ORZEPAM

USP, an antianxiety agent, has the chemical formula, 7-chloro-5-( o -chlorophenyl)-1,3‑-dihydro-3-hydroxy-2 H -1,4-benzodiazepin-2-one: It is a nearly white powder almost insoluble in water.

Each lorazepam tablet, USP to be taken orally, contains 0.5 mg, 1 mg, or 2 mg of lorazepam, USP.

The inactive ingredients present are anhydrous lactose, magnesium stearate, microcrystalline cellulose, and polacrilin potassium.

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The following is the main warning period for Lorazepam: The following is the form of pharmaceutical products for Lorazepam may contain a benzyl alcohol substance that causes pneumonia to be transmitted to infants, or polyethylene glycol, which may cause poisoning in case of exposure to it for long periods.

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Lorazepam in older persons must be cautious, because of their increased sensitivity to the side effects that may be caused by treatment.

The treatment must be carefully informed if the patient suffers from the following health conditions: depression.

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A respiratory system disease.

Studies in healthy volunteers show that in single high doses lorazepam has a tranquilizing action on the central nervous system with no appreciable effect on the respiratory or cardiovascular systems.

Lorazepam is readily absorbed with an absolute bioavailability of 90%.

Peak concentrations in plasma occur approximately 2 hours following administration.

The peak plasma level of lorazepam from a 2 mg dose is approximately 20 ng/mL.

The mean half-life of unconjugated lorazepam in human plasma is about 12 hours and for its major metabolite, lorazepam glucuronide, about 18 hours.

At clinically relevant concentrations, lorazepam is approximately 85% bound to plasma proteins.

Lorazepam is rapidly conjugated at its 3-hydroxy group into lorazepam glucuronide which is then excreted in the urine.

Lorazepam glucuronide has no demonstrable central nervous system (CNS) activity in animals.

The plasma levels of lorazepam are proportional to the dose given.

There is no evidence of accumulation of lorazepam on administration up to 6 months.

Studies comparing young and elderly subjects have shown that advancing age does not have a significant effect on the pharmacokinetics of lorazepam.

However, in one study involving single intravenous doses of 1.5 to 3 mg of lorazepam Injection, mean total body clearance of lorazepam decreased by 20% in 15 elderly subjects of to 84 years of age compared to that in 15 younger subjects of to 38 years of age.

Lorazepam is a drug that belongs to the benzodiazepine family, which has a tranquilizing and sleeping effect, and is linked to its own brain receptors, which activate the "Gamma Amnoborek acid" receptors, which have a tranquilizing effect, and help control the excess neurons in the brain that cause epilepsy.

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Most adverse reactions to benzodiazepines, including CNS effects and respiratory depression, are dose dependent, with more severe effects occurring with high doses.

In a sample of about 3500 patients treated for anxiety, the most frequent adverse reaction to lorazepam was sedation (15.9%), followed by dizziness (6.9%), weakness (4.2%), and unsteadiness (3.4%).

The incidence of sedation and unsteadiness increased with age.

Other adverse reactions to benzodiazepines, including lorazepam are fatigue, drowsiness, amnesia, memory impairment, confusion, disorientation, depression, unmasking of depression, disinhibition, euphoria, suicidal ideation/attempt, ataxia, asthenia, extrapyramidal symptoms, convulsions/seizures, tremor, vertigo, eye function/visual disturbance (including diplopia and blurred vision), dysarthria/slurred speech, change in libido, impotence, decreased orgasm; headache, coma; respiratory depression, apnea, worsening of sleep apnea, worsening of obstructive pulmonary disease; gastrointestinal symptoms including nausea, change in appetite, constipation, jaundice, increase in bilirubin, increase in liver transaminases, increase in alkaline phosphatase; hypersensitivity reactions, anaphylactoid reactions; dermatological symptoms, allergic skin reactions, alopecia; syndrome of inappropriate antidiuretic hormone (SIADH), hyponatremia; thrombocytopenia, agranulocytosis, pancytopenia; hypothermia; and autonomic manifestations.

Paradoxical reactions, including anxiety, excitation, agitation, hostility, aggression, rage, sleep disturbances/insomnia, sexual arousal, and hallucinations may occur.

Small decreases in blood pressure and hypotension may occur but are usually not clinically significant, probably being related to the relief of anxiety produced by lorazepam.

To report SUSPECTED ADVERSE

REACTIONS, contact Aurobindo Pharma USA, Inc.fda.gov/medwatch.

Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma.

In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia.

Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur.

In severe overdosage cases, patients may develop respiratory depression and coma.

Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see ).

Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management.

Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency.

The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy.

Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus).

If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage.

See the flumazenil injection Prescribing

Consider contacting the Poison

Help line or a medical toxicologist for additional overdosage management recommendations.

Concomitant use of benzodiazepines, including lorazepam, and opioids may result in profound sedation, respiratory depression, coma, and death.

Because of these risks, reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone.

If a decision is made to prescribe lorazepam concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation.

