MIDAZOLAM 2MG/ML SOLUTION FOR INJECTION OR INFUSION

PACKAGE LEAFLET INFORMATION FOR THE USER

Midazolam 2mg/ml Solution for Injection or Infusion Midazolam

Special care should be taken if the patient is in a coma. Taking other medicines Taking another medicine while you are being given Midazolam Injection can affect how it or the other medicine works. Please inform your doctor or nurse if you are taking or have recently taken any other medicines, drugs or herbal products, including those you may have bought yourself without a prescription.

If your doctor has decided that you should be given this medicine during labour, your baby might have a low body temperature, floppiness, an abnormal heart rate and breathing or feeding difficulties. If you wish to become pregnant, you should speak to your doctor about the use of Midazolam Injection. Midazolam can enter breast milk. You should not be given Midazolam Injection if you are breast-feeding or wish to breast-feed.

Read all of this leaflet carefully before you start using this medicine. - Keep this leaflet. You may need to read it again. - If you have further questions, please ask your doctor or nurse. - This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours. The name of your medicine is Midazolam 2mg/ml Solution for Injection or Infusion. In the rest of this leaflet it is called Midazolam Injection. In this leaflet: 1. What Midazolam Injection is and what it is used for 2. Before you are given Midazolam Injection 3. How Midazolam Injection should be given 4. Possible side effects 5. How to store Midazolam Injection 6. Further information 1. WHAT MIDAZOLAM INJECTION IS AND WHAT IT IS USED FOR The active ingredient in Midazolam Injection is midazolam which belongs to a group of sedative medicines called benzodiazepines. Midazolam Injection is used: for sedation before and during minor medical, dental or surgical procedures for sedation of patients in intensive care at the start of a general anaesthetic

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2. BEFORE YOU ARE GIVEN MIDAZOLAM INJECTION You should not be given Midazolam Injection if you: are allergic to midazolam or any of the other ingredients contained in Midazolam Injection (see list under heading What Midazolam Injection contains in section 6) have severe breathing problems have severe liver problems. If you have any doubts about whether you should be If any of the above statements apply to you, you should given this medicine then discuss matters with your doctor. not be given Midazolam Injection. Pregnancy and breast-feeding Speak to your doctor before you are given You should not usually be given Midazolam Injection if Midazolam Injection if you: you are pregnant. If Midazolam Injection is given to are elderly women in the first three months of pregnancy, there is are very run down and lack strength a small risk of congenital malformation in the baby have problems with your liver, kidneys or lungs particularly a split in the mouth (cleft palate). Infants have a condition called myasthenia gravis which born to mothers who are given Midazolam Injection causes very weak muscles during the late stages of pregnancy may experience have a personality disorder, depression, aggressive withdrawal symptoms or slow development. tendencies or if you feel suicidal have had problems with addiction to drugs or alcohol

