LOREEV XR

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 ( 5.1 ), Drug Interactions ( 7 )]. The use of benzodiazepines, including LOREEV XR, 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 LOREEV XR and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction [see Warnings and Precautions ( 5.2 )]. The continued use of benzodiazepines, including LOREEV XR, 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 LOREEV XR 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 LOREEV XR or reduce the dosage [see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.3 )]. WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS See full prescribing information for complete boxed warning. Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in 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 ( 5.1 , 7 ) The use of benzodiazepines, including LOREEV XR, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing LOREEV XR and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction ( 5.2 ) Abrupt discontinuation or rapid dosage reduction of LOREEV XR 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 LOREEV XR or reduce the dosage ( 2.4 , 5.3 )

5 WARNINGS AND PRECAUTIONS CNS Depression: May cause CNS depression. Caution patients receiving LOREEV XR against operating machinery or driving a motor vehicle as well to avoid the concomitant use of alcohol and other CNS depressant drugs during treatment ( 5.4 , 7 ) Patients with Depression or Psychosis: Use with caution in patients with signs or symptoms of depression. Prescribe the least number of capsules feasible to avoid intentional overdosage ( 5.5 ) Allergic Reactions to FD&C Yellow No. 5 (Tartrazine): Contains FD&C Yellow No. 5 (tartrazine) which may cause allergic type reactions (including bronchial asthma) in certain susceptible persons ( 5.7 ) Neonatal Sedation and Withdrawal Syndrome: LOREEV XR use during pregnancy can result in neonatal sedation and/or withdrawal ( 5.8 , 8.1 ) 5.1 Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including LOREEV XR, 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 LOREEV XR 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 LOREEV XR than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking LOREEV XR, 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 LOREEV XR 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 Drug Interactions ( 7 )] . 5.2 Abuse, Misuse, and Addiction The use of benzodiazepines, including LOREEV XR, 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 ( 9.2 )] . Before prescribing LOREEV XR and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of LOREEV XR, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of LOREEV XR 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. 5.3 Dependence and Withdrawal Reactions To reduce the risk of withdrawal reactions, use a gradual taper to discontinue LOREEV XR or reduce the dosage (a patient-specific plan should be used to taper the dose) [see Dosage and Administration ( 2.4 )] . 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 LOREEV XR, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of LOREEV XR 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 ( 9.3 )] . 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 ( 9.3 )] . 5.4 Central Nervous System (CNS) Depression Benzodiazepines, including LOREEV XR, may produce CNS depression. Caution patients receiving LOREEV XR against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. Use of benzodiazepines, including LOREEV XR, both used alone and in combination with other CNS depressants, may lead to potentially fatal respiratory depression. Alcohol should be avoided and other CNS depressant drugs used with caution during treatment with LOREEV XR [see Drug Interactions ( 7 )] . 5.5 Patients with Depression or Psychosis LOREEV XR is not recommended for use in patients with a primary depressive disorder or psychosis. Pre-existing depression may emerge or worsen during use of benzodiazepines, including LOREEV XR. In patients with depression, a possibility for suicide should be borne in mind. Consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered in patients with depression. LOREEV XR should not be used in such patients without adequate antidepressant therapy. 5.6 Risk of Paradoxical Reactions Paradoxical reactions (agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) have been reported during benzodiazepine use [see Adverse Reactions ( 6 )] . Such reactions may be more likely to occur in the elderly [see Adverse Reactions ( 8.5 )] . Discontinue LOREEV XR if the patient experiences these reactions. 5.7 Allergic Reactions to FD&C Yellow No. 5 (Tartrazine) LOREEV XR 1 mg capsules contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity [see Contraindications ( 4 )] . 5.8 Neonatal Sedation and Withdrawal Syndrome Use of LOREEV XR 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 Use in Specific Populations ( 8.1 )] . Monitor neonates exposed to LOREEV XR during pregnancy or labor for signs of sedation and monitor neonates exposed to LOREEV XR during pregnancy for signs of withdrawal; manage these neonates accordingly. 5.9 Risk in Patients with Impaired Respiratory Function In patients with impaired respiratory function, respiratory depression and apnea have been reported with benzodiazepines. Closely monitor patients with impaired respiratory function. If signs and symptoms of respiratory depression or apnea occur, consider discontinuing LOREEV XR. 5.10 Laboratory Tests Leukopenia and elevations of LDH have developed in patients receiving lorazepam tablets [see Adverse Reactions ( 6 )] . Periodic blood counts and liver function tests are recommended for patients on long-term therapy.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Risks from Concomitant Use with Opioids [see Warnings and Precautions ( 5.1 )] Abuse, Misuse, and Addiction [see Warnings and Precautions ( 5.2 )] Dependence and Withdrawal Reactions [see Warnings and Precautions ( 5.3 )] Central Nervous System (CNS) Depression [see Warnings and Precautions ( 5.4 )] Patients with Depression or Psychosis [see Warnings and Precautions ( 5.5 )] Allergic Reactions to FD&C Yellow No. 5 (Tartrazine) [see Warnings and Precautions ( 5.7 )] Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions ( 5.8 )] Risk in Patients with Impaired Respiratory Function [see Warnings and Precautions ( 5.9 )] The safety of LOREEV XR in adults is based on studies with lorazepam tablets. The following adverse reactions associated with the use of lorazepam tablets were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In a sample of approximately 3,500 patients treated for anxiety, the most frequent adverse reactions to lorazepam tablets were sedation (15.9%), dizziness (6.9%), weakness (4.2%), and unsteadiness (3.4%). The incidence of sedation and unsteadiness increased with age. The following reported adverse reactions are categorized by System Organ Class (SOC): Blood and Lymphatic System Disorders: agranulocytosis, leukopenia, pancytopenia, thrombocytopenia Endocrine Disorders: syndrome of inappropriate antidiuretic hormone (SIADH) Eye Disorder: eye function/visual disturbance (including diplopia and blurred vision) Gastrointestinal Disorder: constipation, gastrointestinal symptoms including nausea General Disorders and Administration Site Conditions: asthenia, fatigue, hypothermia Hepatobiliary Disorders: jaundice Immune System Disorders: anaphylactoid reactions, hypersensitivity reactions Investigations: increase in bilirubin, increase in liver transaminases (including elevated LDH), increase in alkaline phosphatase Metabolism and Nutrition Disorders: change in appetite, hyponatremia Nervous System Disorders: ataxia, autonomic manifestations, coma, convulsions/seizures, drowsiness, dysarthria/slurred speech, extrapyramidal symptoms, headache, tremor, vertigo, memory impairment Psychiatric Disorders: amnesia, change in libido, confusion, decreased orgasm, depression, disinhibition, disorientation, euphoria, suicidal ideation/attempt, unmasking of depression Reproductive System and Breast Disorders: impotence Respiratory Thoracic and Mediastinal Disorders: apnea, respiratory depression, worsening of obstructive pulmonary disease, worsening of sleep apnea Skin and Subcutaneous Tissue Disorder: allergic skin reactions, alopecia, dermatological symptoms 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 have been reported with immediate-release lorazepam. Many adverse reactions to benzodiazepines, including CNS effects and respiratory depression, are dose dependent, with more severe effects occurring with high doses. Most frequent adverse reactions: sedation, dizziness, weakness, unsteadiness ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Almatica Pharma LLC at 1-877-447-7979 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.