LOREEV XR

Warnings and Precautions ( 5.8 ) 1/2023

1 INDICATIONS AND USAGE LOREEV XR is indicated for the treatment of anxiety disorders in adults who are receiving stable, evenly divided, three times daily dosing with lorazepam tablets. LOREEV XR is a benzodiazepine indicated for the treatment of anxiety disorders in adults who are receiving stable, evenly divided, three times daily dosing with lorazepam tablets ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended dosage of LOREEV XR is equal to the total daily dose of lorazepam tablets (at the previous three times daily dosage) ( 2.1 ) Administer LOREEV XR orally once daily in the morning ( 2.2 ) Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce. Do not crush or chew ( 2.2 ) For dosage adjustments, discontinue LOREEV XR and switch to lorazepam tablets to adjust dosage ( 2.3 ) 2.1 Recommended Dosage Initiate LOREEV XR in patients who are being treated with lorazepam tablets, administered three times daily in evenly divided doses (refer to the Prescribing Information of lorazepam tablets for the recommended dosage of lorazepam tablets). Discontinue lorazepam tablets and administer the first dose of LOREEV XR in the morning the day after the final dose of lorazepam tablets. The recommended once daily dosage of LOREEV XR is equal to the total daily dose of lorazepam tablets. For example, the recommended dosage for patients who have been receiving lorazepam tablets at a dosage of 1 mg three times daily is LOREEV XR 3 mg once daily in the morning. The effectiveness of LOREEV XR use for more than 4 months has not been assessed in clinical studies. Healthcare providers should periodically re-evaluate longer term use of LOREEV XR. 2.2 Administration Information Administer LOREEV XR orally once daily, in the morning, with or without food. Do not crush or chew LOREEV XR. Swallow LOREEV XR capsules whole or open the capsule and sprinkle the entire contents over a tablespoon of applesauce, followed by drinking water. Consume all the sprinkled LOREEV XR in its entirety, (without chewing) within 2 hours; do not store for future use. 2.3 Dosage Increase for Inadequate Clinical Response If the clinical response to LOREEV XR is inadequate and a dosage increase in needed, discontinue LOREEV XR and switch to lorazepam tablets to increase the dosage. If an adequate clinical response is achieved with a stable, evenly divided three times daily dosage of lorazepam tablets, resume LOREEV XR once daily dosing with the total daily dose of lorazepam tablets [see Dosage and Administration ( 2.1 )] . 2.4 Discontinuation or Dosage Reduction of LOREEV XR To reduce the risk of withdrawal reactions, use a gradual taper to discontinue LOREEV XR 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 and Precautions ( 5.3 ), Drug Abuse and Dependence ( 9.3 )] . 2.5 Concomitant Use with UDP-glucuronosyltransferase (UGT) Inhibitors If an UGT inhibitor is initiated during treatment with LOREEV XR, discontinue LOREEV XR and switch to lorazepam tablets to reduce the dosage [see Dosage and Administration ( 2.4 ), Drug Interactions ( 7 )] .

3 DOSAGE FORMS AND STRENGTHS LOREEV XR (lorazepam) extended-release capsules are available as: 1 mg: Hard gelatin capsules with an opaque white body, yellow cap and grey printing ink; "ALM" is printed axially on the yellow cap and "658" is printed axially on the opaque white body 1.5 mg: Hard gelatin capsules with an opaque white body, purple cap and black printing ink; "ALM" is printed axially on the purple cap and "661" is printed axially on the opaque white body 2 mg: Hard gelatin capsules with an opaque white body, orange cap and grey printing ink; "ALM" is printed axially on the orange cap and "663" is printed axially on the opaque white body 3 mg: Hard gelatin capsules with an opaque white body, yellowish-green cap and grey printing ink; "ALM" is printed axially on the yellowish-green cap and "667" is printed axially on the opaque white body Extended-release capsules: 1 mg, 1.5 mg, 2 mg, and 3 mg ( 3 )

4 CONTRAINDICATIONS LOREEV XR is contraindicated in patients with: hypersensitivity to benzodiazepines or to any of the ingredients in LOREEV XR [see Warnings and Precautions ( 5.7 )] . acute narrow-angle glaucoma Hypersensitivity to benzodiazepines or any ingredients in LOREEV XR ( 4 ) Acute narrow-angle glaucoma ( 4 )

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.

7 DRUG INTERACTIONS Table 1 presents clinically significant interactions with LOREEV XR. Use with Opioids: Increase the risk of respiratory depression ( 7 ) CNS depressants: Additive CNS depressant effects (7) Alcohol: Avoid use. Increases the release rate of LOREEV XR (7) UGT Inhibitors: Avoid initiation of UGT inhibitors. Dose reduction requires switching to lorazepam tablets for dose adjustment (7) Table 1: Clinically Significant Drug Interactions with LOREEV XR. Opioids Clinical Impact 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 gamma-aminobutyric acid (GABA A ) 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 [see Warnings and Precautions ( 5.1 )] . Intervention Limit dosage and duration of concomitant use of LOREEV XR and opioids, and monitor patients closely for respiratory depression and sedation. Alcohol Clinical Impact Based on an in vitro study, alcohol increases the release rate of LOREEV XR [see Clinical Pharmacology ( 12.3 )] . Intervention Avoid concomitant use of alcohol during treatment with LOREEV XR [see Warnings and Precautions ( 5.4 )] . CNS-Depressants Clinical Impact Benzodiazepines, including LOREEV XR, increase CNS-depressant effects when administered with other CNS depressants. Concomitant use of clozapine and LOREEV XR may produce marked sedation, excessive salivation, hypotension, ataxia, delirium, and respiratory arrest. Intervention Avoid co-administration of alcohol with LOREEV XR. Use caution if LOREEV XR is co-administered with other CNS-depressants [see Warnings and Precautions (5.4)] . Inhibitors of UGT Clinical Impact Concomitant use of LOREEV XR with UGT inhibitors may increase lorazepam exposure [see Clinical Pharmacology (12.3)] , which may increase the risk of adverse reactions. Intervention Avoid initiating an UGT inhibitor during treatment with LOREEV XR. If an UGT inhibitor is initiated, discontinue LOREEV XR and switch to lorazepam tablets [see Dosage and Administration ( 2.5 )] .

