Each 2 mg VALIUM tablet contains the following excipients: lactose, maize starch, magnesium stearate.

Transcription

1 NAME OF THE MEDICINE VALIUM (diazepam) CAS Registy Numbe: DESCRIPTION VALIUM (diazepam) is a benzodiazepine deivative developed though oiginal Roche eseach. Chemically, diazepam is 7 - chloo - 1,3 - dihydo methyl phenyl - 2H - 1,4 - benzodiazepin one. It is a colouless cystalline compound, insoluble in wate and has a molecula weight of Each 2 mg VALIUM tablet contains the following excipients: lactose, maize stach, magnesium steaate. Each 5 mg VALIUM tablet contains the following excipients: lactose monohydate, maize stach, ion oxide yellow CI77492, magnesium steaate. PHARMACOLOGY Phamacodynamics Mechanism of Action Diazepam is a membe of the goup of classical benzodiazepines and exhibits anxiolytic, sedative, muscle elaxant and anti-convulsant effects. This is pesumed to be the esult of facilitating the action in the bain of gamma-aminobutyic acid, a natually occuing inhibitoy tansmitte. Phamacokinetics Absoption and Bioavailability Afte oal administation, diazepam is apidly and completely absobed fom the gastointestinal tact, with peak plasma concentations appeaing minutes afte oal intake. The speed of onset afte intamuscula (IM) administation is vaiable, depending on the muscle mass used and othe factos. VALIUM PI of 11

2 Distibution Diazepam is 98% potein-bound in the plasma, and is exceted in the uine mainly in the fom of fee o conjugated metabolites. VALIUM and its metabolites coss the blood-bain and placental baies and ae also found in beast-milk. Metabolism VALIUM is metabolised to hydoxy-diazepam (temazepam) and nodiazepam (t½ appoximately 96 hous) and ultimately to oxazepam. The oxidative metabolism of diazepam is mediated by CYP3A and CYP2C19 isoenzymes. Oxazepam and temazepam ae futhe conjugated to with glucuonic acid. Elimination The plasma concentation-time cuve of VALIUM is biphasic; an initial apid and extensive distibution phase with a half-life of up to 3 hous, followed by a polonged teminal elimination phase (half-life hous). The elimination half-life is 90 hous at age 80 and is inceased 2-3-fold in patients with cihosis. Phamacokinetics in Special Populations The elimination half-life may be polonged in the newbon, the eldely and patients with hepatic o enal disease and it should be noted that the plasma concentation may take coespondingly longe to each steady state. INDICATIONS VALIUM is indicated fo the management of anxiety disodes o fo the shot tem elief of the symptoms of anxiety. Anxiety o tension associated with the stess of eveyday life usually does not equie teatment with an anxiolytic. In acute alcohol withdawal, VALIUM may be useful in the symptomatic elief of acute agitation, temo, impending o acute deliium temens and hallucinosis. VALIUM is a useful adjunct fo the elief of eflex muscle spasm due to local tauma (injuy, inflammation) to muscles, bones and joints. It can also be used to combat spasticity due to uppe moto neuon lesions such as ceebal palsy and paaplegia, as well as in athetosis and stiff-man syndome. CONTRAINDICATIONS VALIUM is containdicated in patients with: - known hypesensitivity to benzodiazepines - chonic obstuctive pulmonay disease with incipient espiatoy failue. Oal VALIUM is also containdicated in patients with: - sevee espiatoy insufficiency - sevee hepatic insufficiency VALIUM PI of 11