Please check with your doctor if you are taking or have been given any of the following (or any other medication): Driving and operating machines You should not drive or operate machinery for at least Alcohol and smoking: twelve hours after receiving Midazolam Injection. You alcohol should speak to your doctor about driving if you also disulfiram, a drug used for alcohol dependence take other medicines that can cause sedation. nicotine, from smoking Alcohol and Midazolam Injection Other medicines that cause sedation: You should not drink alcohol for at least eight hours sleeping tablets before or after having an injection of midazolam. medicines used to treat anxiety e.g. other benzodiazepines Important information about the sodium content of medicines used to treat depression, such Midazolam Injection as nefazodone This medicinal product contains less than 1 mmol medicines for epilepsy, such as phenytoin sodium (23mg) per ampoule, i.e. it is essentially some antihistamines, used to treat hayfever sodium-free. medicines used for mental illness, such as clozapine 3. HOW MIDAZOLAM INJECTION nabilone, used to treat vomiting due to SHOULD BE GIVEN cancer therapy You will only be given Midazolam Injection in places with adequate resuscitation equipment and when Medicines used during operations: there is a second member of staff present to help your anaesthetics doctor. Midazolam Injection will be given into a vein in certain pain killers (e.g. fentanyl) If you take or are your arm (intravenous injection) whilst you are lying given these drugs you should have them before you down. Your doctor will decide which dose is suitable receive your Midazolam Injection and will need to be for you. The dose used will depend on what the carefully monitored for problems with your breathing injection is being given for and on your general physical and your heart condition, age, weight, what other medicines you are medicines used to relax your muscles during an taking and your response to the drug. operation (e.g. baclofen) For sedation before and during minor surgery or Medicines that fight infections: dental procedures antibiotics, used to treat bacterial infections, such as erythromycin, clarithromycin, quinupristin with Adults dalfopristin The usual adult dose for sedation of adults before and drugs used to treat fungal infections, such as during minor surgery or dental procedures is 2mg ketoconazole, itraconazole or fluconazole given into a vein over a period of 30 seconds. Further drugs used to treat virus infections, such as injections of 0.5 - 1mg may be given every two amprenavir or ritonavir used for HIV minutes until you are properly sedated. The total dose drugs used for tuberculosis, such as isoniazid or required is usually 2.5 to 7.5mg. rifampicin Elderly Other medicines: The usual dose for the elderly is 1 to 1.5mg, given into medicines to lower your blood pressure, such as to a vein over a period of 30 seconds. Further 0.5 - 1mg diltiazem, verapamil or moxonidine injections may be given every two minutes until you medicines used for pain relief and inflammation such are properly sedated. as aspirin medicines used to treat stomach ulcers, such as Children cimetidine, ranitidine or omeprazole Midazolam Injection is not used in this way in levodopa, a drug used in the treatment of children. Parkinson's disease theophylline, a drug used for asthma and lung If you have kidney or liver disease disease If you have kidney or liver disease you will be given a probenecid, used for gout. lower dose. If you are in intensive care Adults, Elderly and Children Small doses of 1 to 2mg may be given directly into a vein and repeated until sedation is achieved. For the elderly even smaller doses of 0.5 to 1mg may be adequate. Alternatively you may be given 0.03 to 0.3mg/kg body weight over five minutes, followed by 0.03 to 0.2mg/kg body weight every hour given by continuous intravenous infusion (a continuous injection into a vein in your arm).

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Product Summary 1.NAME OF THE MEDICINAL PRODUCT Midazolam 2mg/ml Solution for Injection or Infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Midazolam 2mg/ml. Each 5ml ampoule contains 10mg midazolam. Contains less than 1mmol sodium (23mg) per 5ml ampoule. 3. PHARMACEUTICAL FORM Solution for injection or infusion 4. CLINICAL PARTICULARS 4.1 Therapeutic indication Midazolam may be used as an intravenous sedative before and during minor medical, dental and surgical procedures.

