Lorazepam, 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, to be taken orally, contains 0.5 mg, 1 mg, or 2 mg of lorazepam. The inactive ingredients present are lactose, 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 percent. 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 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 six 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 is 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.

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 for use 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, Clinically Significant Drug Interactions).

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, Clinically Significant Drug Interactions).

Use of benzodiazepines, including lorazepam, may lead to physical and psychological dependence.

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.

Physical and Psychological Dependence

The use of benzodiazepines, including lorazepam, may lead to physical and psychological dependence. The risk of dependence increases with higher doses and longer term use and is further increased in patients with a history of alcoholism or drug abuse or in patients with significant personality disorders. The dependence potential is reduced when lorazepam is used at the appropriate dose for short-term treatment. Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving lorazepam or other psychotropic agents.

In general, benzodiazepines should be prescribed for short periods only (e.g., 2 to 4 weeks). Extension of the treatment period should not take place without reevaluation of the need for continued therapy. Continuous long-term use of product is not recommended. Withdrawal symptoms (e.g., rebound insomnia) can appear following cessation of recommended doses after as little as one week of therapy. Abrupt discontinuation of product should be avoided and a gradual dosage-tapering schedule followed after extended therapy.

Abrupt termination of treatment may be accompanied by withdrawal symptoms. Symptoms reported following discontinuation of benzodiazepines include headache, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, rebound phenomena, dysphoria, dizziness, derealization, depersonalization, hyperacusis, numbness/tingling of extremities, hypersensitivity to light, noise, and physical contact/perceptual changes, involuntary movements, nausea, vomiting, diarrhea, loss of appetite, hallucinations/delirium, convulsions/seizures, tremor, abdominal cramps, myalgia, agitation, palpitations, tachycardia, panic attacks, vertigo, hyperreflexia, short-term memory loss, and hyperthermia. Convulsions/seizures may be more common in patients with preexisting seizure disorders or who are taking other drugs that lower the convulsive threshold such as antidepressants.

There is evidence that tolerance develops to the sedative effects of benzodiazepines.

Lorazepam may have abuse potential, especially in patients with a history of drug and/or alcohol abuse.

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 one 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 per day). The effect was reversible only when the treatment was withdrawn within two 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; 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 Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 central nervous system 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 should be consulted prior to use.

Lorazepam is 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 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.

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

0.5 mg: white, scored, round flat faced beveled edge, debossed with 240 over 0.5 on one side and WATSON on the other side, supplied in unit dose packages of 100 (10 x 10) NDC 60687-401-01.

1 mg: white, scored, round flat faced beveled edge, debossed with 241 over 1 on one side and WATSON on the other side, supplied in unit dose packages of 100 (10 x 10) NDC 60687-355-01.

2 mg: white, scored, round flat faced beveled edge, debossed with 242 over 2 on one side and WATSON on the other side, supplied in unit dose packages of 100 (10 x 10) NDC 60687-367-01.

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

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Actavis Pharma, Inc. as follows:

(0.5 mg / 100 UD) NDC 60687-401-01 packaged from NDC 0591-0240

(1 mg / 100 UD) NDC 60687-355-01 packaged from NDC 0591-0241

(2 mg / 100 UD) NDC 60687-367-01 packaged from NDC 0591-0242

Distributed by:

American Health Packaging

Columbus, OH 43217

8435501/0718

8435501/0718

Lorazepam

(lor azʹ e pam)

Tablets, USP C-IV

What is the most important information I should know about lorazepam tablets?

• Lorazepam is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death.
• Lorazepam tablets can make you sleepy or dizzy, and can slow your thinking and motor skills.
  • Do not drive, operate heavy machinery, or do other dangerous activities until you know how lorazepam tablets affect you.
  • Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking lorazepam tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, lorazepam tablets may make your sleepiness or dizziness much worse.
• Do not take more lorazepam tablets than prescribed.

What are lorazepam tablets?

• Lorazepam tablets are a prescription medicine used:
  • to treat anxiety disorders
  • for the short-term relief of the symptoms of anxiety or anxiety that can happen with symptoms of depression
• Lorazepam tablets are a federal controlled substance (C-IV) because they can be abused or lead to dependence. Keep lorazepam tablets in a safe place to prevent misuse and abuse. Selling or giving away lorazepam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs.
• It is not known if lorazepam tablets are safe and effective in children less than 12 years of age.
• It is not known if lorazepam tablets are safe and effective for use for longer than 4 months.

Do not take lorazepam tablets if you:

• are allergic to lorazepam, other benzodiazepines, or any of the ingredients in lorazepam tablets. See the end of this Medication Guide for a complete list of ingredients in lorazepam tablets.

