Loreev Xr

(Lorazepam)

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Loreev Xr Prescribing Information

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 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 ]

), Drug Interactions (

7 DRUG INTERACTIONS

Table 1 presents clinically significant interactions with LOREEV XR.

Use with Opioids: Increase the risk of respiratory depression
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 ] .
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 ] .
Intervention	Avoid concomitant use of alcohol during treatment with LOREEV XR [see Warnings and Precautions ] .
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 ] .

)].

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 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 ]
.
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.
)].
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 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 , Drug Abuse and Dependence ]
.
), Warnings and Precautions (
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 ]
.
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 ]
.
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 ]
.
)].

Warnings and Precautions (

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 ]

. 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.

)

1/2023

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

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 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 ]
.
)]
.
acute narrow-angle glaucoma

The following serious adverse reactions are described elsewhere in the labeling:

Risks from Concomitant Use with Opioids
[see Warnings and Precautions (
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 ]
.
)]
Abuse, Misuse, and Addiction
[see Warnings and Precautions (
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 ]
.
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.
)]
Dependence and Withdrawal Reactions
[see Warnings and Precautions (
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 ]
.
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 ]
.
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 ]
.
)]
Central Nervous System (CNS) Depression
[see Warnings and Precautions (
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 ]
.
)]
Patients with Depression or Psychosis
[see Warnings and Precautions (
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.
)]
Allergic Reactions to FD&C Yellow No. 5 (Tartrazine)
[see Warnings and Precautions (
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 ]
.
)]
Neonatal Sedation and Withdrawal Syndrome
[see Warnings and Precautions (
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 ]
. 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.
)]
Risk in Patients with Impaired Respiratory Function
[see Warnings and Precautions (
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.
)]

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.

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Loreev Xr Prescribing Information

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