Dependence and withdrawal symptoms The dependence potential of midazolam increases with dose and duration of treatment and is greater in patients with a history of alcohol or drug abuse. It is low when limited to short term use. Due to the possibility of As an intravenous sedative, (either by continuous infusion withdrawal symptoms, midazolam should be gradually or intermittent bolus injection) in critically ill patients in reduced following a prolonged iv administration; abrupt intensive care. discontinuation should be avoided. Withdrawal symptoms As an alternative intravenous agent for the induction of may occur with benzodiazepines following normal use of anaesthesia in high risk and elderly patients where therapeutic doses for only short periods and may be Patients receiving midazolam injection for sedation in the When midazolam has been given for a number of days cardiovascular stability is of particular importance. intensive care situation should receive ventilatory support. and then gradually withdrawn, patients may be awake but associated with physiological and psychological sequelae Induction is more reliable when heavy opiate medication (see Section 4.8 Undesirable effects). This should be show signs of residual sedation for the next 12 to 24 has been administered or when midazolam injection is Safe use for midazolam for periods of over 14 days in considered when treating patients for more than a few hours. This can cause difficulties because patients may given with a narcotic analgesic such as fentanyl. duration has not been established in clinical trials. days. not cough and expectorate well if they are then weaned from ventilatory support. However, while recovering from 4.2 Posology and method of administration Potential drug interactions:the effects of midazolam, patients may not be sufficiently As with other benzodiazepines, extreme caution should be The critically ill patient is exposed to many drugs. Dosage depends on the individual response, age and used if prescribing midazolam for patients with personality sedated to tolerate ventilatory support. In such weight. Midazolam 2mg/ml may be given by intravenous Because of this, there is a potential for drug interactions. disorders. The disinhibiting effects of benzodiazepines circumstances sedation may be provided with a shorter (Refer to Section 4.5 Interactions with other medicaments acting agent while there is recovery from the effects of or slow intravenous injection. may be manifested as the precipitation of suicide in and other forms of interaction). patients who are depressed or show aggressive midazolam. Intravenous sedation behaviour towards self and others. After prolonged iv administration of midazolam injection, One or more intravenous injections to be administered The recommended concentration of a solution for infusion abrupt discontinuation may be accompanied by over a single operating session. This medicinal product contains 0.15mmol sodium per in a critically ill adult patient is 1mg/ml. withdrawal symptoms, therefore a gradual reduction of ampoule. To be taken into consideration by patients on a the drug is recommended. Dosage should be titrated according to an individual's controlled sodium diet. Induction of anaesthesia by slow intravenous injection One or more bolus intravenous injections should be response, age and weight. The end-point of this titration is administered over a single anaesthetic session. dependent on the procedure. Full sedation will be evident Sedation by intermittent bolus dose in intensive care 4.5 Interactions with other medicinal products and by drowsiness and slurred speech, although a response to other forms of interaction Adults Midazolam injection only commands will be maintained. Alcohol: Alcohol should be avoided for at least eight hours The exact dose of midazolam needs to be titrated to the The dose should be titrated against the individual before and after the administration of midazolam due to response of the patient. Midazolam injection should be Adults: 2mg, (1ml of 2mg/ml midazolam injection solution) individual patient response. Small doses of midazolam increased sedative effects. 1.0-2.0mg can be given, and repeated, until the required given by slow intravenous injection until there is a loss of over a period of 30 seconds initially degree of sedation is reached. eyelid reflex, response to commands and voluntary Anaesthetics and narcotic analgesics: Enhanced sedation movements. Elderly: 1 to 1.5mg (0.5-0.75ml of 2mg/ml midazolam or respiratory and cardiovascular depression. If such Midazolam injection and an opioid injection solution) over a period of 30 seconds initially. centrally acting depressant drugs are given parenterally in When midazolam and an opioid are used together, the In anticipating the required dose of midazolam, both the conjunction with intravenous midazolam, severe opioid should be administered first. Both drugs need to be premedication already given and the age of the patient are respiratory and cardiovascular depression may occur; If adequate sedation is not achieved after two minutes, titrated to the individual patient's response and to the level important. Young, fit unpremedicated patients may need incremental doses of 0.5-1mg, (0.25-0.5ml of 2mg/ml careful monitoring is required. When intravenous of sedation thought to be necessary. at least 0.3mg/kg bodyweight, whereas patients midazolam injection solution) should be given until the midazolam is to be administered concurrently with a premedicated with an opiate usually need only 0.2mg/kg narcotic analgesic agent (e.g. fentanyl), it is recommended desired level of sedation is achieved, usually at a total Small doses of midazolam 1-2mg (0.5-1.0ml of 2mg/ml bodyweight. dose of 2.5-7.5mg (about 70 micrograms/kg) in adults. that midazolam be given after the analgesic and that the midazolam injection solution) can be given, and repeated, dose be carefully titrated to meet the patient's needs. until the required degree of sedation is reached. In the Use in the elderly Renal/hepatic impairment: Reduce dose Fentanyl may reduce midazolam clearance. elderly, smaller doses as little as 0.5-1.0mg (0.25-0.5ml of The elderly are more sensitive to the effects of 2mg/ml midazolam injection solution) may be adequate. benzodiazepines. Induction may be adequate with Children Antibacterials: Agents that interfere with metabolism by 0.1mg/kg body weight in premedicated patients and Not recommended. Midazolam injection has not been hepatic enzymes (e.g. isoniazid, erythromycin, The use of these two groups of drugs can increase the 0.2mg/kg body weight in unpremedicated patients. evaluated as an intravenous sedative in children. clarithromycin, quinupristin/dalfopristin) have been shown risk of respiratory depression. If the patient is being given to reduce the clearance of benzodiazepines and may ventilatory support using a mode that depends upon Renal/hepatic impairment: Reduce dose. Combination therapy:potentiate their actions, whilst known inducers of hepatic If analgesia is provided by a narcotic analgesic, the some spontaneous effort by the patient, then the minute Children over seven years enzymes, for example, rifampicin, may increase the analgesic should be administered first. The dose of volume may decrease. Midazolam injection has been shown to be an effective clearance of benzodiazepines. midazolam injection should then be carefully titrated. Low agent for induction of anaesthesia in children over seven total doses of 1-2mg may be adequate with lower total Sedation by continuous infusion in intensive care years of age, at a dose of 0.15mg/kg body-weight. Antidepressants: Enhanced sedation or respiratory and doses of 0.5-1mg in the elderly. Midazolam injection only cardiovascular depression. Midazolam plasma levels Adults, Elderly and children Mode of administration:increased by concomitant nefazodone. For patients already sedated or anaesthetised after an Mode of administration:For the administration of midazolam injection the patient For the administration of midazolam injection the patient operation, a loading dose of midazolam is unnecessary. should be placed in a supine position and remain there Antiepileptics: Enhanced sedation or respiratory or should be placed in a supine position and remain there throughout the procedure. Resuscitation facilities should cardiovascular depression. Midazolam may interact with In other situations a loading dose of 0.03-0.3mg/kg given always be available and a second person, fully trained in throughout the procedure. Resuscitation facilities should other hepatically metabolised drugs, e.g. phenytoin, over a five minute period is recommended, depending on the use of such equipment, always be present. It is always be available and a second person, fully trained in causing potentiation. the level of sedation required. The loading dose should be recommended that patients should remain under medical the use of such equipment, always be present. It is recommended that patients should remain under medical reduced or omitted in hypovolaemic, vasoconstricted or supervision until at least one hour has elapsed from the Antifungals: Ketoconazole, itraconazole, and possibly hypothermic patients, renal or hepatic impairment. supervision until at least one hour has elapsed from the time of injection. They should always be accompanied fluconazole, have been shown to reduce the clearance of time of injection. They should always be accompanied home by a responsible adult. benzodiazepines and may potentiate their actions Maintenance dose home by a responsible adult. A dose between 0.03-0.2mg/kg/hour is recommended, 4.3 Contraindications Antihistamines: Enhanced sedation or respiratory and Patients who have received only midazolam injection for iv starting at the lower dose. Known hypersensitivity to benzodiazepines or any of the cardiovascular depression with sedative antihistamines. sedation prior to minor procedures, should be warned not ingredients. Severe or acute respiratory The dose should be reduced in hypovolaemic, to drive or operate machinery for 12 hours. Where insufficiency/depression. Antihypertensives: Enhanced hypotensive effect. vasoconstricted or hypothermic patients, renal or hepatic midazolam injection is used concurrently with other Severe hepatic insufficiency Enhanced sedative effect possible with moxonidine.

