Zopam Injection

Zopam Injection

diazepam

Manufacturer:

SM Pharmaceuticals

Distributor:

SM Pharmaceuticals
Full Prescribing Info
Contents
Diazepam.
Description
Each 2ml contains Diazepam 10 mg.
Action
Pharmacology: Pharmacodynamics: Mode or Mechanisms of Action: Diazepam is a benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant and amnesic properties.
In general, benzodiazepines act as depressants of the central nervous system (CNS), producing all levels of CNS depression from mild sedation to hypnosis to coma depending on dose.
The precise sites and mechanisms of action have not been completely established. Although various mechanisms of action have been proposed, it is believed that benzodiazepines enhance or facilitate the inhibitory neurotransmitter action of gamma-aminobutyric add (GABA), which is one of the major inhibitory neurotransmitters in the brain and mediates both pre- and post-synaptic inhibition in all regions of the CNS, following interaction between the benzodiazepine and a specific neuronal membrane receptor.
Benzodiazepines reportedly act as agonists at the benzodiazepine receptors, which have been shown to form a component of a functional supra-molecular unit known as the benzodiazepine-GABA receptor-chloride ionophore complex. The receptor complex, believed to reside on neuronal membranes that regulate cell firing, functions mainly in the gating of the chloride channel. Activation of the GABA receptor results in the opening of the chloride channel, allowing the flow of' chloride ions through the neuronal membrane. Usually this results in hyperpolarization of the post-synaptic neuron, which inhibits firing of that neuron. That inhibition translates into decreased neuronal excitability, thus attenuating subsequent depolarising excitatory transmitters.
Benzodiazepines reportedly increase the frequency of the chloride channel opening, probably by enhancing the binding of GABA to its receptor or by facilitating the link of the GABA receptors to the chloride ion channels. Benzodiazepines also appear to act at GABA-independent receptors.
Antianxiety agent; sedative-hypnotic: Believed to stimulate GABA receptors in the ascending reticular activating system. Since GABA is inhibitory, receptor stimulation increases inhibition and blocks both cortical and limbic arousal following stimulation of the brain stem reticular formation.
Amnestic: Mechanism of action has not been determined. However, as may occur with all sedative-hypnotic medications, preanesthetic doses of diazepam impair recent memory and interfere with the establishment of the memory trace, thus producing anterograde amnesia for events occurring while therapeutic concentrations of the benzodiazepine are present.
Anticonvulsant: Appear to act, at least partially, by enhancing presynaptic inhibition. Suppress the spread of seizure activity produced by epileptogenic foci in the cortex, thalamus, and limbic structures but do not abolish the abnormal discharge of the focus.
Skeletal muscle relaxant adjunct: The exact mechanism of action of benzodiazepines has not been completely established but these medications appear to produce skeletal muscle relaxation primarily by inhibiting spinal polysynaptic afferent pathways; however, monosynaptic afferent pathways may also be inhibited. Benzodiazepines may also directly depress motor nerve and muscle function.
Pharmacokinetics: Absorption: Following IM administration: Diazepam absorption may be slow and erratic depending upon the site of administration. When diazepam is injected into the deltoid muscle, absorption is usually rapid and complete.
Distribution: Diazepam 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 redistributed into fat depots and tissues.
Biotransformation: Hepatic. Diazepam is metabolised by oxidation to active, as well as inactive, metabolites before final inactivation as glucuronide conjugates. In addition to desmethyldiazepam, its active metabolites include oxazepam, and temazepam.
Binding: Diazepam is extensively bound (98 - 99%) to albumin in plasma.
Accumulation: During repeated dosing with long half-life benzodiazepines, there is accumulation of the parent compound and/or any pharmacologically active metabolites. Accumulation continues until a steady-state plasma concentration is reached, which usually takes 5 days to 2 weeks after initiation of therapy. Following termination of treatment, drug elimination is slow since active metabolites may remain in the blood for several days or even weeks, possibly resulting in persistent effects.
Half-life: The plasma half-life of diazepam and/or its metabolites is prolonged in neonates, in the elderly, and in patients with liver disease.
Excretion: Diazepam is excreted in the urine, mainly in the form of its metabolites, either free or in conjugated form.
Duration of action: The duration of clinical effects of the benzodiazepines is not always predictable from the elimination half-life.
Indications/Uses
States of excitation-especially: indicated in motor excitation of diverse etiology and paranoid-hallucinatory states.
Status epilepticus.
