Rx only

Lorazepam, USP, an antianxiety agent, has the chemical formula, 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one:

C15H10Cl2N2O2            M.W. 321.16

It is a nearly white powder almost insoluble in water. Each lorazepam tablet, to be taken orally, contains 0.5 mg, 1 mg, or 2 mg of lorazepam, USP. The inactive ingredients present are lactose monohydrate, magnesium stearate, microcrystalline cellulose, and polacrilin potassium.

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 60 to 84 years of age compared to that in 15 younger subjects of 19 to 38 years of age.

Lorazepam tablets are indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety or anxiety associated with depressive symptoms. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.

The effectiveness of lorazepam in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.

Lorazepam is contraindicated in patients with:

• hypersensitivity to benzodiazepines or to any components of the formulation.
• acute narrow-angle glaucoma.

Risks from Concomitant Use with Opioids

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 PRECAUTIONS:Drug Interactions).

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 DRUG ABUSE AND DEPENDENCE: Abuse).

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.

Dependence and Withdrawal Reactions

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 DOSAGE AND ADMINSTRATION: Discontinuation or Dosage Reduction of Lorazepam Tablets).

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.

Acute Withdrawal Reactions

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 DRUG ABUSE AND DEPENDENCE: Dependence).

Protracted Withdrawal Syndrome

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

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 PRECAUTIONS:Drug Interactions).

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.

In patients with depression, a possibility for suicide should be borne in mind; benzodiazepines should not be used in such patients without adequate anti­depressant therapy.

Lorazepam should be used with caution in patients with compromised respiratory function (e.g., COPD, sleep apnea syndrome).

Elderly or debilitated patients may be more susceptible to the sedative effects of lorazepam. Therefore, these patients should be monitored frequently and have their dosage adjusted carefully according to patient response; the initial dosage should not exceed 2 mg.

Paradoxical reactions have been occasionally reported during benzodiazepine use. Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued.

The usual precautions for treating patients with impaired renal or hepatic function should be observed. As with all benzodiazepines, the use of lorazepam may worsen hepatic encephalopathy; therefore, lorazepam should be used with caution in patients with severe hepatic insufficiency and/or encephalopathy. Dosage for patients with severe hepatic insufficiency should be adjusted carefully according to patient response; lower doses may be sufficient in such patients.

In patients where gastrointestinal or cardiovascular disorders coexist with anxiety, it should be noted that lorazepam has not been shown to be of significant benefit in treating the gastrointestinal or cardiovascular component.

Esophageal dilation occurred in rats treated with lorazepam for more than 1 year at 6 mg/kg/day.

The no- effect dose was 1.25 mg/kg/day (approximately 6 times the maximum human therapeutic dose of 10 mg/day). The effect was reversible only when the treatment was withdrawn within 2 months of first observation of the phenomenon. The clinical significance of this is unknown. However, use of lorazepam for prolonged periods and in geriatric patients requires caution, and there should be frequent monitoring for symptoms of upper GI disease.

Safety and effectiveness of lorazepam in children of less than 12 years have not been established.

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 EVENTS, contact Actavis at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

Controlled Substance

Lorazepam tablets contain lorazepam, a Schedule IV controlled substance.

Abuse

Lorazepam tablets are a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction.

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. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders (see WARNINGS: Abuse, Misuse, and Addiction).

The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.

The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

Dependence

Physical Dependence

Lorazepam tablets may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use (see WARNINGS: Dependence and Withdrawal Reactions).

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue lorazepam tablets or reduce the dosage (see DOSAGE and ADMINISTRATION: Discontinuation or Dosage Reduction of Lorazepam Tablets and WARNINGS).

Acute Withdrawal Signs and Symptoms

Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures and suicidality.

Protracted Withdrawal Syndrome

Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.

Tolerance

Tolerance to lorazepam tablets may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of lorazepam tablets may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

In postmarketing experience, overdose with lorazepam has occurred predominantly in combination with alcohol and/or other drugs. Therefore, in the management of overdosage, it should be borne in mind that multiple agents may have been taken.

Symptoms

Overdosage of benzodiazepines is usually manifested by varying degrees of CNS depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion, paradoxical reactions, dysarthria and lethargy. In more serious cases, and especially when other drugs or alcohol were ingested, symptoms may include ataxia, hypotonia, hypotension, cardiovascular depression, respiratory depression, hypnotic state, coma, and death.

Management

General supportive and symptomatic measures are recommended; vital signs must be monitored and the patient closely observed. When there is a risk of aspiration, induction of emesis is not recommended. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Administration of activated charcoal may also limit drug absorption. Hypotension, though unlikely, usually may be controlled with norepinephrine bitartrate injection. Lorazepam is poorly dialyzable. Lorazepam glucuronide, the inactive metabolite, may be highly dialyzable.

The benzodiazepine antagonist flumazenil may be used in hospitalized patients as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections should be consulted prior to use.

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 2 to 6 mg/day given in divided doses, the largest dose being taken before bedtime, but the daily dosage may vary from 1 to 10 mg/day.

For anxiety, most patients require an initial dose of 2 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 2 to 4 mg may be given, usually at bedtime.

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.

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 (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE: Dependence).

Lorazepam Tablets, USP are available in the following dosage strengths:

0.5 mg: white to off-white, round flat-faced, beveled edge tablet, scored on one side debossed with 240 above bisect and 0.5 below bisect and debossed WATSON on the other side, supplied in bottles of 100 (NDC 0591‐0240‐01), 500 (NDC 0591‐0240‐05) and 1000 (NDC 0591‐0240‐10).

1 mg: white to off-white, round flat-faced, beveled edge tablet, scored on one side debossed with 241 above bisect and 1 below bisect and debossed WATSON on the other side, supplied in bottlesof 100 (NDC 0591‐0241‐01), 500 (NDC 0591‐0241‐05) and 1000 (NDC 0591‐0241‐10).

2 mg: white to off-white, round flat-faced, beveled edge tablet, scored on one side debossed with 242 above bisect and 2 below bisect and debossed WATSON on the other side, supplied in bottlesof 100 (NDC 0591‐0242‐01), 500 (NDC 0591‐0242‐05) and 1000 (NDC 0591‐0242‐10).

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

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

Manufactured by:

Watson Pharma Private Limited

Verna, Salcette Goa 403 722 INDIA

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Rev. A 2/2021

This Medication Guide has been approved by the U.S. Food and Drug Administration.                             Rev. A 2/2021

NDC 0591-0240-01

CIV

Lorazepam Tablets, USP

0.5 mg

PHARMACIST: Dispense the accompanying Medication Guide to each patient.



100 Tablets

Rx only

NDC 0591-0241-01

CIV

Lorazepam Tablets, USP

1mg

PHARMACIST: Dispense the  accompanying Medication Guide to each patient.

100 Tablets

Rx only

NDC 0591-0242-01

CIV

Lorazepam Tablets, USP

2 mg

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

100 Tablets

Rx only