Valium 5 mg/10 mg Tablets

VALIUM is only indicated when the disorder is severe, disabling or when the individual is subject to extreme stress. VALIUM is indicated for the following conditions:

• Tablets
• Anxiety: symptomatic relief of anxiety, tension and other somatic or psychological complaints associated with the anxiety syndrome. It can also be used as an adjunct to the treatment of anxiety or excitation associated with psychiatric disorders.
• Muscle relaxation: as an adjunct for the relief of reflex muscle spasm due to local trauma (injury, inflammation). It can also be used to combat spasticity arising from damage to spinal and supraspinal interneurons such as cerebral palsy and paraplegia, as well as athetosis and stiff-man syndrome.

Treatment should be as short as possible. The patient should be reassessed regularly and the need for continued treatment should be evaluated especially when the patient is symptom-free. The overall duration of treatment of anxiety should not be more than 8 to 12 weeks, including a tapering off process. In certain cases, extension beyond the maximum treatment period may be necessary. If so, it should not take place without re-evaluation of the patient's status.

• Injection in Ampoules
• Conscious sedation: diagnostic and therapeutic interventions such as cardioversion, cardiac catheterisation, endoscopy, radiological procedures, minor surgical interventions, reduction of dislocations and fractures, biopsies and dressing of burns, etc. in order to relieve apprehension, anxiety, acute stress and to diminish recollections of such procedures.
• Premedication of anaesthesia: allaying anxiety and tension prior to surgical procedures.
• Excitation: the treatment of excitation states associated with psychiatric disorders, including acute anxiety and panic, as well as in motor unrest and delirium tremens.
• Anti-convulsant effect: the treatment of status epilepticus and other convulsive states.
• Gynaecology and obstetrics: second line treatment of seizures in eclampsia (if magnesium sulphate is unavailable or if seizures continue despite administration of magnesium sulphate).
• Muscle relaxation: as an adjunct for the relief of reflex muscle spasm (including tetanus) due to local trauma (injury, inflammation). It can also be used to combat spasticity arising from damage to spinal and supraspinal interneurons such as cerebral palsy and paraplegia, as well as athetosis and stiff-man syndrome.

Duration of treatment

The duration of treatment should be as short as possible. The patient should be reassessed regularly and the need for continued treatment evaluated, especially if the patient is symptom free. It should not exceed 8 u2013 12 weeks, including the tapering-off period. Extension beyond this period 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 explain precisely how the dosage will be progressively decreased. Moreover, it is important that the patient be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms, should they occur during withdrawal. There is evidence that, in case of short-acting benzodiazepines, withdrawal phenomena can become manifest within the dosage interval especially when the dosage is high. When long-acting benzodiazepines such as diazepam are being used, it is important to warn against changing to short-acting benzodiazepines as withdrawal symptoms may develop.

Tablets

The tablet can be divided into equal halves to facilitate dosing.

Standard adult dosage

For optimal effect, the dosage should be carefully individualised. Treatment should begin at the lowest effective dose appropriate to the particular condition. Average adult dosage for oral administration: Initial dose: 5 - 10 mg. Depending on symptom severity, the usual dose is 5 - 20 mg daily. The maximum single oral dose for adults should not normally exceed 10 mg.

Special dosage instructions

• Chronic respiratory depression, elderly and debilitated patients: Elderly and debilitated patients who are at particular risk of oversedation, respiratory depression and ataxia should be given half of the usual adult dose. These patients should be checked regularly at the start of treatment in order to minimise the dosage and/or frequency of administration to prevent overdose due to accumulation (see section 5.2).
• Hepatic impairment: Patients with severe hepatic impairment should not be treated with VALIUM tablets (see section 4.3). In patients with mild or moderate hepatic impairment, the lowest dose possible should be given.
• Renal Impairment: The usual precautions in treating patients with impaired renal function should be observed.
• Paediatric use: Childrenu2019s dosage: 0,1 - 0,3 mg/kg bodyweight daily. VALIUM should not be given to children without careful assessment of the indication; the duration of treatment must be kept to a minimum. Safety and efficacy have not been demonstrated in children below 6 months of age.

Injection in Ampoules

Warning: I.V. injection of VALIUM should always be slow (approximately 0,5 - 1,0 mL/min) as excessively rapid administration can lead to apnoea; resuscitation apparatus must be kept ready at all times.

Standard adult dosage

For optimal effect, the dosage should be carefully individualised. 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.