Mascular spasm: rapidly relieves severe spasm of central, peripheral, rheumatic or tetanic origin.
Tetanus.
Dosage/Direction for Use
Usual adult dose: States of excitation: 10-20 mg three times daily IM or IV until acute symptoms subside.
Status epilepticus: Initial dose 10-20 mg IV.; in the following hours 20 mg IM or by intravenous drip infusion, as necessary.
Muscular spasm: 10 mg once or twice IV.
Tetanus: 10 mg IV relieves the spastic state for about 8 hours.
Usual paediatric dose: Anticonvulsant: Status epilepticus and severe recurrent convulsive seizures: Children 2 to 5 years of age: Intravenous (slow), 200 to 500 mcg (0.2 to 0.5 mg) every two to five minutes up to a maximum of 5 mg. If necessary, therapy may be repeated in two to four hours.
Children 5 years of age and over: Intravenous (slow), 1 mg every two to five minutes up to a maximum of 10 mg. If necessary, therapy may be repeated in two to four hours.
Note: The intravenous route of administration is preferred; however, if intravenous administration is impossible, the intra-muscular route of administration may be used.
Skeletal muscle relaxant adjunct: Tetanus: Children 2 to 5 years of age: Intramuscular or intravenous, 1 to 2 mg, the dosage being repeated every three or four hours as needed.
Children 5 years of age and over: Intramuscular or intravenous, 5 to 10 mg, the dosage being repeated every three or four hours as needed.
Note: When the intravenous route is used in children, it is recommended that the medication be administered slowly over a three-minute period in a dosage not to exceed 250 mcg (0.25 mg) per kg of body weight. After an interval of fifteen to thirty minutes, the dosage may be repeated.
Usual geriatric dose: Antianxiety agent or Sedative-hypnotic or Amnestic or Anticonvulsant or Skeletal muscle relaxant adjunct: Intramuscular or intravenous, initially 2 to 5 mg per dose, the dosage being increased gradually as needed and tolerated.
Overdosage
Clinical effects of overdose: Confusion, continuing; decreased reflexes; drowsiness, severe; shakiness; slow heartbeat, shortness of breath, or troubled breathing; slurred speech, continuing; staggering; weakness, severe.
Treatment of overdose: For benzodiazepine intoxication, treatment consists of general supportive therapy and includes the following: To decrease absorption: If the patient is conscious (and not at risk of becoming obtunded, comatose, or convulsing based on ingestion), emesis should be induced mechanically or with emetics; also, activated charcoal may be administered orally to increase clearance as well as decrease absorption of the benzodiazepine.
If the patient is unconscious, gastric lavage may be performed with a cuffed endotracheal tube in place to prevent aspiration of vomitus.
To enhance elimination: Intravenous fluids may be administered to promote diuresis.
Specific treatment: Oxygen should be administered if respiration is depressed.
Hypotension may be controlled, if necessary, by intravenous administration of vasopressors such as dopamine, norepinephrine, or metaraminol.
Flumazenil is now available, and other agents are currently under investigation to determine the usefulness as antagonists to reverse the effects of the benzodiazepines.
Monitoring: Respiration, pulse, and blood pressure should be monitored.
Supportive care: An adequate airway should be maintained.
Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.
Contraindications
Zopam Injection is contraindicated in patients with a known sensitivity to this drug; acute narrow angle glaucoma; and open angle glaucoma unless patients are receiving appropriate therapy. Also contraindicated in infants and children under 2 years of age.
Warnings
As this preparation contains Benzyl Alcohol, its use should be avoided in children under 2 years of age. Not to be used in neonates.
Anaphlaxis (severe allergic reaction) and angiodema (severe facial swelling) which can occur as early as the first time the product is taken.
Complex sleep: related behaviours which may include sleep driving, making phone calls, preparing and eating food while sleeping.
When used intravenously, the following procedures should be undertaken to reduce the possibility of venous thrombosis, phlebitis, local irritation, swelling, and rarely, vascular impairment: the solution should be injected slowly, taking at least 1 minute for each 5 mg (1 mL) given; do not use small veins, such as those on the dorsum of the hand or wrist; extreme care should be taken to avoid intra-arterial administration or extravasation.
Do not mix or dilute Zopam with other solutions or drugs in syringe or infusion flask. If it is not feasible to administer Zopam directly IV, it may be injected slowly through the infusion tubing as close as possible to the vein insertion.