impairment. central nervous system depressants (e.g. potent analgesics) recovery may be prolonged. Patients should therefore be assessed carefully before being allowed to go Midazolam injection and an opioid When opioid analgesics are used, the rate of infusion of home or resume normal activities. midazolam should be titrated carefully to the sedative needs of the patient. Low doses of midazolam 0.01 to Sedation in the critically ill patient:Midazolam injection can be given intravenously by two 0.1mg/kg/hour may be used to start. methods for this purpose, either by continuous infusion or by intermittent bolus dose. Both have their own The use of these two groups of drugs can increase the advantages and disadvantages and the appropriate risk of respiratory depression. If the patient is being given method of giving midazolam injection will need to be ventilatory support using a mode that depends upon determined for each patient. some spontaneous effort by the patient, then the minute volume may decrease. The dose of midazolam injection needed to sedate critically ill patients varies considerably between patients. Whenever a continuous infusion of midazolam is used The dose should be titrated to the desired state of (with or without an opioid analgesic), its need should be sedation. This will depend on clinical need, physical assessed on a daily basis in order to reduce the risk of accumulation and prolonged recovery. Each day the status, age and concomitant medication. infusion of midazolam should be stopped or its rate Midazolam injection can also be given in combination with reduced and the patient seen to recover from its effect. If an opioid. The opioid may be used for its analgesic effects recovery is prolonged (>2 hours) a lower dose should be or as an antitussive agent to help the patient tolerate the used when it is restarted. A sedation score should be tracheal tube and ventilatory support. used routinely.