Special dosage instructions

• Elderly and debilitated patients: Elderly patients should be given a reduced dose. These patients should also be checked regularly at the start of treatment in order to minimise the dosage and/or the frequency of administration to prevent overdose due to accumulation (see section 5.2).
• Hepatic Impairment: Patients with severe hepatic impairment should not be treated with VALIUM tablets (see section 4.3). In patients with mild or moderate hepatic impairment, the lowest dose possible should be given. These patients should also be checked regularly at the start of treatment in order to minimise the dosage and/or the frequency of administration to prevent overdose due to accumulation (see section 5.2).
• Renal Impairment: The usual precautions in treating patients with impaired renal function should be observed.
• Anaesthesiology: Premedication: 10 mg i.m.; children 0,1 - 0,2 mg/kg bodyweight, 1 hour before induction of anaesthesia. Conscious sedation before stressful therapeutic interventions: 10 mg i.m.; children 0,1 - 0,2 mg/kg bodyweight. Adapting the dose to the patientu2019s 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 cannot be used: 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 u2013 10 mg i.v.

Tetanus: A dosage of 0,1 - 0,3 mg/kg bodyweight should be given i.v. in intervals of 1 - 4 hours. Alternatively by continuous infusion or by 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, after which, treatment should be continued orally.

VALIUM is contraindicated in patients with:

• a known history of hypersensitivity to benzodiazepines or any of the excipients;
• severe respiratory insufficiency;
• severe hepatic impairment as benzodiazepines may precipitate hepatic encephalopathy;
• sleep apnoea syndrome;
• myasthenia gravis.

VALIUM is not recommended for the primary treatment of psychotic illness.

VALIUM should not be used alone to treat depression or anxiety associated with depression as suicide may occur in such patients.

Dependence on other CNS depressants including alcohol, except in the acute withdrawal reactions. (See section 4.4).

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 cardiovascular depression (See section 4.5 and 4.9).

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.

Medicine abuse and dependence: Medical history of alcohol or drug abuse VALIUM should be used with extreme caution in patients with a history of alcohol or drug abuse, see Dependence below. VALIUM should be avoided in patients with dependence on CNS depressants including alcohol. (See section 4.3). An exception to the latter is the management of acute withdrawal reactions.

Dependence: There is a potential for abuse and the development of physical and psychological dependence, especially with prolonged use and high doses. The risk of dependence is greater in patients with a medical history of alcohol and/or drug abuse. VALIUM should be used with extreme caution in patients with a history of alcohol or drug abuse.

Withdrawal: Once physical dependence had developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headache, diarrhoea muscle pain, convulsions, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases, the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of extremities, hypersensitivity to light, noise and physical contact, hallucinations or convulsions. Withdrawal symptoms may occur after long periods of ordinary therapeutic doses. VALIUM may increase the frequency and severity of attacks of grand mal epilepsy, during treatment or abrupt withdrawal.

When benzodiazepines are used, withdrawal symptoms may develop when switching from a long-acting benzodiazepine, like diazepam (see section 5.2) to a benzodiazepine with a considerably shorter elimination half-life.

Rebound anxiety: A transient syndrome, whereby the symptoms that led to treatment with VALIUM, recur in an enhanced form may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety 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 gradually decreased.

Hepatic impairment: Benzodiazepines may have a contributory role in precipitating episodes of hepatic encephalopathy in severe hepatic impairment. VALIUM is therefore contraindicated in patients with severe hepatic insufficiency (see section 4.3). Special caution should be exercised when administering VALIUM to patients with mild to moderate hepatic impairment (see section 4.3).

Psychiatric and u2018paradoxicalu2019 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 VALIUM. Should this occur, the use of VALIUM should be discontinued. They are more likely to occur in children and in the elderly.

Amnesia: It should be borne in mind that VALIUM may induce anterograde amnesia. Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour.

Tolerance: Some loss of response to the effects of VALIUM may develop after repeated use for a prolonged period of time.

Paediatric use: VALIUM should be used in paediatrics with extreme caution and only when other therapeutic alternatives are not available. Safety and effectiveness in paediatric patients below the age of 6 months have not been established (see section 4.2).

Use in the elderly and debilitated patients: Extreme care must be used when using VALIUM, particularly by the i.v. route, in the elderly, in very ill patients and to those with limited pulmonary reserve because of the possibility that apnoea and/or cardiac arrest, and prolonged sedation and confusion may occur. See also section 4.2.

Respiratory Insufficiency: A lower dose is recommended for patients with chronic respiratory insufficiency, due to the risk of respiratory depression (see section 4.3).

Sleep apnoea: VALIUM is contraindicated in patients with sleep apnoea due to possible additive effects on respiratory depression (see section 4.3).

Myasthenia gravis patients: Extreme caution should be taken when using VALIUM to a patient with myasthenia gravis, owing to pre-existing muscle weakness. (See section 4.3).