Profound sedation, respiratory depression coma, and death may result from the concomitant use of Zopam with benzodiazepines. Observational studies have demonstrated that concomitant use of opioids and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
If the decision is made to newly prescribe a benzodiazepine and an opioid together, prescribe the lowest effective dosages and minimum duration of concomitant use.
If the decision is made to prescribe a benzodiazepine in a patient already receiving an opioid, prescribe a lower initial dose of the benzodiazepine than indicated in the absence of an opioid, and titrate based on clinical response.
If the decision is made to prescribe a lower initial dose of the opioid, and titrate based on clinical response.
Follow patients closely for signs and symptoms of respiratory depression and sedation. Advice both patients and caregivers about the risks of respiratory depression and sedation when Zopam is used with benzodiazepines. Advice patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of benzodiazepines (see Interactions).
Special Precautions
Diazepam should be used with caution in patients with renal or hepatic dysfunction, circulatory insufficiency and myasthenia gravis (because of the pre-existing muscle weakness). A lower dose is recommended for patients with chronic respiratory insufficiency, due to the risk of respiratory depression.
Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.
Psychiatric and paradoxical reactions: Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. Should this occur, the use of the drug should be discontinued. They are more likely to occur in children and in the elderly.
Elderly and debilitated patients are particularly susceptible to the side effects and may require lower doses. Alertness and performance at skilled tasks may be impaired. Patients should be warned not to drive vehicles or operate machinery.
Alcohol may potentiate these effects.
Cross-senitivity and/or related problems: Patients sensitive to one of the benzodiazepines may be sensitive to the other benzodiazepines also.
Use in Pregnancy: Diazepam crosses the placenta.
First trimester: Diazepam has been reported to increase the risk of congenital malformations when used during the first trimester of pregnancy. Risk-benefit must be carefully considered. However, since the use of benzodiazepines (with the possible exception of anticonvulsant use) is rarely a matter of urgency, it should be avoided during pregnancy, especially during the first trimester.
When diazepam is used as anticonvulsant, risk-benefit must be considered since recent reports suggest an increased incidence of congenital abnormalities in children whose mothers used anticonvulsants during pregnancy: however, a definite cause and effect relationship has not been established.
Chronic usage of benzodiazepines during pregnancy may cause physical dependence with resulting withdrawal symptoms in the neonate.
Use of benzodiazepine hypnotics during the last weeks of pregnancy may result in neonatal CNS depression.
Labour: Use of benzodiazepines just prior to or during labour may cause neonatal flaccidity.
Delivery: When diazepam is administered in doses of more than 30 mg (especially, intramuscularly or intravenously) to women within 15 hours before delivery, the neonate may develop apnea, hypotonia, hypothermia, a reluctance to feed, and impaired metabolic response to cold stress.
Use in Lactation: Diazepam is distributed into breast milk.
Since neonates metabolise benzodiazepines more slowly than adults and accumulation of the benzodiazepine and/or its metabolites may occur, use by nursing mothers may cause sedation, and possibly feeding difficulties and weight loss in the infant.
Use in Children: Children, especially the very young, are usually more sensitive to the CNS effects of benzodiazepines. Prolonged CNS depression may be produced in the neonate because of inability to biotransform the benzodiazepine into inactive metabolites.
Use in Elderly: Geriatric patients are usually more sensitive to the CNS effects of benzodiazepines. It is recommended that dosage is limited to the smallest effective dose and increased gradually, if necessary, to decrease the possibility of development of ataxia, dizziness, and oversedation. A retrospective case-control study has shown that elderly patients receiving long-acting benzodiazepines are more likely than those receiving short-acting benzodiazepines to suffer falls and fall-related fractures.
However, both groups had an increased risk of these sequelae as compared to older patients who did not receive benzodiazepines or who received other short-acting sedative-hypnotics.
Parenteral administration of benzodiazepines may be more likely to cause apnea, hypotension, bradycardia, or cardiac arrest in geriatric patients.
Use In Pregnancy & Lactation
Pregnancy: Diazepam crosses the placenta.
First trimester: Diazepam has been reported to increase the risk of congenital malformations when used during the first trimester of pregnancy. Risk-benefit must be carefully considered. However, since the use of benzodiazepines (with the possible exception of anticonvulsant use) is rarely a matter of urgency, it should be avoided during pregnancy, especially during the first trimester.
When diazepam is used as anticonvulsant, risk-benefit must be considered since recent reports suggest an increased incidence of congenital abnormalities in children whose mothers used anticonvulsants during pregnancy: however, a definite cause and effect relationship has not been established.
