Lorazepam

ADVERSE REACTIONS 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 3,500 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 Chartwell RX, LLC. at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

CONTRAINDICATIONS Lorazepam is contraindicated in patients with: • hypersensitivity to benzodiazepines or to any components of the formulation. • acute narrow-angle glaucoma.

DESCRIPTION Lorazepam, an antianxiety agent, has the chemical formula, 2 H -1,4-benzodiazepin-2-one, 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-, (±)-: C 15 H 10 Cl 2 N 2 O 2 MW: 321.16 Lorazepam, USP is a white or a practically white powder almost insoluble in water. Each mL of Lorazepam for oral administration contains 2 mg of lorazepam. The inactive ingredients present are polyethylene glycol and propylene glycol. image description

DOSAGE AND ADMINISTRATION

INDICATIONS AND USAGE 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.

WARNINGS

DRUG ABUSE AND DEPENDENCE

OVERDOSAGE 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 WARNINGS: Abuse, Misuse, and Addiction ). 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 Information. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

CLINICAL PHARMACOLOGY 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 two 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 mg 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.

20230901

2

Lorazepam Lorazepam PROPYLENE GLYCOL POLYETHYLENE GLYCOL, UNSPECIFIED LORAZEPAM LORAZEPAM

ANDA079244

Lorazepam

Lorazepam

62135-549

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Lorazepam Oral Concentrate, USP (CIV) 2 mg/mL - NDC 62135-549-43 - 30 mL - Bottle Label image description

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 ).

Medication Guide Lorazepam Oral Concentrate, USP, CIV (lor A ze pam) What is the most important information I should know about lorazepam? 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. Get emergency help right away if any of the following happens: shallow or slowed breathing breathing stops (which may lead to the heart stopping) excessive sleepiness (sedation) Do not drive or operate heavy machinery until you know how taking lorazepam with opioids affects you. Risk of abuse, misuse, and addiction. There is a risk of abuse, misuse, and addiction with benzodiazepines including lorazepam which can lead to overdose and serious side effects including coma and death. Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including lorazepam. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. You can develop an addiction even if you take lorazepam exactly as prescribed by your healthcare provider. Take lorazepam exactly as your healthcare provider prescribed. Do not share your lorazepam with other people. Keep lorazepam in a safe place and away from children. Physical dependence and withdrawal reactions. Lorazepam can cause physical dependence and withdrawal reactions. Do not suddenly stop taking lorazepam. Stopping lorazepam suddenly can cause serious and life-threatening side effects, including, unusual movements, responses or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months, including anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. Do not take more lorazepam than prescribed or take lorazepam for longer than prescribed. What is lorazepam? Lorazepam is 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 is a federal controlled substance (C-IV) because it can be abused or lead to dependence. Keep lorazepam in a safe place to prevent misuse and abuse. Selling or giving away lorazepam 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 is safe and effective for use in children less than 12 years of age. It is not known if lorazepam is safe and effective for use for longer than 4 months. Do not take lorazepam if you: are allergic to lorazepam, other benzodiazepines, or any of the ingredients in Lorazepam Oral Concentrate. See the end of this Medication Guide for a complete list of ingredients in Lorazepam Oral Concentrate. Before you take lorazepam, tell your healthcare provider about all 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. Taking lorazepam late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems). Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with lorazepam. There is a pregnancy registry for women who take lorazepam during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with lorazepam, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/pregnancyregistry/. are breastfeeding or plan to breastfeed. Lorazepam passes into your breast milk. Breastfeeding during treatment of lorazepam may cause your baby to have sleepiness, feeding problems, and decreased weight gain. Talk to your healthcare provider about the best way to feed your baby if you take lorazepam. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking lorazepam with certain other medicines can cause side effects or affect how well lorazepam or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider. How should I take lorazepam? Take lorazepam exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much lorazepam to take and when to take it. If you take too much lorazepam, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of lorazepam? Lorazepam may cause serious side effects, including: See “What is the most important information I should know about lorazepam?” Lorazepam 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 affects you. Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking lorazepam without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, lorazepam may make your sleepiness or dizziness much worse. Depression. Pre-existing depression may emerge or worsen during use of benzodiazepines including lorazepam. The most common side effects of lorazepam include: • sedation • weakness • dizziness • unsteadiness These are not all the possible side effects of lorazepam. 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? Store lorazepam at a cold temperature. Refrigerate at 2°C to 8°C (36°F to 46°F) and protect from light. Keep lorazepam and all medicines out of the reach of children. General information about the safe and effective use of lorazepam. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use lorazepam for a condition for which it was not prescribed. Do not give lorazepam 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 that is written for health professionals. What are the ingredients in Lorazepam Oral Concentrate? Active ingredient: lorazepam Inactive ingredients: polyethylene glycol and propylene glycol. For information, please call 1-845-232-1683. Manufactured for: Chartwell RX, LLC. Congers, NY 10920 L71401 Revised April 2023 This Medication Guide has been approved by the U.S. Food and Drug Administration

HOW SUPPLIED Lorazepam Oral Concentrate, USP The 2 mg per mL oral concentrate is supplied as a clear colorless to light yellow solution. NDC 62135-549-43: Bottle of 30 mL PROTECT FROM LIGHT Store at cold temperature. Refrigerate at 2° to 8°C (36° to 46°F) [See USP Controlled Cold Temperature]. Dispense from this bottle. Discard opened bottle after 90 days . Manufactured for: Chartwell RX, LLC. Congers, NY 10920 L71400 Revised 04/2023-01 Print Medication Guide at www.chartwellpharma.com/medguides

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation (see WARNINGS and PRECAUTIONS ). The use of benzodiazepines, including lorazepam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing lorazepam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (see WARNINGS ). The continued use of benzodiazepines, including lorazepam, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of lorazepam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue lorazepam or reduce the dosage ( DOSAGE AND ADMINISTRATION and WARNINGS ).

PRECAUTIONS 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.