ANXIENAD

Lorazepam is a short-acting and rapidly cleared benzodiazepine used commonly as a sedative and anxiolytic.

It was developed by DJ

Richards, presented and marketed initially by Wyeth Pharmaceuticals in the USA in 1977.

The first historic FDA label approval is reported in by the company Mutual Pharm.

Lorazepam is

FDA-approved for the short-term relief of anxiety symptoms related to anxiety disorders and anxiety associated with depressive symptoms such as anxiety-associated insomnia.

It is as well used as an anesthesia premedication in adults to relieve anxiety or to produce sedation/amnesia and for the treatment of status epilepticus.

Some off-label indications of lorazepam include rapid tranquilization of an agitated patient, alcohol withdrawal delirium, alcohol withdrawal syndrome, muscle spasms, insomnia, panic disorder, delirium, chemotherapy-associated anticipatory nausea and vomiting, and psychogenic catatonia.

The effect of lorazepam in

GABA-A receptors produces an increase in the frequency of opening of the chloride ion channel.

However, for its effect to generate, the neurotransmitter is required.

The anticonvulsant properties of lorazepam are thought to be related to the binding to voltage-dependent sodium channels in which the sustained repetitive firing gets limited by the slow recovery of sodium channels due to the benzodiazepine effect.

The effect of lorazepam seems to be very compartmental which was observed with a different generation of sleepiness and a dizziness effect.

Receptor Positive allosteric modulator

GABA(A) Receptor Benzodiazepine Binding Site Ligand.

Readily absorbed with an absolute bioavailability of 90% when given Oral.

Intramuscular 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

Oral, the time to attained maximum concentration is observed to be of 2 hours.

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.

Lorazepam is hepatically metabolized by

CYP450 isoenzymes and extensively conjugated to the 3-0-phenolic glucuronide.

This is an inactive metabolite and is eliminated mainly by the kidneys.

Hover over products below to view reaction partners Lorazepam Lorazepam glucuronide.

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.

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

Following the administration of 1 mg of lorazepam in healthy adult male volunteers and using a multi-doses equation based on a one-compartment model, the average elimination half-life of lorazepam was estimated to be 11 hours and 8 hours for sublingual and oral doses respectively.

The absorption half-life was calculated to be 55 minutes for oral doses and 15 minutes for sublingual doses.

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

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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.

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.

• hypersensitivity to benzodiazepines or to any components of the formulation.

• acute narrow-angle glaucoma.

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.