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LOREEV XR during pregnancy. Health care providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or by visiting online at https://womensmentalhealth.org/pregnancyregistry. Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions ( 5.8 ), Clinical Considerations] . Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data) . In animal studies, administration of lorazepam during the organogenesis period of pregnancy resulted in increased incidences of fetal malformations at doses greater than those used clinically. Data for benzodiazepines suggest the possibility of increased neuronal cell death and long-term effects on neurobehavioral function based on findings in animals following prenatal or early postnatal exposure at clinically relevant doses (see Data) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates. Monitor neonates exposed to LOREEV XR during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to LOREEV XR during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions ( 5.8 )] . Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings. Animal Data Reproductive studies in animals were performed in mice, rats, and two strains of rabbits. A low incidence of malformations (reduction of tarsals, tibia, metatarsals, mal-rotated limbs, gastroschisis, malformed skull, and microphthalmia) were seen in drug-treated rabbits without relationship to dosage. Although all of these anomalies were not present in the concurrent control group, they have been reported to occur randomly in historical controls. At doses of 40 mg/kg and higher there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen at lower doses. In published animal studies, administration of benzodiazepines or other drugs that enhance GABAergic inhibition to neonatal rats has been reported to result in widespread apoptotic neurodegeneration in the developing brain. The window of vulnerability to these changes in rats (postnatal days 0-14) includes a period of brain development that takes place during the third trimester of pregnancy in humans. 8.2 Lactation Risk Summary Lorazepam is present in breastmilk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. The effects of lorazepam on milk production are unknown. Because of the …

12.1 Mechanism of Action Lorazepam exerts its effect for the treatment of anxiety disorders through binding to the benzodiazepine site of the gamma-aminobutyric acid-A (GABA A ) receptors in the brain and enhances GABA-mediated synaptic inhibition.

11 DESCRIPTION LOREEV XR contains lorazepam, a benzodiazepine. Lorazepam is a nearly white crystalline powder and is practically insoluble in water and slightly soluble in alcohol. It is a 1:1 mixture of (R) and (S) isomers. The chemical name is ±-7-chloro-5-( o -chlorophenyl)-1,3-dihydro-3-hydroxy-2 H -1,4-benzodiazepin-2-one and its structural formula is: Molecular formula: C 15 H 10 Cl 2 N 2 O 2 ; Molecular weight: 321.16 LOREEV XR is intended for oral administration. Each capsule contains 1 mg, 1.5 mg, 2 mg, or 3 mg of lorazepam. The inactive ingredients are colloidal silicon dioxide, corn starch, gelatin, glyceryl monostearate, hypromellose, lactose monohydrate, methyl acrylate methyl methacrylate and methacrylic acid (7:3:1) copolymer 280000 dispersion, microcrystalline cellulose, polysorbate 80, talc, titanium dioxide, and triethyl citrate. Additionally, the capsule shells contain the following colorants: 1 mg capsules: FD&C Yellow No. 5 1.5 mg capsules: FD&C Blue No. 1 and FD&C Red No. 3 2 mg capsules: D&C Yellow No. 10 and FD&C Red No. 3 3 mg capsules: D&C Yellow No. 10, FD&C Blue No. 1, FD&C Yellow No. 6

10 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 and Precautions ( 5.2 )] . 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 lifethreatening 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 medical toxicologist for additional overdosage management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING LOREEV XR (lorazepam) extended-release capsules are available as: 1 mg: Hard gelatin capsules with an opaque white body, yellow cap and grey printing ink; "ALM" is printed axially on the yellow cap and "658" is printed axially on the opaque white body. NDC 52427-658-30, bottle of 30 capsules with child-resistant closure NDC 52427-658-01, bottle of 100 capsules with child-resistant closure 1.5 mg: Hard gelatin capsules with an opaque white body, purple cap and black printing ink; "ALM" is printed axially on the purple cap and "661" is printed axially on the opaque white body. NDC 52427-661-30, bottle of 30 capsules with child-resistant closure NDC 52427-661-01, bottle of 100 capsules with child-resistant closure 2 mg: Hard gelatin capsules with an opaque white body, orange cap and grey printing ink; "ALM" is printed axially on the orange cap and "663" is printed axially on the opaque white body. NDC 52427-663-30, bottle of 30 capsules with child-resistant closure NDC 52427-663-01, bottle of 100 capsules with child-resistant closure 3 mg: Hard gelatin capsules with an opaque white body, yellowish-green cap and grey printing ink; "ALM" is printed axially on the yellowish-green cap and "667" is printed axially on the opaque white body. NDC 52427-667-30, bottle of 30 capsules with child-resistant closure NDC 52427-667-01, bottle of 100 capsules with child-resistant closure Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep bottles tightly closed. Dispense in a tight container.