Lorazepam

INDICATIONS AND USAGE Lorazepam tablets USP 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 tablets USP 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.

DOSAGE AND ADMINISTRATION 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 ).

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

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 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, anaphylacticoid 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. CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA at 1-800-FDA-1088 or www.fda.gov/medwatch OR LEADING PHARMA, LLC AT 1-844-740-7500.

Clinically Significant Drug Interactions The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation. The benzodiazepines, including Lorazepam, produce increased CNS-depressant effects when administered with other CNS depressants such as alcohol, barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anesthetics. Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, hypotension, ataxia, delirium, and respiratory arrest. Concurrent administration of lorazepam with valproate results in increased plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage should be reduced to approximately 50% when coadministered with valproate. Concurrent administration of lorazepam with probenecid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid. The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation. Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam.

DESCRIPTION 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 white or practically white, crystalline powder, practically insoluble in water, sparingly soluble in Ethanol (96%), slightly soluble in Chloroform and Ether, sparingly or slightly soluble in Dichloromethane. Soluble in Acetone and glacial Acetic acid. 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 lactose monohydrate, magnesium stearate, microcrystalline cellulose, and polacrilin potassium. 1

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.

HOW SUPPLIED Lorazepam tablets USP are available in the following dosage strengths: 0.5 mg, white to off-white, round, flat-faced beveled edge tablets debossed with “U32” on one side and plain on other side. Bottles of 10 NDC 13107-083-11 Bottles of 100 NDC 13107-083-01 Bottles of 500 NDC 13107-083-05 Bottles of 1000 NDC 13107-083-99 1 mg, white to off-white, round, flat-faced beveled edge tablets debossed with “U33” on one side and bisect on other side. Bottles of 10 NDC 13107-084-11 Bottles of 100 NDC 13107-084-01 Bottles of 500 NDC 13107-084-05 Bottles of 1000 NDC 13107-084-99 2 mg, white to off-white, round flat-faced beveled edge tablets debossed with a bisect separating “U” and “34” on one side and “2” on the other side. Bottles of 10 NDC 13107-085-11 Bottles of 100 NDC 13107-085-01 Bottles of 500 NDC 13107-085-05 Bottles of 1000 NDC 13107-085-99 DISPENSE IN A TIGHT, LIGHT-RESISTANT CONTAINER AS DESCRIBED IN THE USP. STORE AT 20°C to 25°C (68°to 77°F). [SEE USP CONTROLLED ROOM TEMPERATURE.] Manufactured by: Aurolife Pharma LLC Dayton, NJ 08810 Manufactured for: Aurobindo Pharma USA, Inc. Dayton, NJ 08810 Revised:11/2017 MEDICATION GUIDE LORAZEPAM Tablets, USP CIV 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. LORAZEPAM can make you sleepy or dizzy, and can slow your thinking and motor skills. o Do not drive, operate heavy machinery, or do other dangerous activities until you know how LORAZEPAM affects you. o 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. Do not take more LORAZEPAM than prescribed. What is LORAZEPAM? LORAZEPAM is a prescription medicine used: o to treat anxiety disorders o 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 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. See the end of this Medication Guide for a complete list of ingredients in LORAZEPAM. Before you take LORAZEPAM, 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 may harm your unborn baby. You and your healthcare provider should decide if you should take LORAZEPAM 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. You should not breastfeed while taking 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 affe …