Orazepam

Uses

Orazepam is used for the treatment of anxiety states; including anxiety associated with phobic & obsessional states, psychosomatic, organic or psychotic illness, insomnia associated with anxiety, nervousness, restlessness, nausea and vomiting related to chemotherapy and anticonvulsants, and as a premedicant before dental or general surgery or prior to investigative procedures where there may be discomfort. Orazepam is not recommended in anxiety states in children but may be used as premedicant before surgery at a dose of 0.05 mg/Kg in children aged 5 to 13 years. The dosage of Orazepam tablet should be increased gradually when needed to avoid adverse effects. When higher dosage is used, the evening dose should be increased before the daytime.

Orazepam is also used to associated treatment for these conditions: Agitation, Alcohol Withdrawal Delirium, Alcohol Withdrawal Syndrome, Anxiety, Anxiety Disorders, Catatonia, Chemotherapy-Induced Nausea and Vomiting (CINV), Delirium, Insomnia, Muscle Spasms, Panic Disorder, Refractory seizure disorders, Preanesthetic medication therapy

How Orazepam works

Orazepam allosterically binds on the benzodiazepine receptors in the post-synaptic GABA-A ligand-gated chloride channel in different sites of the central nervous system (CNS). This binding will result in an increase on the GABA inhibitory effects which is translated as an increase in the flow of chloride ions into the cell causing hyperpolarization and stabilization of the cellular plasma membrane.

According to the binding site of lorazepam, we can observe different activities as the binding in the amygdala is known to help mainly in anxiety disorders while the binding in the cerebral cortex helps in seizure disorders.

Dosage

Orazepam dosage

Oral-

Frequency of administration and duration of therapy should be individualized according to patient's response. The usual range is 2 to 6 mg/day given in divided doses, the largest dose being taken before bedtime, but the largest dosage may vary from 1 to 10 mg/day. For anxiety, most patients require an initial dose of 2 to 3 mg/day given b.i.d. or t.i.d. For elderly or debilitated patients, an initial dosage of 1 to 2 mg/day in divided doses is recommended, to be adjusted as needed and tolerated. For insomnia 1 to 2 mg before bedtime and as premedicant 1 to 2 mg the night before surgery and 1 to 2 hour before surgery.

Injection-

Acute anxiety:

• Adult:IV/IM: 25-30 mcg/kg repeated 6 hrly if necessary. Give IV inj at a rate of not more than 2 mg/min into a large vein.
• Child:<12 yrNot recommended.
• Elderly:Half the usual adult dose or less.

Premedication in surgery:

• Adult:50 mcg/kg given pre-op over 30-45 min (IV) or 60-90 min (IM).
• Child:<12 yrNot recommended.
• Elderly:Half the usual adult dose or less.

Status epilepticus:

• Adult:4 mg as a single dose, into a large vein at a rate not more than 2 mg/min. May be repeated once after 10-15 min if seizures recur.
• Child:2 mg as single dose.
• Elderly:Half the usual adult dose or less.

Injection: Dilute with an equal volume of compatible diluent (e.g. sterile water for inj, NaCl 0.9% inj, dextrose 5% inj).

Oral concentrate solution: Dose should be added to 30 mL or more of diluent (e.g. water, juice, carbonated or soda-like beverage) or to semi-solid food (e.g. applesauce, pudding).

Side Effects

Adverse reactions are usually observed at the beginning of therapy and generally disappeared on continued medication or upon decreasing the dose. The most frequent adverse reactions of Orazepam are sedation followed by dizziness, weakness and unsteadiness. Less frequent adverse reactions are disorientation, depression, nausea, change in appetite, headache, sleep disturbance, agitation, dermatological symptoms, eye-function disturbance, together with various gastrointestinal symptoms and autonomic manifestations.

Toxicity

The LD50 observed by oral administration in a mouse is of 1850 mg/kg. When an overdose administration is registered, signs of CNS and respiratory depression are rapidly observed. An overdose stage can result in profound sedation, deep respiratory depression, coma, and death. When overdose is observed, it is recommended to administer emergency symptomatic medical support with attention to produce an increase in lorazepam elimination.