Ampoules: Injection into very small veins and intra-arterial injection 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.

Plastic materials: VALIUM is adsorbed to plastic infusion bags and infusion sets especially those containing polyvinyl chloride (PVC), leading to a reduction in VALIUM concentration by 50 % or more, especially where prepared bags are stored 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 VALIUM (see section 6.6). When infusing VALIUM caution should be exercised when switching between PVC and non-PVC-containing bags and infusion sets.

Ingredients: The benzyl alcohol (an excipient) contained in VALIUM injection may lead to irreversible damage (including metabolic acidosis, respiratory depression and convulsion) in the newborn, especially in the premature. Therefore, for these patients the ampoules should only be used if no therapeutic alternative is available. Given intravenously, effects on the cardiovascular system can occur; this may consist of a decrease in blood pressure, left ventricular stroke work and an increase in heart rate.

Tablets: Lactose Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take VALIUM.

Caution should be observed in patients suffering from anxiety accompanied by an underlying depressive disorder. The action of other central nervous system depression substances such as narcotics, barbiturates and monoamine oxidase inhibitors may be enhanced. (See section 4.3). Withdrawal should be gradual in patients receiving high doses for prolonged periods of time. Patients should be cautioned regarding the additive effect of alcohol. VALIUM should be given with caution to the elderly, and to patients with hepatic or renal dysfunction, obstructive airways disease and arteriosclerosis. VALIUM should be given with caution to infants, who may not be able to metabolise diazepam. (See section 4.6).

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).

Pharmacokinetic interactions: 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 diazepamu2019s oxidative metabolic pathways simultaneously; moderate effects only occur even with strong inhibitors if they affect only one of diazepamu2019s 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 diazepamu2019s effects in patients with increased sensitivity, e.g. due to their age, reduced liver function or treatment with other medicines 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 medicines on the pharmacokinetics of diazepam: Enzyme Inhibitors The following therapeutic classes/medicines can provoke increased and prolonged sedation (see also Interactions with food):

• Azole derivatives: 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 31 h 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.
• Serotonin reuptake inhibitors: The serotonin reuptake inhibitor fluvoxamine is also an inhibitor of both of diazepamu2019s 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.
• Contraceptives: 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. There is some limited evidence that benzodiazepines can increase the incidence of break-through bleeding in women with hormonal contraceptives. A medicine interaction causing pregnancy was not observed.
• Proton pump inhibitors: The proton pump inhibitor omeprazole, a CYP2C19 and CYP3A4 inhibitor, administered at a dose of 20 mg once daily increased the diazepam AUC by 40 % and the half-life by 36 %, at a dose of 40 mg once daily omeprazole increased the diazepam AUC by 122 % and the half-life by 130 %. The elimination of desmethyl-diazepam was reduced as well.
• Histamine H2-receptor antagonists: 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: Disulfiram inhibits the metabolism of diazepam (median decrease in clearance 41 %, increase in half-life 37 %) and probably the further metabolism of diazepamu2019s active metabolites. Enhanced sedative effects may result.
• Isoniazid: 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.
• Diltiazem: The calcium channel blocker diltiazem, a substrate for the same CYP isozymes as diazepam and an inhibitor of CYP3A4, increased AUC (by approximately 25 %) and prolonged half-life (by 43% in extensive CYP2C19 metabolisers) of diazepam with little differences between subjects with different CYP2C19 phenotypes. In the presence of diltiazem exposure to desmethyl-diazepam also tended to increase.
• Idelalisib: 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.
• Psychostimulants: The psychostimulants modafinil and armodafinil induce CYP3A4 and inhibit CYP2C19; they may prolong the elimination of diazepam and cause excessive sedation.

Enzyme inducers: The following therapeutic classes/medicines can lead to decreased plasma concentrations and as such decreased effectiveness of diazepam; monitor for loss of efficacy:

• Rifampicin: 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, VALIUM 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: 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.

Other Pharmacokinetic interactions: 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 medicines increase the rate of diazepam absorption. Cisapride may lead to a temporary increase in the sedative effects of orally administered benzodiazepines due to faster 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 medicines: Ketamine Diazepam pre-treatment 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. 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: Opioids 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 medicines. Alcohol and other CNS depressants should be avoided in patients receiving VALIUM. (See sections 4.4 and 4.9). Enhanced side effects such as sedation and cardio-respiratory depression may also occur when VALIUM is co-administered with other centrally acting depressants such as antipsychotics, anxiolytics or sedatives, antidepressants, hypnotics, anticonvulsants, narcotic analgesics, anaesthetics and sedative antihistamines, barbiturates or 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. Antiparkinsonian agent Reversible loss of control of Parkinsonu2019s disease has been seen in some patients treated with combined levodopa and diazepam. This might be caused by decreased striatal dopamine levels. Xanthines The xanthines theophylline and caffeine oppose the sedative and possibly anxiolytic effects of diazepam partially through blocking of adenosine receptors. Interactions with food Grapefruit juice contains strong inhibitors of CYP3A4. Diazepam exposure was strongly increased (AUC 3,2-fold; C max 1,5-fold) and time to reach maximum concentration was delayed when diazepam was given with grapefruit juice instead of water. 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. DILATREND may potentiate the effect of other concomitantly administered medicines that are antihypertensive in action or have hypotension as part of their adverse effect profile.