In patients already receiving an opioid analgesic, prescribe a lower initial dose of lorazepam than indicated in the absence of an opioid and titrate based on clinical response.

If an opioid is initiated in a patient already taking lorazepam, prescribe a lower initial dose of the opioid and titrate based upon clinical response.

Advise both patients and caregivers about the risks of respiratory depression and sedation when lorazepam is used with opioids.

Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see ).

Abuse, Misuse, and Addiction The use of benzodiazepines, including lorazepam, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death.

Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see ).

Before prescribing lorazepam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool).

Use of lorazepam, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of lorazepam along with monitoring for signs and symptoms of abuse, misuse, and addiction.

Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug.

If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue lorazepam or reduce the dosage (a patient-specific plan should be used to taper the dose) (see ).

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.

The continued use of benzodiazepines, including lorazepam, may lead to clinically significant physical dependence.

Abrupt discontinuation or rapid dosage reduction of lorazepam after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see ).

In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see ).

Pre-existing depression may emerge or worsen during use of benzodiazepines including lorazepam.

Lorazepam is not recommended for use in patients with a primary depressive disorder or psychosis.

Use of benzodiazepines, including lorazepam, both used alone and in combination with other CNS depressants, may lead to potentially fatal respiratory depression (see ).

As with all patients on

CNS-depressant drugs, patients receiving lorazepam should be warned not to operate dangerous machinery or motor vehicles and that their tolerance for alcohol and other CNS depressants will be diminished.

Use of lorazepam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see ).

Monitor neonates exposed to lorazepam during pregnancy or labor for signs of sedation and monitor neonates exposed to lorazepam during pregnancy for signs of withdrawal; manage these neonates accordingly.

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Lorazepam tablets are administered orally.

For optimal results, dose, frequency of administration, and duration of therapy should be individualized according to patient response.

To facilitate this, 0.5 mg, 1 mg, and 2 mg tablets are available.

The usual range is to 6 mg/day given in divided doses, the largest dose being taken before bedtime, but the daily dosage may vary from to 10 mg/day. For anxiety, most patients require an initial dose of to 3 mg/day given two times a day or three times a day. For insomnia due to anxiety or transient situational stress, a single daily dose of to 4 mg may be given, usually at bedtime.

For elderly or debilitated patients, an initial dosage of to 2 mg/day in divided doses is recommended, to be adjusted as needed and tolerated.

The dosage of lorazepam tablets should be increased gradually when needed to help avoid adverse effects.

When higher dosage is indicated, the evening dose should be increased before the daytime doses.

Discontinuation or Dosage Reduction of Lorazepam Tablets To reduce the risk of withdrawal reactions, use a gradual taper to discontinue lorazepam tablets or reduce the dosage.

If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level.

Subsequently decrease the dosage more slowly.

Tablets, USP are available in the following dosage strengths: 1 mg, white to off-white, round, flat-faced beveled edge tablets debossed with ‘U33’ on one side and bisect on the other side.

Bottles of 30 NDC 68788-7428-03 Bottles of 60 NDC 68788-7428-06 Bottles of 90 NDC 68788-7428-09 Bottles of 100 NDC 68788-7428-01 Bottles of 120 NDC 68788-7428-08 Keep bottles tightly closed.

Keep out of reach of children.

Store at 20° to 25°C (68° to 77°F). .

Dispense in a tight, light-resistant container as described in the USP.

Dispense with Medication Guide available at

Distributed by: Aurobindo Pharma USA, Inc.

Windsor, NJ 08520.

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including lorazepam, during pregnancy.

Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal.

Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates.

Monitor neonates exposed to lorazepam during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems.

Monitor neonates exposed to lorazepam during pregnancy for signs of withdrawal.

Manage these neonates accordingly (see ).

Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects.

Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted.

In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Reproductive studies in animals were performed in mice, rats, and two strains of rabbits.

Occasional anomalies (reduction of tarsals, tibia, metatarsals, malrotated limbs, gastroschisis, malformed skull, and microphthalmia) were seen in drug-treated rabbits without relationship to dosage.

Although all of these anomalies were not present in the concurrent control group, they have been reported to occur randomly in historical controls.

At doses of 40 mg/kg and higher, there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen at lower doses.

Lorazepam is present in breast milk.

There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk.

The effects of lorazepam on milk production are unknown.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lorazepam and any potential adverse effects on the breastfed infant from lorazepam or from the underlying maternal condition.

Infants exposed to lorazepam through breast milk should be monitored for sedation, poor feeding and poor weight gain.

Clinical studies of lorazepam generally were not adequate to determine whether subjects aged and over respond differently than younger subjects; however, the incidence of sedation and unsteadiness was observed to increase with age (see ).

Age does not appear to have a significant effect on lorazepam kinetics (see ).

Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered.

Greater sensitivity (e.g., sedation) of some older individuals cannot be ruled out.

In general, dose selection for an elderly patient should be cautious, and lower doses may be sufficient in these patients See DOSAGE AND ADMINISTRATION.