4.4 Special warnings and precautions for use Midazolam injection should be used with caution in patients with renal or hepatic dysfunction (see 4.2 Posology and Method of Administration), chronic pulmonary insufficiency, myasthenia gravis, coma, or a known history of drug or alcohol abuse. Midazolam may enhance the effects of other CNS depressants and may result in severe respiratory or cardiovascular depression. Their concurrent use should be avoided. Elderly or debilitated patients are more prone to the CNS effects of benzodiazepines and, therefore, lower doses are required (see 4.2 Posology and Method of Administration).

Patients who have kidney or liver disease, who have a low body temperature, or who are severely dehydrated A smaller dose should be given. Patients who are receiving certain pain killers (e.g. fentanyl) If you take or are given these drugs you should have them before you are given your Midazolam Injection. Low doses of Midazolam Injection (0.01 to 0.1mg/kg body weight per hour) may be used to start.

dizziness, ringing in your ears, loss of appetite, tremor, sweating, irritability, increased sensation, abnormal taste, feeling sick, being sick, stomach pains, rapid heart beat, high blood pressure or low blood pressure on standing. Rare and more serious withdrawal symptoms include muscle twitching, confusion, paranoia, fits, hallucinations, and delirium. Broken sleep with vivid dreams may persist for some weeks after withdrawal.

5. HOW TO STORE MIDAZOLAM INJECTION Keep out of the reach and sight of children. This medicine should not be used if the expiry date on the ampoule has passed. The expiry date refers to the last day of that month.

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4. POSSIBLE SIDE EFFECTS Like many medicines Midazolam Injection may cause Monitoring of Response side effects in some patients, although not everybody Patients who receive Midazolam Injection for sedation gets them. The side effects are generally mild. If you in intensive care should be on a ventilator. If you receive are elderly or very run-down you are more likely to a continuous intravenous infusion of Midazolam have side effects. Injection, the infusion should be stopped / reduced everyday to see how you recover from its effect. If If you experience any of the following, you should recovery takes more than two hours, a lower dose contact your doctor or nurse immediately: should be used. skin rashes or other allergic reactions (with swelling of the face and eyes and difficulty breathing in severe At the start of a general anaesthetic cases) One or more intravenous injections may be given until problems breathing or if you stop breathing. This is you are sedated. more likely to occur if you are elderly or if your dose is too high or it is given too quickly Adults your heart stopping. If you have not received any pre-medication the usual adult dose is about 0.3mg/kg body weight. If you have Less serious side effects include: received pre-mediation however, you may only need Heart and circulation problems about 0.2mg/kg body weight. slow pulse chest pain Elderly low blood pressure The elderly are more sensitive to Midazolam Injection inflammation of your veins so the doses required tend to be lower than for adults. If you have not received any pre-medication the usual Nervous system problems: dose is about 0.2mg/kg body weight. However, if you dizziness, lack of coordination and over sedation with have received pre-mediation you may only need about a risk of falls and other accidents 0.1mg/kg body weight. headaches confusion Children over seven years slurred speech The usual dose for children over seven years is about drowsiness 0.15mg/kg body weight. tremor uncontrolled jerky movements If you have kidney or liver disease reduced alertness If you have kidney or liver disease you will be given a forgetfulness lower dose. Mental problems: If you are given more Midazolam Injection than numbed emotions you should depression A doctor or nurse will give you this medicine. If you delirium after surgery think that you have been given too much, inform your doctor or nurse. Signs that you have been given too Gut problems: much Midazolam Injection include: confusion; reduction dry mouth in consciousness; feeling drowsy; breathing difficulties; stomach problems lack of co-ordination; speech impairment; low blood pressure and muscle weakness. In the case of a severe Other side effects include: overdose, coma can occur and you could stop fatigue breathing. As the level of medicine falls in your blood hangover effect you may get severe agitation; inability to sleep and pain on injection possibly major fits. hiccups problems with your vision If you think you have missed a dose of jaundice (a yellowing of the skin and whites of Midazolam Injection the eyes) A doctor or nurse will give you this medicine. If you difficulty in passing water think you have missed a dose, inform your doctor or incontinence (the inability to control when you go nurse. the toilet) changes in sexual desire Stopping Midazolam Injection blood problems If you are given Midazolam Injection for a long time, there is a risk of becoming dependent on it in which some patients, particularly if they are children or case you may have withdrawal symptoms when you elderly, may become irritable, aggressive, hostile, stop taking it. The dose should be reduced gradually to overexcited, uninhibited, overanxious or have reduce the risk of withdrawal symptoms and you hallucinations. should never stop your Midazolam Injection abruptly. Your doctor will decide when to stop your treatment If any of the side effects get serious, or if you notice any with Midazolam Injection. side effects not listed in this leaflet, please contact your doctor or nurse immediately. Withdrawal symptoms include anxiety, depression, impaired concentration, inability to sleep, headache,

