New Zealand Data Sheet
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Hypnovel 150108
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New Zealand Data Sheet
®
Midazolam as hydrochloride.
Ampoules 5mg/5ml and 15mg/3ml midazolam for i.v., i.m., intranasal, oral and rectal administration. Excipients Sodium chloride (9 mg/ml sodium chloride in the 5mg/5ml Hypnovel ampoule, 5mg/ml sodium chloride in the 15mg/3ml Hypnovel ampoule), hydrochloric acid, sodium hydroxide, water for injection.
Clear to slightly yellow liquid, odourless and practically free from particles in colourless glass ampoules.
Midazolam, the active ingredient of Hypnovel, is a derivative of the imidazobenzodiazepine group. The free base is a lipophilic substance with low solubility in water. The basic nitrogen in position 2 of the imidazobenzodiazepine ring system enables the active ingredient of Hypnovel to form water-soluble salts with acids. These produce a stable and well tolerated injection solution.
The pharmacological action of midazolam is characterized by rapid onset and, because of rapid metabolic transformation, short duration. Because of its low toxicity, midazolam has a wide therapeutic range.
Hypnovel has a very rapid sedative and sleep-inducing effect of pronounced intensity. It also exerts an anxiolytic, an anticonvulsant and a muscle-relaxant effect.
After i.m. or i.v. administration anterograde amnesia of short duration occurs (the patient does not recall events that occurred during the peak of activity of the compound).
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Pharmacokinetics
Absorption after i.m. injection Absorption of midazolam from the muscle tissue is rapid and complete. Maximum plasma concentrations are reached within 30 minutes. The absolute bioavailability after i.m. injection is over 90%.
Absorption after rectal administration After rectal administration midazolam is absorbed quickly. Maximum plasma concentration is reached in about 30 minutes. The absolute bioavailability is about 50%.
Midazolam is absorbed quickly. Mean peak plasma concentrations are reached within 10.2 to 12.6 minutes. The bioavailability is between 55 and 57%.
Oral midazolam is absorbed rapidly from the gastrointestinal tract and undergoes extensive first-pass hepatic metabolism. Peak plasma concentrations are reached within 1 hour. Bioavailability is between 40 and 50%.
When midazolam is injected i.v., the plasma concentration-time curve shows one or two distinct phases of distribution. The volume of distribution at steady state is 0.7-1.2 l/kg. 96-98% of midazolam is bound to plasma proteins. The major fraction of plasma protein binding is due to albumin. There is a slow and insignificant passage of midazolam into the cerebrospinal fluid. In humans, midazolam has been shown to cross the placenta slowly and to enter foetal circulation. Small quantities of midazolam are found in human milk.
Midazolam is almost entirely eliminated by biotransformation. Midazolam is hydroxylated by the cytochrome P450 3A4 isozyme. a -hydroxymidazolam is the major urinary and plasma metabolite. Plasma concentrations of a -hydroxymidazolam are 12% of those of the parent compound. The fraction of the dose extracted by the liver has been estimated to be 30-60%. a -hydroxymidazolam is pharmacologically active, but contributes only minimally (about 10%) to the effects of intravenous midazolam. There is no evidence of a genetic polymorphism in the oxidative metabolism of midazolam (see Interactions).
In healthy volunteers, the elimination half-life is between 1.5 - 2.5 hours. Plasma clearance is in the range of 300-500 ml/min. 60-80% of the dose is excreted in urine as glucuroconjugated α -
elimination half-life of the metabolite is shorter than 1 hour. When midazolam is given by i.v. infusion, its elimination kinetics do not differ from those following bolus injection.
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Pharmacokinetics in Special Populations Elderly In adults over 60 years of age, the elimination half-life may be prolonged up to four times.
The rate of rectal absorption in children is similar to that in adults. However, the elimination half-life (t½) after i.v. and rectal administration is shorter in children 3-10 years as compared with that in adults. The difference is consistent with an increased metabolic clearance in children.
In neonates the elimination half-life is on average 6-12 hours, probably due to liver immaturity and the clearance is reduced (see Precautions).
The elimination half-life in cirrhotic patients may be longer and the clearance smaller as compared to those in healthy volunteers (see Precautions).
