended dose in humans of 1 mg/kg on a mg/m2 basis) and in hamsters at 280 mg/kg/day (38 times the maximum recommended dose in humans).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate

Maize starch

Starch, Pregelatinised (Maize starch)

Magnesium stearate

Iron Oxide Yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Diazepam tablets are available in Clear PVC - Aluminium foil blister and White opaque HDPE container closed with white opaque polypropylene closure.

Pack sizes:

Blister packs: 10, 20, 28, 30, 40 and 60 tablets.

HDPE pack:

1000 tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Milpharm Limited

1 Roundwood Avenue,

Stockley Park, Uxbridge,

UB11 1AF

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 16363/0839

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

02/04/2025

10 DATE OF REVISION OF THE TEXT

07/10/2026