Loreev XR (lorazepam): FDA label

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Indications

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 )

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 )

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 )

5.1Risks 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.

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 )] .

Pregnancy and breastfeeding

8.1Pregnancy 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.

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.

Loreev XR

Indications

Contraindications

Warnings and precautions

5.1Risks from Concomitant Use with Opioids

Two medicines in one question?

5.2Abuse, Misuse, and Addiction

5.3Dependence and Withdrawal Reactions

5.4Central Nervous System (CNS) Depression

5.5Patients with Depression or Psychosis

5.6Risk of Paradoxical Reactions

5.7Allergic Reactions to FD&C Yellow No. 5 (Tartrazine)

5.8Neonatal Sedation and Withdrawal Syndrome Use of

5.9Risk in Patients with Impaired Respiratory Function

5.10Laboratory Tests Leukopenia

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Pregnancy Exposure Registry

Adverse reactions

Composition

Strengths and forms

Official product information

At a glance

Guidelines