Chronic usage of benzodiazepines during pregnancy may cause physical dependence with resulting withdrawal symptoms in the neonate.
Use of benzodiazepine hypnotics during the last weeks of pregnancy may result in neonatal CNS depression.
Labour: Use of benzodiazepines just prior to or during labour may cause neonatal flaccidity.
Delivery: When diazepam is administered in doses of more than 30 mg (especially, intramuscularly or intravenously) to women within 15 hours before delivery, the neonate may develop apnea, hypotonia, hypothermia, a reluctance to feed, and impaired metabolic response to cold stress.
Breast-feeding: Diazepam is distributed into breast milk.
Since neonates metabolise benzodiazepines more slowly than adults and accumulation of the benzodiazepine and/or its metabolites may occur, use by nursing mothers may cause sedation, and possibly feeding difficulties and weight loss in the infant.
Adverse Reactions
Geriatric and debilitated patients, children (especially the very young), and patients with liver disease or low serum albumin are usually more sensitive to the CNS effects of benzodiazepines. Parenteral administration of benzodiazepines may cause apnea, hypotension, bradycardia, or cardiac arrest, especially in geriatric or severely ill patients and in patients with limited pulmonary reserve or unstable cardiovascular status or if intravenous administration of medication is too rapid.
Parenteral benzodiazepines have produced hypotension or muscular weakness in some patients, especially when used concurrently with narcotics, barbiturates, or alcohol.
Coughing, depressed respiration, dyspnea, hyperventilation, laryngospasm, and pain in throat and chest have been reported when parenteral diazepam was administered in peroral endoscopic procedures.
The following side / adverse effects have been selected on the basis of their potential clinical significance.
Those indicating need for medical attention: Incidence less frequent: Intolerance to benzodiazepines (confusion); mental depression.
Incidence rare: Allergic reaction (skin rash or itching); behaviour problems (including difficulty in concentrating and outbursts of anger); blood dyscrasias, including agranulocytosis, anemia, leukopenia, neutropenia (chills, fever, and / or sore throat; ulcers or sores in mouth or throat, continuing; unusual tiredness or weakness ); thrombocytopenia (unusual bleeding or bruising); extra-pyramidal effects, dystonic (uncontrolled movements of body, including the eyes), hepatic dysfunction (yellow eyes or skin), hypotension; memory impairment; muscle weakness; paradoxical reactions (including hallucinations; insomnia; unusual excitement, nervousness, or irritability); phlebitis or venous thrombosis (redness, swelling, or pain at injection site); seizures.
Incidence of phlebitis or venous thrombosis is more common with diazepam.
There may be an increased incidence and severity of seizures, especially on initiation or abrupt withdrawal of diazepam in patients with epilepsy or history of seizures.
Those indicating need for medical attention only if they continue or are bothersome.
Incidence more frequent: Ataxia (clumsiness or unsteadiness); dizziness or lightheadedness; drowsiness when used as a hypnotic; slurred speech.
Incidence less frequent or rare: Abdominal or stomach cramps or pain; blurred vision or other changes in vision; changes in libido; constipation; diarrhoea; dryness of mouth or increased thirst; euphoria; headache; increased bronchial secretions or watering of mouth; muscle spasm; nausea or vomiting; problems with urination; tachycardia / palpitations; trembling; unusual tiredness or weakness.
Dependence: Dependence may develop after regular use of diazepam or other benzodiazepines, even in therapeutic doses for short periods. Drug dependence is generally characterised by a strong desire to take the drug, a tendency to increase the dose owing to development of tolerance, a physical and psychological dependence on the drug, and a characteristic abstinence syndrome on withdrawal. In the context of benzodiazepine dependence, physical dependence with the development of withdrawal symptoms on drug discontinuation is common. The extent to which tolerance occurs has been debated but appears to occur more often to effects on psychomotor performance than to anxiolytic effects. Drug-seeking behaviour is uncommon with therapeutic doses of benzodiazepines.
Withdrawal symptoms include anxiety, insomnia, head ache, dizziness, tinnitus, loss of appetite, tremor, perspiration, irritability, perceptual disturbances such as hypersensitivity to visual and auditory stimuli and metallic taste, nausea, vomiting, abdominal cramps, palpitations, and orthostatic hypotension. Rare and more serious symptoms include muscle twitching, confusional or paranoid psychosis, convulsions, hallucinations, and delirium tremens. The time at which symptoms develop varies with the duration of action of the benzodiazepine used. Benzodiazepines should not be discontinued abruptly after regular use for even a few weeks, but withdrawn by gradual reduction of the dose over a period of weeks.