The elimination half-life in patients with chronic renal failure is similar to that in healthy volunteers.
The elimination half-life of midazolam is prolonged in the critically ill.
The elimination half-life is longer in patients with congestive heart failure compared with that in healthy subjects (see Precautions).
Premedication before induction of anaesthesia (i.m. or, especially in children, rectal, intranasal or oral administration).
Conscious sedation before diagnostic or surgical interventions carried out under local anaesthesia (i.v. administration), or in children intranasal or oral administration.
Long-term sedation in intensive care units (i.v. administration as bolus injection or continuous infusion). Induction and maintenance of anaesthesia. As an induction agent in inhalation anaesthesia or a sleep- inducing component in combined anaesthesia, including total intravenous anaesthesia (i.v. injection, i.v. infusion).
Ataralgesia in combination with ketamine in children (i.m. administration). Dosage and Administration
In the case of elderly patients with organic cerebral changes or impaired cardiac and respiratory function, the dosage should be determined with caution, the special factors relating to each patient being taken into consideration.
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Initial and subsequent intravenous injections must be given slowly (approximately 2.5mg in 10 seconds for induction of anaesthesia and 1mg in 30 seconds for conscious sedation). The medicine takes effect about two minutes after the injection is started.
Intramuscular administration In patients suffering from pain before an intervention.
Administration alone or in combination with anticholinergics and possibly analgesics. These doses should be administered about 30 minutes before induction of anaesthesia.
Adults: 0.07-0.10 mg per kg bodyweight i.m. according to age and general condition of the patient. Usual dosage about 5mg.
mg per kg bodyweight i.m.).
Children: for preoperative sedation. Rectal administration of the ampoule solution by means of a plastic applicator fixed on the end of a syringe, 0.35-0.45 mg/kg bodyweight 20-30 minutes before induction of general anaesthesia. If the volume to be administered is too small, water may be added up to a total volume of 10 ml.
Children: 0.5mg / kg, 15-30 minutes prior to anaesthesia.
Intravenous conscious sedation For conscious sedation in diagnostic or surgical interventions carried out under local anaesthesia.
operation. Further doses of 1mg may be given as necessary. A total dose greater than 5mg is not usually necessary to reach the desired endpoint. In cases of severe illness, particularly if the patient is in poor general condition or of advanced age, the initial dose must be reduced to 1-1.5mg. Total doses greater than 3.5mg are not usually necessary.
Children: 0.2mg / kg, 10-15 minutes before the intervention.
Children: 0.2 - 0.5mg / kg, 15-30 minutes before the intervention.
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Sedation in Intensive Care Units Intravenous sedation For sedation in ICU, the dosage should be individualised and Hypnovel titrated to the desired state of sedation according to the clinical need, physical status, age, concomitant medication.
Loading dose: 0.03 - 0.3 mg/kg.
even be omitted in hypovolemic, vasoconstricted and hypothermic patients.
Intravenous injection Adults Induction: the dose is 10-15 mg i.v. in combination with analgesics. A sufficiently deep level of sleep is generally achieved after 2-3 minutes.
injected i.v. The dose and the intervals between doses vary according to the individual patient's reaction. Alternatively, Hypnovel can be administered by continuous infusion.
Adults: for intravenous anaesthesia combined with ketamine, 0.03 - 0.1 mg/kg/hr; narcotics, 0.03 - 0.3 mg/kg/hr. High-risk surgical patients, elderly and debilitated patients require lower dosages.
(ataralgesia) is recommended. Hypnovel i.m. (0.15-0.20 mg per kg bodyweight) in combination with 50-100 mg ketamine i.m. (4-8 mg per kg bodyweight). A sufficiently deep level of sleep is generally achieved after 2-3 minutes.
When Hypnovel is given with potent analgesics, the latter should be administered first so that the sedative effects of Hypnovel can be safely titrated on top of any sedation caused by the analgesic.
Compatibility with infusion solutions. The Hypnovel ampoule solution can be diluted with sodium chloride 0.9%, dextrose 5% and 10%, levulose 5%, Ringer's solution and Hartmann's solution in a mixing ratio of 15 mg midazolam per 100-1,000 ml infusion solution. These solutions remain physically and chemically stable for 24 hours at room temperature (or three days at 5 ° C). When administered orally, the bitter taste of Hypnovel injection may be masked by small quantities of apple juice, sweetened fruit syrup or powdered soft drink.