3 - sleep apnoea syndome - myasthenia gavis - dependence on CNS depessants including alcohol. An exception to the latte is the management of acute withdawal eactions. Benzodiazepines ae not ecommended fo the pimay teatment of psychotic illness. Benzodiazepines should not be used alone to teat depession o anxiety associated with depession as suicide may occu in such patients. PRECAUTIONS Patients should be advised that thei toleance fo alcohol and othe CNS depessants will be diminished and that these medications should eithe be eliminated o given in educed dosage in the pesence of VALIUM. Such concomitant use has the potential to incease the clinical effects of VALIUM, possibly including sevee sedation, clinically elevant espiatoy and/o cadiovascula depession (see PRECAUTIONS; Inteactions with Othe Medicines). In geneal, benzodiazepines should be pescibed fo shot peiods only (e.g. 2-4 weeks). Continuous long-tem use of VALIUM is not ecommended. Thee is evidence that toleance develops to the sedative effects of benzodiazepines. Afte as little as one week of theapy, withdawal symptoms can appea following the cessation of ecommended doses (e.g. ebound insomnia following cessation of a hypnotic benzodiazepine). Following the polonged use of VALIUM at theapeutic doses, withdawal fom the medication should be gadual. An individualised withdawal timetable needs to be planned fo each patient in whom dependence is known o suspected. Peiods fom 4 weeks to 4 months have been suggested. As with othe benzodiazepines, when teatment is suddenly withdawn, a tempoay incease in sleep distubance can occu afte use of VALIUM (see PRECAUTIONS Dependence). Since VALIUM contains lactose, patients with ae heeditay poblems of galactose intoleance (the Lapp lactase deficiency o glucose-galactose malabsoption) should not take this medicine. Hypotension Although hypotension has occued aely, VALIUM should be administeed with caution to patients in whom a dop in blood pessue might lead to cadiac o ceebal complications. This is paticulaly impotant in eldely patients. Amnesia Tansient amnesia o memoy impaiment has been epoted in association with the use of benzodiazepines. Anteogade amnesia may occu using theapeutic dosages: the isk inceasing at highe dosages. Amnestic effects may be associated with inappopiate behaviou VALIUM PI of 11

4 Acute Naow-angle Glaucoma Caution should be used in the teatment of patients with acute naow-angle glaucoma (because of atopine-like side effects). Impaiment of Fetility Repoductive studies in ats showed deceases in the numbe of pegnancies and in the numbe of suviving offsping following administation of oal doses of 100 mg/kg/day (22-fold the MRHD on a body suface aea basis) to both males and females pio to and duing mating and thoughout gestation and lactation. No advese effects wee obseved at 10 mg/kg/day (60 mg/m 2 /day, twice the MRHD). Use in Pegnancy - Categoy C The safety of VALIUM fo use in human pegnancy has not been established. Diazepam and its metabolites eadily coss the placenta. An inceased isk of congenital malfomation associated with the use of benzodiazepines duing the fist timeste of pegnancy has been suggested. Benzodiazepines should be avoided duing pegnancy unless thee is no safe altenative. Benzodiazepines coss the placenta and may cause hypotension, hypotonia, educed espiatoy function and hypothemia in the newbon infant. Continuous teatment duing pegnancy and administation of high doses in connection with delivey should be avoided. Withdawal symptoms in newbon infants have been epoted with this class of dugs. Special cae must be taken when VALIUM is used duing labou and delivey, as single high doses may poduce iegulaities in the foetal heat ate and hypotonia, poo sucking, hypothemia and modeate espiatoy depession (floppy infant syndome) in the neonate. With newbon infants it must be emembeed that the enzyme system involved in the beakdown of the dug is not yet fully developed (especially in pematue infants). Teatogenicity Diazepam was found to be teatogenic in mice at intavenous doses of 45 mg/kg o geate and oal doses of 100 mg/kg o geate (both 10-fold the MRHD on a body suface aea basis), as well as in hamstes at 280 mg/kg (41-fold the MRHD). The espective no-effect doses wee 50 mg/kg (5-fold the MRHD) in mice and 200 mg/kg (30-fold the MRHD) in hamstes. Malfomations included exencephaly, canioschisis, kinking of the spinal cod, and cleft palate with and without cleft lip. Malfomations wee not obseved in ats o abbits at espective doses of up to 300 and 50 mg/kg/day (geate than 20-fold the MRHD). Delayed development has been epoted in offsping fom seveal animal species teated with diazepam duing pegnancy o duing pegnancy and lactation. Use in Lactation VALIUM is exceted in human beast milk and may cause dowsiness and feeding difficulties in the infant. Beast-feeding is not ecommended in patients eceiving oal VALIUM. VALIUM PI of 11