Pregnancy: The safety of diazepam for use in 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. Continuous administration of benzodiazepines during pregnancy may give rise to the so-called floppy-infant syndrome, manifested by hypotension, reduced respiratory function and hypothermia in the newborn child (see section 5.2). Withdrawal symptoms in newborn infants have been reported with VALIUM. Special care must be taken when VALIUM is used during labour and delivery, as high single doses may produce irregularities in the foetal heart rate and hypotonia, poor sucking, hypothermia and moderate respiratory depression in the neonate. With newborn infants it must be remembered that the enzyme system involved in the breakdown of the medicine is not yet fully developed (especially in premature infants).

Breastfeeding: Since diazepam passes into breast milk, VALIUM should not be administered to breast feeding mothers.

Women of childbearing potential: If VALIUM is prescribed to a woman of childbearing potential, she should be advised to contact her medical practitioner regarding discontinuation of VALIUM, if she intends to become or suspects that she is pregnant.

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. If sleep duration is insufficient or alcohol is consumed, the likelihood of impaired alertness may be increased (see section 4.5).

Summary of the safety profile: Fatigue, drowsiness and muscle weakness are usually dose-related. Drowsiness is more common in elderly and debilitated patients and in those receiving high doses.

Description of selected adverse reactions:

Psychiatric disorders: Less frequent: Paradoxical reactions such as restlessness, agitation, irritability, disorientation, aggressiveness, nervousness, hostility, anxiety, delusion, anger, nightmares, abnormal dreams, hallucinations, psychoses, hyperactivity, inappropriate behaviour and other adverse behavioural effects are known to occur. Drowsiness, confusional state, numbed emotions and mood disturbances, depression, reduced alertness, changes in libido. Physical and psychic dependence (see section 4.4).

Nervous system disorders: Less frequent: Headache, ataxia, dizziness, hypersalivation, slurred speech, dysarthria, tremor, anterograde amnesia, decreased alertness. VALIUM may increase the frequency and severity of attacks of grand mal epilepsy, during treatment or abrupt withdrawal.

Eye disorders: Less frequent: Diplopia, blurred vision.

Ear and labyrinth disorders: Less frequent: Vertigo.

Cardiac disorders: Less frequent: Cardiac failure including cardiac arrest.

Vascular disorders: Less frequent: Hypotension, circulatory depression.

Respiratory, thoracic and mediastinal disorders: Less frequent: Respiratory depression including respiratory failure due to a depressant effect on the respiratory centre and cardiovascular collapse, may occur following intravenous and intramuscular administration. Cardio-respiratory depression may occur if VALIUM is administered rectally.

Gastrointestinal disorders: Less frequent: Constipation, nausea. dry mouth. After several days of high doses of VALIUM injection, diarrhoea, sometimes accompanied by colic-like stomach pains, may occur.

Hepato-biliary disorders: Less frequent: Jaundice.

Skin and subcutaneous tissue disorders: Less frequent: Skin reactions.

Renal and urinary disorders: Less frequent: Incontinence, urinary retention.

General disorders and administration site conditions: Frequent: Venous thrombosis, phlebitis, local irritation, swelling, tenderness. Less frequent: Vascular changes, particularly after rapid i.v. injection. I.m. injection can result in local pain, in some cases accompanied by erythema at the site of injection, fatigue.

Investigations: Less frequent: Variations in pulse rate, elevated transaminases and alkaline phosphatase.

Injury, poisoning and procedural complications: Less frequent: There have been reports of falls and fractures in benzodiazepine users, including VALIUM. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

Symptoms: Manifestations of overdosage include somnolence, confusion, coma, respiratory and cardiovascular depression and hypotension. VALIUM commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of VALIUM may be life-threatening if the medicine is taken alone, and 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. VALIUM respiratory depressant effects are more serious in patients with respiratory disease.

Treatment: Monitor the patientu2019s vital signs and institute supportive measures as indicated by the patientu2019s 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. If CNS depression is severe consider the use of flumazenil, 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 medicines that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil, for further information on the correct use of this medicine.