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Contraindications
Use of this medicine in patients with known hypersensitivity to benzodiazepines or to any component of the product.
Hypnovel ampoules should be used only when age- and size-appropriate resuscitation facilities are available, as i.v. administration of Hypnovel may depress myocardial contractility and cause apnoea. Severe cardiorespiratory adverse events have occurred on rare occasions. These have included respiratory depression, apnoea, respiratory arrest and/or cardiac arrest. Such life-threatening incidents are more likely to occur in adults over 60 years of age, those with pre-existing respiratory insufficiency or impaired cardiac function and paediatric patients with cardiovascular instability, particularly when the injection is given too rapidly or when a high dosage is administered.
When Hypnovel is used for premedication, adequate observation of the patient after administration is mandatory as interindividual sensitivity varies and symptoms of overdose may occur.
Special caution should be exercised when administering Hypnovel parenterally to patients representing a higher risk group: ·
·
debilitated or chronically ill patients ·
patients with impaired respiratory function ·
patients with impaired kidney function, impaired hepatic function or with impaired cardiac function ·
paediatric patients with cardiovascular instability
These higher-risk patients require lower dosages (see Dosage and Administration) and should be continuously monitored for early signs of alterations of vital functions.
Some loss of efficacy has been reported when Hypnovel has been used as long-term sedation in intensive care units (ICU).
When Hypnovel is used in long-term sedation in ICU, it should be borne in mind that physical dependence on Hypnovel may develop. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a medical history of alcohol and/or drug abuse.
During prolonged treatment with Hypnovel ampoules in ICU, physical dependence may develop. Therefore, abrupt termination of the treatment will be accompanied by withdrawal symptoms. The following symptoms may occur: headaches, muscle pain, anxiety, tension, restlessness, confusion, irritability, rebound insomnia, mood changes, hallucinations and convulsions. Since the risk of withdrawal symptoms is greater after abrupt discontinuation of treatment, it is recommended that the dose is decreased gradually.
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Concomitant use of Alcohol/CNS Depressants The concomitant use of Hypnovel with alcohol and/or CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of Hypnovel possibly including severe sedation, clinically relevant respiratory and/or cardiovascular depression.
Hypnovel should be avoided in patients with a medical history of alcohol or drug abuse.
Hypnovel causes anterograde amnesia (frequently this effect is very desirable in situations such as before and during surgical and diagnostic procedures), the duration of which is directly related to the administered dose. Prolonged amnesia can present problems in outpatients, who are scheduled for discharge following intervention.
After receiving Hypnovel parenterally, patients should be discharged from hospital or consulting room only when recommended by the treating physician and if accompanied by an attendant. It is recommended that the patient is accompanied when returning home after discharge.
Paradoxical reactions such as agitation, involuntary movements (including tonic/clonic convulsions and muscle tremor), hyperactivity, hostility, rage reaction, aggressiveness, paroxysmal excitement and assault, have been reported to occur with Hypnovel. These reactions may occur with higher doses and/or when the injection is given rapidly. The rare incidence of susceptibility to such reactions has been reported among children and at higher i.v. doses in the elderly. Should such symptoms suggestive of a paradoxical reaction occur, the response to Hypnovel should be evaluated before proceeding.
Elimination of midazolam may be altered in patients receiving compounds that inhibit or induce certain hepatic enzymes (particularly cytochrome P450 3A4) and the dose of midazolam may need to be adjusted accordingly (see Interactions).
When midazolam is given intravenously for a prolonged period and in combination with saquinavir, an initial dose reduction of midazolam of 50% is recommended (see Interactions).
It is advisable to lower doses of intravenous midazolam when co-administered with erythromycin (see Interactions).
Displacement of midazolam from its plasma protein binding sites by sodium valproate may increase the response to midazolam. Care should be taken to adjust the midazolam dose in patients with epilepsy on treatment with sodium valproate (see Interactions).
Elimination of midazolam may also be delayed, in patients with liver dysfunction, low cardiac output and in neonates (see Pharmacokinetics in special populations).