This medicine should not be stored above 25C. Store the ampoule in the outer carton in order to protect from light. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Midazolam Injection contains The active ingredient in Midazolam Injection is midazolam. The injection is available in 5ml ampoules. Each ampoule contains 10mg of the active ingredient in 5ml of solution. The other ingredients are sodium chloride, hydrochloric acid solution, sodium hydroxide solution and water for injections. What Midazolam Injection looks like and contents of the pack Midazolam Injection is a clear, colourless solution. Midazolam Injection is available in cartons containing 10x5ml glass ampoules. Marketing Authorisation Holder: Wockhardt UK Ltd, Ash Road North, Wrexham, LL13 9UF, UK. Manufacturer: CP Pharmaceuticals Ltd, Ash Road North, Wrexham, LL13 9UF, UK. Other formats: To listen to or request a copy of this leaflet in Braille, large print or audio please call, free of charge: 0800 198 5000 (UK Only) Please be ready to give the following information: Product Name
Midazolam 2mg/ml Solution for Injection or Infusion

Reference Number
29831/0140

This is a service provided by the Royal National Institute of Blind People. Date of leaflet preparation: July 2008

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Antipsychotics: Enhanced sedation or respiratory and cardiovascular depression. Severe hypotension, collapse, respiratory depression, potentially fatal respiratory arrest and unconsciousness have been reported in a few patients on benzodiazepines and clozapine. Caution is advised when initiating clozapine therapy in patients taking benzodiazepines. Antivirals: Concomitant use of midazolam with HIV-protease inhibitors (e.g. amprenavir, ritonavir) should be avoided due to the risk of extreme sedation and respiratory depression. Anxiolytics and hypnotics: Enhanced sedation or respiratory and cardiovascular depression with other anxiolytics and hypnotics. Calcium-channel blockers: Diltiazem and verapamil have been shown to reduce the clearance of benzodiazepines and may potentiate their actions. Dopaminergic agents: Midazolam may cause inhibition of levodopa. Disulfiram: Has been shown to reduce clearance of benzodiazepines and may potentiate their actions. Muscle relaxants: e.g. baclofen Midazolam may cause potentiation, with increased CNS depressant effects. Nabilone: Enhanced sedation or respiratory and cardiovascular depression. Nicotine: Benzodiazepine metabolism is accelerated by smoking. Non-steroidal anti-inflammatory drugs: The induction of anaesthesia with midazolam is more rapid in patients pre-treated with aspirin. Probenecid: May reduce midazolam clearance. Sedatives: Enhanced sedation or respiratory and cardiovascular depression.

4.7 Effects on ability to drive and use machines The concurrent use of midazolam with other central nervous system depressants, may result in a prolonged recovery. A careful assessment should be undertaken prior to allowing the patient to go home or resume normal activities. Patients treated with midazolam injection should not drive or use machinery for twelve hours after receiving this medicine. 4.8 Undesirable effects Side-effects are usually mild. Cardiovascular: Midazolam may cause bradycardia, chest pain and decreases in cardiac output, stroke volume and systemic vascular resistance. These effects are important in those patients with a reduced myocardial oxygen delivery capacity or suffering hypovolaemia. Also, hypotension, particularly with high dosage, and cardiac arrest. Local thrombophlebitis may occur. CNS: Elderly or debilitated patients are particularly susceptible to the CNS side effects of benzodiazepines. It is recommended that dosage be limited to the smallest effective dose and increased gradually, if necessary, to decrease the possibility of development of ataxia, dizziness and oversedation, which may lead to falls and other accidents (see 4.2 Posology and method of administration). Disorders of the eye: Visual disturbances. Gastrointestinal: dry mouth, gastrointestinal disturbances. General: Fatigue and a hangover effect. Local pain on injection. Hiccups. Haematological: Blood dyscrasias. Hepatic: Jaundice. Immunological: Skin reactions and other hypersensitivity reactions, including anaphylaxis, are rare. Neurological: Headaches, confusion, slurred speech, tremor, drowsiness, reduced alertness, anterograde amnesia, extrapyramidal effects.

