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Diazepam 10mg/2ml
- NAME OF THE MEDICINAL PRODUCT
Diazepam-hameln 5 mg/ml Injection
- QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 5 mg of diazepam.
- PHARMACEUTICAL FORM
Solution for injection.
Clear, colourless to pale yellow liquid.
- CLINICAL PARTICULARS
4.1 Therapeutic indications
Diazepam is an anxiolytic, anticonvulsant and central muscle- relaxant. Diazepam is used to relieve anxiety and provide sedation in severe acute anxiety or agitation and for the management of agitation associated with delirium tremens.
Diazepam is used to relieve acute muscle spasm and tetanus.
Acute convulsions including status epilepticus, also convulsions due to poisoning and febrile convulsions. As an adjunct during endoscopy, in dentistry, surgery, radiology. Cardiac catheterisation, cardioversion, used pre-operatively to relieve anxiety, provide sedation, light anaesthesia.
4.2 Posology and method of administration
Diazepam-hameln 5 mg/ml Injection may be given IV, IM or by IV infusion.
Adults
Severe acute anxiety or agitation 10 mg IV or IM injection which may be repeated after an interval of not less than 4 hours.
Delirium Tremens
10-20 mg IV or IM. Higher doses may be needed depending on severity of symptoms.
Acute Muscle Spasm
10 mg IV, IM injection which may be repeated after an interval of not less than 4 hours.
Tetanus
Initially an IV dose of 0.1-0.3 mg/kg body weight, repeated at intervals of 1-4 hours. Continuous IV infusion of 3-10 mg/kg body weight per 24 hours can also be used. The chosen dose should be related to the severity of the case and in extremely severe case higher doses have been used.
Status epilepticus, convulsions due to poisoning
10-20 mg IV or IM, repeated if necessary 30-60 minutes later. If indicated, this may be followed by slow intravenous infusion (maximum dose 3 mg/kg body weight over 24 hours).
Pre-operative medication or premedication
0.2 mg/kg body weight. The usual adult dose is 10-20 mg but higher doses may be necessary according to the clinical response.
Elderly or Debilitated Patients
Doses should not exceed half those normally recommended.
Children
Status epilepticus, convulsions due to poisoning, febrile convulsions
0.2-0.3 mg/kg body weight IV (or IM).
Tetanus
As for adults.
Pre-operative medication or premedication
0.2 mg/kg body weight. The injection should be given slowly 0.5 ml per minute. Diazepam injection should be given into a large vein of the antecubital fossa, the patient in a supine position throughout the procedure to reduce the possibility of hypotension or apnoea occurring.
4.3 Contraindications
– Patients with known hypersensitivity to diazepam, benzodiazepines, and any of the ingredients.
– Severe respiratory insufficiency
– Sleep apnea syndrome
– Myasthenia gravis
– Severe hepatic insufficiency
– Diazepam injection should not be used in phobic or obsessional states nor be used alone in the treatment depression or anxiety associated with depression due to the risk of suicide being precipitated in this patient group.
- Diazepam injection should not be used for the primary treatment of psychotic illness.
- In common with other benzodiazepines the use of diazepam may be associated with amnesia and Diazepam Injection should not be used in cases of loss or bereavement as psychological adjustment may be inhibited.
4.4 Special warnings and precautions for use
Except in emergencies, a second person should always be present during the intravenous use of diazepam and facilities for resuscitation should always be available. Patients should ideally remain under medical supervision until at least one hour has elapsed from the time of injection. They should always be accompanied home by a responsible adult, with a warning not to drive or operate machinery for 24 hours.
The IM use of diazepam injection can lead to a rise in serum creatinine phosphokinase activity, with a maximum level occurring between 12 and 24 hours after injection. This fact should be taken into account in the differential diagnosis of myocardial infarction.
The absorption from IM injection of diazepam may be variable, particularly for the gluteal muscles. This route of administration should only be used if IV administration is not possible.
The elderly, and patients with impaired renal and/or hepatic function may be particularly susceptible to the adverse effects of diazepam listed.
Extreme care must be taken when administering diazepam injection to very ill patients and to those with limited pulmonary reserve, because of the possibility of respiratory depression or apnoea.
Use with caution in patients with myasthenia gravis, porphyria, known history of drug or alcohol abuse, or organic brain changes, particularly arteriosclerosis.