Drug Interactions
Alcohol or CNS depression-producing medications, other: Concurrent use may increase the CNS depressant effects of either these medications or benzodiazepines; caution is recommended and dosage of one or both agents should be reduced; when a benzodiazepine is used concurrently with an opioid analgesic, the dosage of the opioid analgesic should be reduced by at least one-third and administered in small increments.
Antacids: Concurrent use may delay, but not reduce, the absorption of diazepam.
Antiepileptics: Carbamazepine, phenobarbitone, and phenytoin are all inducers of hepatic drug-metabolising enzymes. Therefore, in patients receiving long-term therapy with these drugs the metabolism of benzodiazepines may be enhanced.
Cimetidine or Contraceptives, estrogen-containing, oral or Disulfiram or Erythromycin: Concurrent use may inhibit the hepatic metabolism of benzodiazepines that are metabolised by oxidation, especially diazepam, resulting in delayed elimination and increased plasma concentrations.
Clozapine: Collapse, sometimes accompanied by respiratory depression or arrest, has been reported in a few patients receiving clozapine concurrently with benzodiazepines. Caution is advised when clozapine is administered concomitantly with any agent that may depress respiration, and the dosage of clozapine should be titrated upwards slowly. Some clinicians have recommended that benzodiazepines be discontinued at least 1 week prior to initiation of therapy with clozapine.
Fentanyl derivatives: Premedication with diazepam may decrease the dose of a fentanyl derivative required for induction of anesthesia and decrease the time of loss of consciousness with induction doses; also, administration of diazepam prior to or during surgery may decrease risk of patient recall of surgical events post-operatively; however, these potential benefits must be weighed against the potential risks of concurrent use, such as increased risk of' severe hypotension and respiratory depression, and delayed recovery time, especially when the benzodiazepine is administered intravenously.
Hypotension-producing medications, other: Concurrent use may potentiate the hypotensive effects of benzodiazepine preanesthetics used in surgery; dosage adjustments may be necessary. Concurrent use of mecamylamine or trimethaphan may potentiate the hypotensive response, with increased risk of severe hypotension, shock, and cardiovascular collapse during surgery. Caution is advised during titration of calcium channel blocker dosage for those patients taking benzodiazepine preanesthetics, since the combination may result in excessive hypotension.
Isoniazid: Concurrent use may inhibit the elimination of diazepam, resulting in increased plasma concentrations; dosage adjustment may be necessary.
Ketamine: Premedication with diazepam prolongs the half-life of ketamine, resulting in an enhanced effect.
Levodopa: Concurrent use with benzodiazepines may decrease the therapeutic effects of levodopa.
Omeprazole: Concurrent use of omeprazole may prolong the elimination of diazepam.
Rifampin: Concurrent use may enhance the elimination of diazepam, resulting in decreased plasma concentrations; dosage adjustment may be necessary.
Sodium valproate: Sodium valproate has been reported to displace diazepam from plasma-protein binding sites.
Theophylline: Theophylline counteracts with the sedative and psychomotor effects of diazepam.
Xanthines: There are reports of aminophylline given intravenously reversing the sedation from intravenous diazepam. Theophylline also counteracts the sedative and psychomotor effects of diazepam.
Benzodiazepines: Due to additive pharmacologic effect, the concomitant use of opioids with benzodiazepines increases the risk of respiratory depression, profound sedation, coma and death.
The concomitant use of opioids and benzodiazepines increases the risk of respiratory depression because of actions at different receptors sites in the central nervous system that control respiration. Opioids interact primarily at μ-receptors, and benzodiazepines interact at GABAA sites. When opioids and benzodiazepines are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate (see Precautions).
Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation.
Caution For Usage
Stability: Do not mix or dilute this medication with other solutions, intravenous fluids, or medications, because the resulting admixtures are unstable. Diazepam is adsorbed to the plastic of intravenous infusion bags and tubing.
Incompatibilities: Diazepam injection is physically incompatible with aqueous solutions.
Storage
Store below 30°C. Protect from light and freezing.
Shelf-Life: 3 years.
MIMS Class
ATC Classification
N05BA01 - diazepam ; Belongs to the class of benzodiazepine derivatives anxiolytics. Used in the management of anxiety, agitation or tension.
Presentation/Packing
Inj 10 mg/2 mL (colourless, clear, sterile solution) x 10's.
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