Before you take lorazepam tablets, tell your healthcare provider about all of your medical conditions, including if you:

• have or have had depression, mood problems, or suicidal thoughts or behavior
• have a history of drug or alcohol abuse or addiction
• have lung disease or breathing problems (such as COPD, sleep apnea syndrome)
• have liver or kidney problems
• have or have had seizures
• are pregnant or plan to become pregnant. Lorazepam tablets may harm your unborn baby. You and your healthcare provider should decide if you should take lorazepam tablets while you are pregnant.
• are breastfeeding or plan to breastfeed. Lorazepam passes into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take lorazepam tablets. You should not breastfeed while taking lorazepam tablets.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Taking lorazepam tablets with certain other medicines can cause side effects or affect how well lorazepam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.

How should I take lorazepam tablets?

• Take lorazepam tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how many lorazepam tablets to take and when to take it.
• If you take too many lorazepam tablets, call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid while taking lorazepam tablets?

• Lorazepam tablets can cause you to be drowsy. Do not drive a car or operate heavy machinery until you know how lorazepam tablets affect you.
• You should not drink alcohol while taking lorazepam tablets. Drinking alcohol can increase your chances of having serious side effects.

What are the possible side effects of lorazepam tablets?

Lorazepam tablets may cause serious side effects, including:

• See “What is the most important information I should know about lorazepam tablets?”
• Depression. Pre-existing depression may emerge or worsen during use of benzodiazepines including lorazepam tablets.
• Abuse and dependence. Taking lorazepam tablets can cause physical and psychological dependence. Physical and psychological dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical and psychological dependence and drug addiction.
• Withdrawal symptoms. You may have withdrawal symptoms if you stop taking lorazepam tablets suddenly. Withdrawal symptoms can be serious and include seizures. Mild withdrawal symptoms include a depressed mood and trouble sleeping. Talk to your healthcare provider about slowly stopping lorazepam tablets to avoid withdrawal symptoms.

The most common side effects of lorazepam tablets include:

• sedation
• weakness
• dizziness
• unsteadiness

These are not all the possible side effects of lorazepam tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store lorazepam tablets?

• Store lorazepam tablets in a tightly closed container at 68° to 77°F (20° to 25°C).
• Keep lorazepam tablets and all medicines out of the reach of children.

General information about the safe and effective use of lorazepam tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use lorazepam tablets for a condition for which it was not prescribed. Do not give lorazepam tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about lorazepam tablets that is written for health professionals.

What are the ingredients in lorazepam tablets?

Active ingredient: lorazepam, USP

Inactive ingredients: lactose, magnesium stearate, microcrystalline cellulose and polacrilin potassium

Distributed by:

American Health Packaging

Columbus, OH 43217

8435501/0718

This Medication Guide has been approved by the U.S. Food and Drug Administration.

NDC 60687- 401-01

Lorazepam

Tablets, USP    CIV

0.5 mg

100 Tablets (10 x 10)               Rx Only

PHARMACIST: Dispense with the accompanying Medication

Guide to each patient.

Each Tablet Contains:

Lorazepam, USP......................................................................0.5 mg

Usual Dosage: See package insert for full prescribing information.

Store at 20° to 25°C (68° to 77°F); excursions permitted between

15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

The drug product contained in this package is from

NDC # 0591-0240, Actavis Pharma, Inc.

Packaged and Distributed by:

American Health Packaging

Columbus, Ohio 43217

740101

0440101/1118

Lorazepam

Tablet, USP    CIV

0.5 mg

NDC 60687- 355-01

Lorazepam

Tablets, USP     CIV

1 mg

100 Tablets (10 x 10)               Rx Only

PHARMACIST: Dispense with the accompanying Medication

Guide to each patient.

Each Tablet Contains:

Lorazepam, USP......................................................................... 1 mg

Usual Dosage: See package insert for full prescribing information.

Store at 20° to 25°C (68° to 77°F); excursions permitted between

15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

The drug product contained in this package is from

NDC # 0591-0241, Actavis Pharma, Inc.

Packaged and Distributed by:

American Health Packaging

Columbus, Ohio 43217

735501

0435501/0419

Lorazepam

Tablet, USP   CIV

1 mg

NDC 60687- 367-01

Lorazepam

Tablets, USP    CIV

2 mg

100 Tablets (10 x 10)               Rx Only

PHARMACIST: Dispense with the accompanying Medication

Guide to each patient.

Each Tablet Contains:

Lorazepam, USP......................................................................... 2 mg

Usual Dosage: See package insert for full prescribing information.

Store at 20° to 25°C (68° to 77°F); excursions permitted between

15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

The drug product contained in this package is from

NDC # 0591-0242, Actavis Pharma, Inc.

Packaged and Distributed by:

American Health Packaging

Columbus, Ohio 43217

736701

0436701/0419

Lorazepam

Tablet, USP   CIV

2 mg