5 Paediatic Use Polonged cental nevous system depession has been obseved in neonates due to inability to tansfom the dug. In view of lack of adequate clinical expeience, oal use is not ecommended in childen younge than 6 months. Use in Eldely o Debilitated Patients An inceased isk of falls and factues has been ecoded in eldely benzodiazepine uses. Eldely o debilitated patients may be paticulaly susceptible to the sedative effects of benzodiazepines and associated giddiness, ataxia and confusion, which may incease the isk of a fall. Lowe doses should be used fo eldely and debilitated patients. Impaied Renal/Live Function and Blood Dyscasias Patients with impaied enal o hepatic function should use benzodiazepine medication with caution and dosage eduction may be advisable. In ae instances, some patients taking benzodiazepines have developed blood dyscasias, and some have had elevation of live enzymes. As with othe benzodiazepines, peiodic blood counts and live function tests ae ecommended. Depession, Psychosis and Schizophenia VALIUM is not ecommended as pimay theapy in patients with depession and/o psychosis. In such conditions, psychiatic assessment and supevision ae necessay if benzodiazepines ae indicated. Benzodiazepines may incease depession in some patients and may contibute to deteioation in seveely distubed schizophenics with confusion and withdawal. Suicidal tendencies may be pesent o uncoveed and potective measues may be equied. Paadoxical Reactions Paadoxical eactions such as estlessness, agitation, iitability, aggessiveness, delusion, nightmaes, hallucinations, psychoses, inappopiate behaviou and othe advese behavioual effects, acute age, stimulation o excitement may occu. Should such eactions occu, VALIUM should be discontinued. They ae moe likely to occu in childen and in the eldely. Cacinogenicity The cacinogenic potential of oal diazepam has been studied in seveal odent species. An incease in the incidence of malignant hepatocellula tumous occued in male ats and mice following lifetime dietay administation of diazepam at 75 mg/kg/day (17- and 8-fold the MRHD on a body suface aea basis, espectively). This was not obseved in female ats and mice teated with 75 mg/kg/day o hamstes teated with 120 mg/kg/day (18-fold the MRHD). VALIUM PI of 11

6 Genotoxicity Limited data fom a numbe of studies have povided weak evidence of a genotoxic potential Diazepam has been shown to induce aneuploidy in spem obtained fom both mice and humans teated with appoximately 10 mg/m 2 /day (less than the MRHD). Impaied Respiatoy Function Caution in the use of VALIUM is ecommended in patients with espiatoy depession. In patients with chonic obstuctive pulmonay disease, benzodiazepines can cause inceased ateial cabon dioxide tension and deceased oxygen tension. A lowe dose is ecommended fo patients with chonic espiatoy insufficiency, due to the isk of espiatoy depession. Epilepsy When VALIUM is administeed to pesons with convulsive disodes, an incease in the fequency and/o seveity of gand mal seizues may occu, necessitating inceased anti-convulsant medication. Abupt withdawal of benzodiazepines in pesons with convulsive disodes may be associated with a tempoay incease in the fequency and/o seveity of seizues. Abuse Exteme caution must be execised in administeing VALIUM to individuals with a histoy of alcohol o dug abuse, dependence on CNS depessants, those known to be addiction pone, o those whose histoy suggests they may incease the dosage on thei own initiative. It is desiable to limit epeat pesciption without adequate medical supevision. Dependence The use of benzodiazepines and benzodiazepine-like agents may lead to the development of physical and psychic dependence (see ADVERSE EFFECTS), as defined by the pesence of a withdawal syndome on discontinuation of the dug. The isk of dependence inceases with dose and duation of teatment. It is moe ponounced in patients on long-tem theapy and/o high dosage and paticulaly so in pedisposed patients with a histoy of alcohol o dug abuse. Toleance, as defined by a need to incease the dose in ode to achieve the same theapeutic effect, seldom occus in patients eceiving ecommended doses unde medical supevision. Toleance to sedation may occu with benzodiazepines, especially in those with dug seeking behaviou. Withdawal symptoms, simila in chaacte to those noted with babituates and alcohol, have occued once physical dependence to benzodiazepines has developed o following abupt discontinuation of benzodiazepines. These symptoms ange fom insomnia, anxiety, dysphoia, palpitations, panic attacks, vetigo, myoclonus, akinesia, hypesensitivity to light, sound and touch, abnomal body sensations (e.g. feeling of motion, metallic taste), depesonalisation, deealisation, delusional beliefs, hypeeflexia and loss of shot tem memoy, to a majo syndome which may include convulsions, temo, abdominal and muscle camps, confusional state, deliium, hallucinations, hypethemia, psychosis, vomiting and sweating. Such manifestations of withdawal, especially the moe seious ones, ae moe common in patients who have eceived excessive doses ove a polonged peiod. Howeve, withdawal symptoms have been epoted following abupt discontinuation of benzodiazepines taken continuously at theapeutic levels. Accodingly, VALIUM should be teminated VALIUM PI of 11