Due to an increased risk of apnoea, extreme caution is advised when sedating pre-term and former pre-term patients whose trachea is not intubated.
Rapid injection should be avoided in the neonatal population.
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The neonate also has reduced and/or immature organ function and is also vulnerable to profound and/or prolonged respiratory effects of Hypnovel. Therefore, careful monitoring of respiratory rate and oxygen saturation is required.
Paediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful respiratory rate and oxygen saturation monitoring are essential (see Pre-term Infants and Neonates above).
Adverse haemodynamic events have been reported in paediatric patients with cardiovascular instability; rapid intravenous administration should be avoided in this population.
Sedation, amnesia, impaired concentration and impaired muscular function adversely affect the ability to drive or use machines. Prior to receiving Hypnovel, the patient should be warned not to drive a vehicle or operate a machine until completely recovered.
As with any substance with CNS depressant and/or muscle-relaxant properties, particular care should be taken when administering Hypnovel to a patient with myasthenia gravis, owing to pre-existing muscle weakness.
Insufficient data are available on midazolam to assess its safety during pregnancy. Benzodiazepines should be avoided during pregnancy unless there is no safer alternative. The administration of midazolam in the last trimester of pregnancy or at high doses during labour has been reported to produce irregularities in the foetal heart rate, hypotonia, poor sucking and hypothermia and moderate respiratory depression in the neonate. Moreover, infants born to mothers who received benzodiazepines chronically during the latter stage of pregnancy may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period.
Since midazolam passes into breast milk, Hypnovel should not be administered to breast-feeding mothers.
The following adverse effects have been reported to occur post-marketing when Hypnovel is injected: Central and peripheral nervous system and psychiatric disorders Drowsiness and prolonged sedation, reduced alertness, confusion, euphoria, hallucinations, fatigue, headache, dizziness, ataxia, postoperative sedation, anterograde amnesia, the duration of which is directly related to the administered dose. Anterograde amnesia may still be present at the end of the procedure and in isolated cases prolonged amnesia has been reported.
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Paradoxical reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity, hostility, rage reaction, aggressiveness, paroxysmal excitement and assault, have been reported, particularly among children and the elderly.
Convulsions have been reported in premature infants and neonates. Dependence Use of Hypnovel - even in therapeutic doses - may lead to the development of physical dependence. After prolonged i.v. administration, discontinuation, especially abrupt discontinuation of the product, may be accompanied by withdrawal symptoms including withdrawal convulsions.
Nausea, vomiting, constipation, dry mouth.
Severe cardiorespiratory adverse events have occurred on rare occasions. These have included respiratory depression, apnoea, respiratory arrest and/or cardiac arrest. Such life-threatening incidents are more likely to occur in adults over 60 years of age and those with pre-existing respiratory insufficiency or impaired cardiac function, particularly when the injection is given too rapidly or when a high dosage is administered (see Precautions).
The following other cardiorespiratory adverse events have been reported: hypotension, slight increase in heart rate, bradycardia, vasodilating effects, dyspnoea and hiccough. In isolated cases laryngospasm has occurred following injection of Hypnovel.
Skin rash, urticarial reaction, pruritus.
Generalised hypersensitivity reactions (skin reactions, cardiovascular reactions, bronchospasm), angioedema, anaphylactic shock.
Erythema and pain on injection site, thrombophlebitis, thrombosis.
There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.
The metabolism of midazolam is predominantly mediated by cytochrome P450 3A4 (CYP3A4) isozyme. Approximately 25 % of the total cytochrome P450 system in the adult liver is from the CYP3A4 subfamily. Inhibitors (see Precautions) and inducers of this isozyme may lead to interaction with midazolam.
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Interactions Studies conducted with Hypnovel Ampoules CYP3A4 inhibitors Azole antifungals Ketoconazole increased the plasma concentration of intravenous midazolam by 5-fold while the terminal half-life increased by about 3-fold. If parenteral midazolam is co-administered with the strong CYP3A inhibitor ketoconazole, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Staggered dosing and dosage adjustment should be considered, especially if more than a single iv dose of midazolam is administered.
Fluconazole and itraconazole both increased the plasma concentrations of intravenous midazolam by 2 – 3-folds associated with an increase in terminal half-life by 2.4-fold for itraconazole and 1.5-fold for fluconazole, respectively.