Diazepam injection should be used with caution in patients in whom a drop in blood pressure might lead to cardiovascular or cerebrovascular complications.
Diazepam enhance the side-effects of alcohol.
The dependence potential of diazepam 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. Withdrawal symptoms may occur with benzodiazepines following normal use of therapeutic doses for only short periods and may be associated with physiological and psychological sequelae including depression. This should be considered when treating patients for more than a few days; abrupt discontinuation should be avoided and the dose reduced gradually.
Abuse of diazepam have been reported.
Paradoxical reactions and other adverse behavioural effects are known to occur when using benzodiazepines. They are more likely to occur in children and in the elderly. Should this occur, the use of the drug should be discontinued.
Extreme caution should be used if prescribing diazepam for patients with personality disorders. The disinhibiting effects of benzodiazepines may be manifested as the precipitation of suicide in patients who are depressed or show aggressive behaviour towards self and others.
Diazepam-hameln contains propylene glycol. There have been rare reports of propylene glycol toxicity (e.g. increased anion gap, metabolic acidosis, hyperosmolality, renal impairment) with the potential for organ system failure and circulatory shock, in patients treated with continuous infusions of diazepam. Central nervous system toxicity, including seizures, as well as unresponsiveness, tachypnoea, tachycardia and diaphoresis have also been associated with propylene glycol toxicity. Symptoms may be more likely to develop in patients with renal or hepatic impairment and in paediatric patients.
Amnesia: Transient amnesia or memory impairment has been reported in association with the use of benzodiazepines. Anterograde amnesia may occur using therapeutic dosages: the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behavior.
4.5 Interaction with other medicinal products and other forms of interaction
Alcohol: Enhanced sedation or respiratory or CNS depression with concomitant administration of diazepam. Concomitant use should be avoided.
General anaesthetics and narcotic analgesics: Enhanced sedation or respiratory and cardiovascular depression. If such centrally acting depressant drugs are given parenterally in conjunction with intravenous diazepam, severe respiratory and cardiovascular depression may occur; careful monitoring is required. When intravenous diazepam is to be administered concurrently with a narcotic analgesic agent (e.g. fentanyl), it is recommended that diazepam be given after the analgesic and that the dose be carefully titrated to meet the patient’s needs. Premedication with diazepam may decrease the dose of fentanyl derivatives required for induction of anaesthesia.
Antibacterials: Agents that interfere with metabolism by hepatic enzymes (isoniazid and to a lesser extent erythromycin) may reduce the clearance of diazepam and potentiate its action. Known inducers of hepatic enzymes, for example, rifampicin, may increase the clearance of benzodiazepines diazepam.
Antidepressants: Enhanced sedation or respiratory or CNS depression with concomitant administration of mirtazapine or tricyclic antidepressants. Diazepam plasma levels increased by concomitant fluvoxamine or fluoxetine.
Antiepileptics: Enhanced sedaion or respiratory and cardiovascular depression. Known inducers of hepatic enzymes, for example, carbamazepine, phenobarbital and phenytoin, may increase the clearance of benzodiazepines, however, despite enzyme stimulation, the net effect of adding these antiepileptics can be augmentation of benzodiazepine-induced sedation. Serum phenytoin levels may rise, fall or remain unaltered. In addition, phenytoin may cause diazepam serum levels to fall. Concomitant sodium valproate may increase serum levels of diazepam, with associated drowsiness.
Antihistamines: Enhanced sedation or respiratory and cardiovascular depression with sedative antihistamines.
Antihypertensives: Enhanced hypotensive effect with concomitant administration of ACE inhibitors or beta-blockers or calcium-channel blockers or hydralazine. Enhanced sedative effect with alpha blockers and possibly moxonidine.
Antipsychotics: Enhanced sedation or respiratory and cardiovascular depression. Increased plasma concentrations of zotepine. 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. Increased risk of hypotension, bradycardia and respiratory depression with concomitant administration of parenteral benzodiazepines with intramuscular olanzapine.
Antivirals: Amprenavir, ritonavir and saquinavir have been shown to reduce the clearance of diazepam and may potentiate its actions, with risk of extreme sedation and respiratory depression – avoid concomitant use.
Anxiolytics: Enhanced sedation or respiratory and cardiovascular depression with other anxiolytics.
Digoxin: Reduced clearance of digoxin.
Disulfiram: has been shown to reduce clearance and may potentiate actions of benzodiazepines.