4.9 Overdose a) Symptoms The symptoms of mild overdose may include confusion, impairment of consciousness with somnolence or a sleep-like state, little or no respiratory depression, ataxia, dysarthria, hypotension and muscular weakness. Cardiac rate and rhythm remain normal in the absence of anoxia or severe hypotension. In severe overdose, deep coma, or other manifestations of severe depression of brainstem vital functions, particularly the respiratory centre, may occur As drug levels fall, severe agitation, insomnia and, possibly, major convulsions may develop. b) Treatment Treatment is symptomatic. Respiration, heart rate, blood pressure and body temperature should be monitored and supportive measures taken to maintain cardiovascular function. Ventilation should be used to support respiratory function if appropriate. Flumazenil is a specific antidote for use in midazolam overdosage but expert advice is essential since adverse effects may occur (e.g. convulsions in patients dependent on benzodiazepines). 5. PHARMACOLOGICAL PROPERTIES 5.1Pharmacodynamic properties Midazolam is a soluble benzodiazepine with marked properties of suppression of tension, agitation and anxiety as well as sedative and hypnotic effects. In addition, midazolam demonstrates muscle relaxant and anticonvulsive properties. In clinical use, the main action is sleep induction. Midazolam binds to specific receptors in the central nervous system (CNS). The benzodiazepine receptors in the CNS have a close functional connection with receptors of the GABA-ergic transmitter system. After binding to the benzodiazepine receptor, midazolam augments the inhibitory effect of GABA-ergic transmission. 5.2 Pharmacokinetic properties Midazolam is highly lipid soluble and crosses the blood brain barrier. These properties qualify it for intravenous use in short term anaesthetic procedures since it acts promptly on the brain, and its initial effects decrease rapidly as it is distributed into fat deposits and tissues. Following the administration of 150 micrograms/kg intravenously, plasma concentrations in the range 291-425 ng/ml are reached within five minutes. Midazolam is almost completely absorbed following intramuscular injection, peak plasma levels being attained within 45 minutes. Midazolam is extensively protein bound (94-98%). The volume of distribution is between 0.8 and 1.7 litres/kg. Midazolam crosses the placenta. It is not known whether midazolam enters breast milk, but this is likely as it is known to occur with other benzodiazepines. Midazolam is extensively metabolised in the liver, involving the P450 IIIA enzymes. The principal metabolite, 1-hydroxy midazolam, appears in the urine as a glucuronide. The metabolite is less pharmacologically active than midazolam and has a shorter half-life of about one hour. Midazolam has a mean elimination half-life of two to three hours. The half-life is short compared with other benzodiazepines. Less than 1% midazolam is excreted unchanged via the kidneys and the drug is cleared virtually entirely by the liver. The half-life of midazolam is prolonged in neonates, in the elderly and patients with liver disorders. 5.3 Preclinical safety data In vitro and in vivo microbial and mammalian test systems have revealed no evidence of mutagenicity. No evidence of carcinogenic potential was seen in rats or mice given oral midazolam maleate in doses up to 25 times the human recommended daily dose for two years.