Posaconazole increased the plasma concentrations of intravenous midazolam by about 2-fold Erythromycin Co-administration of Hypnovel and erythromycin prolonged the elimination half-life of midazolam from 3.5 to 6.2 hours. Although only relatively minor pharmacodynamic changes were observed, it is advised to adjust doses of intravenous midazolam, especially if high doses are being administered (see Precautions).
Cimetidine increased the steady-state plasma concentration of midazolam by 26%, whereas ranitidine had no effect.
Co-administration of midazolam and cimetidine or ranitidine had no clinically significant effect on the pharmacokinetics and pharmacodynamics of midazolam. These data indicate that intravenous midazolam can be used in usual doses with cimetidine and ranitidine and dosage adjustment is not required.
There is no pharmacokinetic and pharmacodynamic interaction between cyclosporin and midazolam. Therefore, the dosage of midazolam needs no adjustment when given concomitantly with cyclosporin.
Nitrendipine did not affect the pharmacokinetics and pharmacodynamics of midazolam. Both medicines can be given concomitantly and no dosage adjustment of midazolam is required.
Saquinavir and other HIV protease inhibitors: Upon co-administration with ritonavir boosted lopinavir, the plasma concentrations of intravenous midazolam increased by 5.4-fold, associated with a similar increase in terminal half-life. If parenteral midazolam is co-administered with HIV protease inhibitors, treatment setting should follow the description in the section above for ketoconazole within azole antifungals (see Precautions). Oral contraceptives The pharmacokinetics of intramuscular midazolam was not affected by the use of oral contraceptives. Both medicines can be given concomitantly and no dosage adjustment of midazolam is required.
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Other interactions Sodium valproate Displacement of midazolam from its plasma protein binding sites by sodium valproate may increase the response to midazolam and, therefore, care should be taken to adjust the midazolam dosage in patients with epilepsy (see Precautions).
Midazolam had no effect on the plasma protein binding of lidocaine in patients undergoing anti- arrhythmic therapy or regional anaesthesia with lidocaine.
Alcohol may enhance the sedative effect of midazolam. The i.v. administration of Hypnovel decreases the minimum alveolar concentration (MAC) of halothane required for general anaesthesia.
The symptoms of overdose are mainly an intensification of the pharmacological effects; drowsiness, mental confusion, lethargy and muscle relaxation or paradoxical excitation. As with other benzodiazepines, overdosage should not present a threat to life unless combined with other CNS depressants including alcohol. More serious symptoms would be areflexia, hypotension, cardiorespiratory depression, apnoea and, rarely, coma. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease. Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.
In most cases only observation of vital functions is required and initiate supportive measures as indicated by the patient’s clinical state. In the management of overdose special attention should be paid to the respiratory and cardiovascular functions in intensive care.
If taken orally further absorption should be prevented using an appropriate method (e.g. treatment within 1-2 hours with activated charcoal). If activated charcoal is used airway protection is imperative for drowsy patients. In case of mixed ingestion gastric lavage may be considered, however not as a routine measure.
If CNS depression is severe, consider the use of the benzodiazepine antagonist Anexate® (active ingredient: flumazenil). This should only be administered under closely monitored conditions. It has a short half-life (about an hour); therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Special Remarks
Do not dilute Hypnovel ampoule solutions with macrodex 6% in dextrose (see Special Dosage Instructions).
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Do not mix Hypnovel ampoule solutions in alkaline injections. Midazolam precipitates in sodium bicarbonate.
Store below 30 o C (approved to 35 ° C).
Keep the ampoules in the outer carton in order to protect from light.
Ampoules are for use in one patient only. Hypnovel ampoules should not be frozen because they can burst. Furthermore, precipitation can occur which dissolves on shaking at room temperature.
This medicine should not be used after the expiry date shown on the pack.
Controlled Drug (C5) Package Quantities
Ampoules, 5mg/5ml 10's Ampoules, 15mg/3ml 5's
Roche Products (New Zealand) Ltd PO Box 109113 Newmarket, Auckland 1149
Medical enquiries: 0800 656 464
8 January 2015 Document Outline
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