7 by tapeing the dose to minimise occuence of withdawal symptoms. Patients should be advised to consult with thei physician befoe eithe inceasing the dose o abuptly discontinuing the medication. Rebound phenomena have been descibed in the context of benzodiazepine use. Rebound insomnia and anxiety mean an incease in the seveity of these symptoms beyond pe-teatment levels following cessation of benzodiazepines. Rebound phenomena in geneal possibly eflect e-emegence of peexisting symptoms combined with withdawal symptoms descibed ealie. Some patients pescibed benzodiazepines with vey shot half-lives (in the ode of 2 to 4 hous) may expeience elatively mild ebound symptoms in between thei egula doses. Withdawal/ebound symptoms may follow high doses fo elatively shot peiods. Inteaction with Othe Medicines Enhanced effects on sedation, espiatoy depession (including apnoea) and haemodynamic instability may occu when VALIUM is co-administeed with any centally acting depessants, which themselves poduce CNS depession (e.g. babituates, alcohol, anxiolytics, sedatives, antidepessants including ticyclic anti-depessants and non-selective MAO inhibitos, hypnotics, antiepileptic dugs, phenothiazines and othe anti-psychotics, skeletal muscle elaxants, anti-histamines, nacotic analgesics and anaesthetics. Alcohol should be avoided in patients eceiving VALIUM (see PRECAUTIONS). Concomitant use with alcohol is not ecommended due to enhancement of the sedative effect. The oxidative metabolism of diazepam, leading to the fomation of nodiazepam and temazepam, is mediated pedominantly by the CYP2C19 and CYP3A cytochome P450 isoenzymes, espectively. Consequently, substates which ae modulatos of CYP3A o CYP2C19, may potentially alte the phamacokinetics of diazepam. Nodiazepam and temazepam ae futhe metabolised to oxazepam. Diazepam may inteact with disulfiam, cimetidine, ketoconazole, fluvoxamine, fluoxetine, diltiazem o omepazole esulting in inceased plasma levels of VALIUM. Patients should be obseved closely fo evidence of enhanced benzodiazepine esponse (e.g. inceased and polonged sedation) duing concomitant teatment with eithe disulfiam o cimetidine; some patients may equie a eduction in benzodiazepine dosage. Thee have also been epots that the metabolic elimination of phenytoin is affected by diazepam. Cisapide may lead to a tempoay incease in the sedative effects of oally administeed benzodiazepines due to faste absoption. The anti-cholinegic effects of othe dugs including atopine and simila dugs, anti-histamines and anti-depessants may be potentiated. Inteactions have been epoted between some benzodiazepines and anti-convulsants, with changes in the seum concentation of the benzodiazepine o anti-convulsant. It is ecommended that patients be obseved fo alteed esponses when benzodiazepines and anti-convulsants ae pescibed togethe and that seum level monitoing of the anti-convulsant is pefomed moe fequently. See the OVERDOSAGE section fo wanings about othe cental nevous system depessants, including alcohol. VALIUM PI of 11

8 Effects on Laboatoy Tests Mino EEG changes, usually low voltage fast activity, of no known clinical significance have been epoted with benzodiazepine administation. Diazepam can inhibit binding of thyoxine and liothyonine to thei binding poteins esulting in eoneously abnomal values fom thyoid function test. Ability to Dive and Use Machines Sedation, amnesia, impaied concentation and impaied muscle function may advesely affect the ability to dive o opeate machiney. As with all patients taking CNS depessant medications, patients eceiving VALIUM should be waned not to opeate dangeous machiney o moto vehicles until it is known that they do not become dowsy o dizzy fom VALIUM theapy. Abilities may be impaied on the day following use. ADVERSE EFFECTS Most commonly epoted undesiable effects ae fatigue, dowsiness, muscle weakness and ataxia; they ae usually dose-elated. Isolated instances of neutopenia have been seen. Dizziness has been epoted occasionally with oal VALIUM. Anteogade amnesia may occu using theapeutic dosages, the isk inceasing at highe doses. Amnestic effects may be associated with inappopiate behaviou. Nevous System Disodes: Amnesia, fatigue, dowsiness, muscle weakness, ataxia, dysathia, slued speech, headache, temo, dizziness. Psychiatic Disodes: Paadoxical eactions such as estlessness, acute hypeexcitation, agitation, iitability, anxiety, inceased muscle spasticity, insomnia, sleep distubances, nightmaes, hallucinations, aggession, delusion, ange, psychoses, abnomal behaviou, stimulation and othe advese behavioual effects ae known to occu when using benzodiazepines. Should these occu, use of the dug should be discontinued. They ae moe likely to occu in childen and in the eldely. Confusion, emotional povety, aletness deceased, depession, libido inceased o deceased. Chonic use (even at theapeutic doses) of oal VALIUM may lead to the development of physical dependence: discontinuation of the theapy may esult in withdawal o ebound phenomena (see PRECAUTIONS; Dependence). Abuse of benzodiazepines has been epoted (see PRECAUTIONS; Dependence) Injuy, Poisoning and Pocedual Complications: An inceased isk fo falls and factues has been epoted in eldely benzodiazepine uses. VALIUM PI of 11