In humans, the risk of congenital abnormalities from the ingestion of therapeutic doses of benzodiazepines is slight, although a few epidemiological studies have pointed to an increased risk of cleft palate. There are case reports of congenital abnormalities and mental retardation in prenatally exposed children following overdosage and intoxication with benzodiazepines. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium Chloride Hydrochloric Acid Solution 3M Sodium Hydroxide Solution 3M Water for Injections 6.2 Incompatibilities Midazolam is incompatible with alkaline solutions (due to reduced solubility) and some medicines. Published data show that midazolam injection is incompatible with alkaline injections such as some antibiotic and steroid injections, bumetanide, frusemide, omeprazole sodium, sodium bicarbonate and thiopental sodium. It is also incompatible with dimenhydrinate, foscarnet sodium, imipenem with cilastin, pentobarbital sodium, albumin, clonidine, perphenazine, prochlorperazine, ranitidine and certain parenteral solutions, including parenteral nutrition solutions. Mixture or dilution with Hartmann's solution is not recommended, as the potency of midazolam decreases. Compatibility must be checked before administration, if intended to be mixed with other drugs. 6.3 Shelf life Three years. 6.4Special precautions for storage Do not store above 25C. Keep container in outer carton. 6.5 Nature and contents of container Neutral glass ampoules Type I Ph Eur 5ml packed in 5 or 10s in an outer printed carton 6.6 Special precautions for disposal The injection is for single patient use and should be used immediately after opening. The injection should not be used if particles are present. Any unused portion should be discarded. Midazolam for infusion may be prepared by dilution with infusion fluids containing 5% glucose, 4% glucose with 0.18% sodium chloride or 0.9% sodium chloride. Chemical and physical in-use stability has been demonstrated for 24 hours at 25C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8C, unless dilution has taken place in controlled and validated aseptic conditions. 7. MARKETING AUTHORISATION HOLDER Wockhardt UK Ltd, Ash Road North Wrexham, LL13 9UF 8. MARKETING AUTHORISATION NUMBER(S) PL 29831/0140 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 27 March 2007 10. DATE OF REVISION OF THE TEXT November 2007

Ulcer-healing drugs: Cimetidine, ranitidine and omeprazole Psychiatric: Increased risk of postoperative delirium. have been shown to reduce the clearance of Numbed emotions. In susceptible patients, an unnoticed benzodiazepines and may potentiate their actions. depression may become evident. Paradoxical reactions (including aggressive behaviour, hostility, hallucinations, Xanthines: Benzodiazepine metabolism is accelerated by disinhibition, excitation, irritability and increased anxiety) xanthines. are known to occur with benzodiazepines and are more likely in children and the elderly. 4.6 Pregnancy and lactation There is no evidence regarding the safety of midazolam in Reproductive: Changes in libido pregnancy. It should not be used, especially in the first and third trimesters, unless the benefit is considered to Respiratory: Midazolam can produce, respiratory outweigh the risk. depression, apnoea and may cause respiratory arrest following iv administration, especially in the elderly with If the product is prescribed to a woman of childbearing pre-existing respiratory insufficiency or when the dose is potential she should be warned to contact her physician excessive or administered too rapidly. regarding discontinuance of the product if she intends to become or suspects that she is pregnant. Urinary: urinary retention, incontinence. There may be a small increase in the risk of congenital malformation, particularly oral cleft, with the use of benzodiazepines in the first trimester. In labour, high single doses or repeated low doses have been reported to produce effects on the neonate, such as hypothermia, hypotonia, moderate respiratory depression, irregularities in the foetal heart rate, and poor suckling in the neonate (floppy infant syndrome). Withdrawal symptoms: Development of dependence is common after regular use, even in therapeutic doses for short periods, particularly in patients with a history of drug or alcohol abuse or marked personality disorders. Discontinuation may be associated with withdrawal symptoms or rebound phenomena (see 4.4 Special Warnings and Precautions for Use). Symptoms of benzodiazepine withdrawal include anxiety, depression, impaired concentration, insomnia, headache, Infants born to mothers who take benzodiazepines dizziness, tinnitus, loss of appetite, tremor, perspiration, chronically during the latter stages of pregnancy may irritability, perceptual disturbances such as hypersensitivity develop physical dependence and may be at some risk for to physical, visual, and auditory stimuli and abnormal developing withdrawal symptoms in the postnatal period. taste, nausea, vomiting, abdominal cramps, palpitations, mild systolic hypertension, tachycardia, and orthostatic A small number of children exposed in utero to hypotension, Rare and more serious withdrawal benzodiazepines have shown slow development in the symptoms include muscle twitching, confusional or early years but by four years of age have developed paranoid psychosis, convulsions, hallucinations, and a normally. state resembling delirium tremens. Broken sleep with vivid dreams and increased REM sleep may persist for Since benzodiazepines are found in the breast milk, some weeks after withdrawal of benzodiazepines. benzodiazepines should not be given to breast-feeding mothers.