Diuretics: Enhanced hypotensive effect when benzodiazepines and diuretics are used concomitantly.
Dopaminergic agents: diazepam may cause inhibition of levodopa.
Hypnotics: Enhanced sedation or respiratory and cardiovascular depression.
Lofexidine: Enhanced sedation or respiratory and cardiovascular depression.
Muscle relaxants: Increased CNS depressant effects with baclofen and tizanidine.
Nabilone: Enhanced sedation or respiratory and cardiovascular depression.
Nicotine: Diazepam metabolism is accelerated by smoking.
Nitrates: Enhanced hypotensive effect when benzodiazepines and nitrates are used concomitantly.
Oral contraceptives: May reduce the clearance of diazepam and may potentiate its actions.
Sedatives: Enhanced sedation or respiratory and cardiovascular depression.
Sodium oxybate: Enhanced CNS depressant effects of sodium oxybate with concomitant benzodiazepines.
Ulcer-healing drugs: Cimetidine, omeprazole and esomeprazole have been shown to reduce the clearance of diazepam and may potentiate its actions.
Xanthines: Diazepam metabolism is accelerated by theophylline. Sedative effects of diazepam reduced by caffeine. Sedative effects of diazepam reversed with concomitant administration of aminophylline
4.6 Pregnancy and lactation
There is no evidence as to drug safety in human pregnancy, nor is there evidence from animal studies, that it is free from hazard. Do not use during pregnancy, especially during the first and last trimesters unless there are compelling reasons.
Results of retrospective studies suggest an increased risk of congenital malformation in infants or mothers who received diazepam during the first trimester of pregnancy. An increase in foetal heart rate has occurred after diazepam use during labour. Hypoactivity, hypotonia, hypothermia, apnoea, feeding problems, hyperbilirubinaemia and kernicterus have been reported in neonates born to mothers who receive large doses
of diazepam (generally greater than 30 mg) shortly before delivery.
Diazepam has been detected in breast milk. If possible diazepam should be avoided during breast feeding.
4.7 Effects on ability to drive and use machines
Sedation, amnesia and impaired muscular function may adversely affect the Ability to drive or use machines. If insufficient sleep occurs, the likelihood of impaired alertness may be increased (See also interactions).
4.8 Undesirable effects
The most common adverse reactions reported for diazepam are fatigue, drowsiness, muscle weakness and ataxia. Neutropenia has been rarely reported.
Blood and lymphatic system disorders: Blood dyscrasias including thrombocytopenia and agranulocytosis reported with diazepam.
Immune system disorders: Hypersensitivity reactions, including anaphylaxis, are rare.
Psychiatric disorders: In susceptible patients, an unnoticed depression may become evident. Paradoxical reactions (including aggression, rage, hostility, hallucinations, nightmares, disinhibition, euphoria, excitation, irritability, restlessness, increased anxiety, agitation, inappropriate behaviour and insomnia) are known to occur with benzodiazepines and may be quite severe with diazepam. They are more likely to occur in children and the elderly.
Nervous system disorders: Elderly or debilitated patients are particularly susceptible to the CNS 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). Long term use of benzodiazepines in the elderly may be associated with an increased risk of dementia. Headaches, confusion, slurred speech, tremor, reduced alertness and drowsiness. Anterograde amnesia may occur when using therapeutic doses, the risk increasing at higher doses (see 4.4 Special Warnings and Special Precautions for Use). Amnestic effects may be associated with inappropriate behaviour. Extrapyramidal effects and convulsions have occurred rarely with diazepam.
Eye disorders: Visual disturbances.
Ear and labyrinth disorders: Rarely, vertigo
Cardiac disorders: Hypotension, particularly with high dosage, bradycardia, chest pain. Cardiac arrest may occur with diazepam injection.
Vascular disorders: Diazepam injection may be associated with thrombophlebitis and venous thrombosis.
Respiratory, thoracic and mediastinal disorders: Rarely, respiratory depression and apnoea, particularly with high dosage.
Gastrointestinal disorders: Rarely, salivation changes, including dry mouth or excessive salivation and gastrointestinal disturbances including nausea.
Hepatobiliary disorders: Raised liver enzymes, jaundice and cholestasis.
Skin and subcutaneous tissue disorders: Skin reactions such as Steven-Johnson syndrome, urticaria, rash.