9 Gastointestinal Disodes: Nausea, dy mouth o hypesalivation, constipation and othe gastointestinal distubances. Eye Disodes: Diplopia, vision blued. Vascula Disodes: Hypotension, ciculatoy depession. Investigations: Iegula heat ate, vey aely inceased tansaminases, inceased blood alkaline phosphatase. Renal and Uinay Disodes: Incontinence, uinay etention. Skin and Subcutaneous Tissue Disodes: Skin eactions, such as ash. Ea and Labyinth Disodes: Vetigo. Cadiac Disodes: Cadiac failue including cadiac aest. Respiatoy Disodes: Respiatoy depession including espiatoy failue. Hepatobiliay Disodes: Vey aely jaundice. Haemopoietic Disodes: Isolated instances of neutopenia DOSAGE AND ADMINISTRATION Oal Fo maximal beneficial effect, the dosage should be caefully individualised. Dosage may need to be educed in patients with hepatic o enal disease as the elimination half-life may be polonged in this sub-goup. Eldely patients should be given a educed dose. These patients should be checked egulaly at the stat of teatment in ode to minimise the dosage and/o fequency of administation to pevent ovedose due to accumulation. Usual Adult Dosage: 5-40 mg daily. Aveage dosage fo ambulatoy patients: 2 mg thee times daily o 5 mg in the evening and 2 mg once o twice duing the day. Eldely o debilitated patients: 2 mg twice daily o half the usual adult dose. Childen 6 months to 3 yeas: 1-6 mg daily, 4 to 14 yeas: 4-12 mg daily o calculated fom mg/kg bodyweight. Hospital teatment of tension, excitation, moto unest: mg thee times daily until the acute symptoms subside. Muscle spasm: mg daily. Benzodiazepines should not be given to childen without caeful assessment of the indication; the duation of teatment must be kept to a minimum. VALIUM PI of 11

10 OVERDOSAGE Symptoms Ovedosage of benzodiazepines is usually manifested by degees of cental nevous system depession anging fom dowsiness to coma. In mild cases, symptoms include dowsiness, dysathia, nystagmus, mental confusion and lethagy. In moe seious cases, symptoms may include ataxia, aeflexia, hypotonia, hypotension, apneoa, cadioespiatoy depession, coma and vey aely death. Coma may be moe potacted and cyclical, paticulaly in eldely patients. Benzodiazepine espiatoy depessant effects ae moe seious in patients with espiatoy disease. Benzodiazepines incease the effects of othe cental nevous system depessants, including alcohol. When combined with othe CNS depessants, the effects of ovedosage ae likely to be sevee and may pove fatal. Teatment Teatment of ovedose is symptomatic; institute suppotive measues as indicated by the patient s clinical state. If the ovedosage is known to be small, obsevation of the patient and monitoing of thei vital signs only may be appopiate. In adults o childen who have taken an ovedose of benzodiazepines within 1-2 hous, conside activated chacoal with aiway potection if indicated. If CNS depession is sevee conside the use of flumazenil (Anexate ), a benzodiazepine antagonist. This should only be administeed unde closely monitoed conditions. It has a shot half-life (about an hou), theefoe patients administeed flumazenil will equie monitoing afte its effects have won off. Flumazenil may pecipitate seizues and is to be used with exteme caution in the pesence of dugs that educe seizue theshold (e.g. ticyclic antidepessants) and epileptic patients who have been teated with benzodiazepines. Refe to the pescibing infomation fo flumazenil (Anexate ), fo futhe infomation on the coect use of this dug. Haemopefusion and haemodialysis ae not useful in benzodiazepine intoxication. Contact the Poisons Infomation Cente fo advice on management of ovedosage. PRESENTATION AND STORAGE CONDITIONS Tablets 2 mg (white, scoed, maked Roche 2 on evese): 50's 5 mg (yellow, scoed, maked Roche 5 on evese): 50's Stoe below 30 C Disposal of Medicines The elease of medicines into the envionment should be minimised. Medicines should not be disposed of via wastewate and disposal though household waste should be avoided. Unused o expied medicines should be etuned to a phamacy fo disposal. VALIUM PI of 11

11 POISON SCHEDULE OF THE MEDICINE Schedule 4 Pesciption only medicine NAME AND ADDRESS OF THE SPONSOR Roche Poducts Pty Limited ABN Inman Road Dee Why NSW 2099 Date of TGA Appoval: 2 Febuay 2010 VALIUM PI of 11