There is no evidence of carcinogenicity nor mutagenicity. At doses higher than 40 mg/kg there is evidence of fetal resorption and increase in fetal loss.

Precaution

In patients with depression accompanying anxiety, a possibility for suicide should be borne in mind. For elderly or debilitated patients, the initial daily dosage should not exceed 2 mg in order to avoid over sedation. The usual precautions for treating patients with impaired renal or hepatic function and with acute and chronic pulmonary insufficiency should be observed. Use of Orazepam for prolonged period and gastric patients requires caution and there should be frequent monitoring for symptoms of upper gastrointestinal disease. Machineries should be avoided during taking Orazepam.

Interaction

Orazepam may potentiate the central depressant effect when combined with other drugs with central depressant action. Such drugs include alcohol, general anesthetics, tricyclic antidepressants and monoamine oxidase inhibitors.

Food Interaction

• Avoid alcohol.
• Limit caffeine intake.
• Take with food.

[Moderate] GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents.

Use in combination may result in additive central nervous system depression and
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol.

Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Orazepam Drug Interaction

Major: acetaminophen / hydrocodoneModerate: aripiprazole, diphenhydramine, duloxetine, escitalopram, pregabalin, quetiapine, sertraline, cetirizineMinor: metoprololUnknown: amphetamine / dextroamphetamine, aspirin, omega-3 polyunsaturated fatty acids, polyethylene glycol 3350, esomeprazole, levothyroxine, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol

Orazepam Disease Interaction

Major: acute alcohol intoxication, closed-angle glaucoma, drug dependence, renal/liver disease, respiratory depression, seizures, prolonged hypotension, prematurityModerate: depression, obesity, paradoxical reactions, upper GI disease

Volume of Distribution

The reported volume of distribution of lorazepam is 1.3 L/kg. It is important to mention that due to the lipophilicity of lorazepam, it does not redistribute as fast in the brain.

Elimination Route

Readily absorbed with an absolute bioavailability of 90% when given orally. When intramuscularly administered a dose of 4 mg, lorazepam is completely and rapidly absorbed and achieves a maximal serum concentration of 48 ng/ml in 15-30 minutes. When administered orally, the time to attained maximum concentration is observed to be of 2 hours.

Half Life

When administered parentally, the registered half-life of lorazepam is of 14 hours.

Clearance

In vivo studies with lorazepam have shown a clearance rate of 5.8 ml.min/kg.

Elimination Route

When a single 2 mg oral dose is given to healthy subjects, 88% of the administered dose is recovered in urine and 7% was recovered in feces. From the excreted dose in urine, the major form is the glucuronide version that represents 74% while only 0.3% of the dose is recovered as unchanged lorazepam.

Pregnancy & Breastfeeding use

Safety of Orazepam in pregnancy has not been established. Because the use of this drug is rarely a matter of urgency, the use of Orazepam during this period should almost always be avoided.

It is not known whether oral Orazepam is excreted in human milk like other benzodiazepine tranquilizers. As a general rule, nursing should not be undertaken while a patient is on a drug since many drugs are excreted in human milk.

Contraindication

Orazepam should not be given to patients with a previous sensitivity to benzodiazepines or with acute narrow-angle glaucoma and myasthenia gravis.

Special Warning

Debilitated patient: Half the usual adult dose or less.

Renal Impairment: May require reduced doses.

Mild to Moderate Hepatic Impairment: May require reduced doses.

Severe Hepatic Impairment: Contraindicated.

Acute Overdose

Overdosage of Orazepam is usually manifested by varying degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion and lethargy. In more serious cases and especially when other drugs or alcohol were ingested, symptoms may include ataxia, hypotonia, hypotension, hypnotic states (stages I to III), coma.

Storage Condition

Tablet: Store between 20-25°C.

Injection or oral concentrate solution: Store between 2-8°C. Do not freeze. Protect from light.

Innovators Monograph

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