Musculoskeletal and connective tissue disorders: Muscle weakness.
Renal and urinary disorders: Urinary retention, incontinence.
Reproductive system and breast disorders: Inhibition of female orgasm, changes in libido, gynaecomastia and rarely, increased prolactin levels and galactorrhoea. Plasma testosterone concentrations may be increased in men taking diazepam.
General disorders and administration site conditions: Fatigue and a hangover effect. Diazepam injection may be associated with pain. Inadvertent intra-arterial administration of diazepam has resulted in ischaemia and tissue necrosis.
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, dizziness, tinnitus, loss of appetite, tremor, perspiration, irritability, perceptual disturbances such as hypersensitivity to physical, visual, and auditory stimuli and abnormal taste, nausea, vomiting, abdominal cramps, muscle aches/cramps, palpitations, mild systolic hypertension, tachycardia, and orthostatic hypotension. Rare and more serious withdrawal symptoms include muscle twitching, confusional or paranoid psychosis, convulsions, hallucinations, and a state resembling delirium tremens. Broken sleep with vivid dreams and increased REM sleep may persist for some weeks after withdrawal of benzodiazepines.
4.9 Overdosage
Diazepam overdosage may result in somnolence, confusion, coma and diminished reflexes. Hypotension and respiratory depression rarely occur.
Treatment of benzodiazepine intoxication consists of general supportive therapy. Hypotension may be controlled if necessary by IV administration of adrenaline.
- PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Diazepam is a benzodiazepine tranquilliser with anticonvulsant, sedative, muscle relaxant and amnesic properties. It is used in the treatment of anxiety and tension states, as a sedative and pre-medicant, in the control of muscle spasm as in tetanus, and in the management of alcohol withdrawal symptoms. It is of value in patients undergoing orthopaedic procedures endoscopy and cardioversion.
5.2 Pharmacokinetic properties
Diazepam can be administered intravenously, intramuscularly, or as a suppository.
The onset of action is 1- 5 minutes for IV administration and 15-30 minutes for IM administration.
The duration of the diazepam’s main pharmacological effects is 15 minutes to 1 hour for both routes of administration.
Peak plasma levels are achieved 30 minutes to 2 hours after oral administration. When diazepam is administered as an intramuscular injection, absorption is slow, erratic and incomplete.
Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. It easily crosses both the blood-brain barrier and the placenta, and is excreted into breast milk. After absorption, diazepam is redistributed into muscle and adipose tissue. Continual daily doses of diazepam will quickly build up to a high concentration in the body (mainly in adipose tissue).
Diazepam is metabolised in the liver via the cytochrome P450 enzyme system. It has a biphasic half-life of 1-2 and 2-5 days, and has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Diazepam’s other active metabolites include temazepam and oxazepam. These metabolites are conjugated with glucuronide, and are
excreted primarily in the urine. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug.
Diazepam has a half-life (t1/2α) of 20-50 hours, and desmethyldiazepam has a half-life of 30-200 hours.
Most of the drug is metabolised; very little diazepam is excreted unchanged.
In humans, the protein binding of diazepam is around 98.5%.
- PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Ethanol
Propylene glycol
Sodium hydroxide
Water for injections
6.2 Incompatabilities
Diazepam injection should not be mixed with other drugs or IV fluids and should not normally be diluted except when given slowly in large intravenous infusions of normal saline or dextrose. Not more than 40 mg of diazepam should be added to 500 ml infusion solution. The solution should be freshly made up and used within six hours.
6.3 Shelf life
24 months from manufacturing date.
*Do not use if the drug is out of date
6.4 Special precautions for storage
Do not store above 30°C. Do not freeze.
Keep the ampoules in the outer carton in order to protect from light.
6.5 Nature and contents of container
Type I clear glass ampoule, 2 ml. Packed in cardboard cartons to contain 10 ampoules x 2 ml.
6.6 Specification
In house
- MANUFACTURER
hameln pharmaceuticals gmbh
Langes Feld 13
31789 Hameln
Germany
- MARKETING AUTHORISATION HOLDER
BIVID CO., LTD
62/36 Truong Cong Dinh, Ward 14
Tan Binh Dist., Ho Chi Minh City
Vietnam
- MARKETING AUTHORISATION NUMBER
VN-19414-15
Inform your doctor about undesirable side-effects
besides the side-effects written in direction
Keep out of reach of children!