Loreev XR

Drug Description

What is Loreev XR and how is it used?

Loreev XR is a prescription medicine used to treat the symptoms of Anxiety Disorders, Preoperative Sedation, Anterograde Amnesia, and Status Epilepticus. Loreev XR may be used alone or with other medications.

Loreev XR belongs to a class of drugs called Antianxiety Agents; Anxiolytics, Benzodiazepines; Anticonvulsants, Benzodiazepine. 

It is not known if Loreev XR is safe and effective in children. 

What are the possible side effects of Loreev XR?

Loreev XR may cause serious side effects including:

• hives, 
• difficulty breathing, 
• swelling of your face, lips, tongue, or throat, 
• severe dizziness, 
• slow or breathing that stops, 
• weak or shallow breathing, 
• difficult to wake up, 
• severe drowsiness, 
• unusual changes in mood or behavior, 
• sudden restless feeling or excitement, 
• thoughts of self-harm, 
• confusion, 
• aggression, 
• hallucination, 
• sleep problems, 
• vision changes, 
• dark urine, and
• yellowing of the skin or eyes (jaundice)

Get medical help right away, if you have any of the symptoms listed above.

The most common side effects of Loreev XR include:

• dizziness, 
• drowsiness,
• weakness, and 
• feeling unsteady 

Tell the doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Loreev XR. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

LOREEV XR
(lorazepam) capsule, extended release

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, DRUG INTERACTIONS].
• 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].
• 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, WARNINGS AND PRECAUTIONS].

 

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-2H-1,4-benzodiazepin-2-one and its structural formula is:

Molecular formula: C₁₅H₁₀Cl₂N₂O₂; - Molecular weight: 321.16

LOREEV XR is intended for oral administration. Each capsule contains 1 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

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

 

Indications & Dosage

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.

 

DOSAGE AND ADMINISTRATION

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.

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.

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 Recommended Dosage].

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].

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 Discontinuation Or Dosage Reduction Of LOREEV XR, DRUG INTERACTIONS].

 

HOW SUPPLIED

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

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

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

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.

Distributed by Almatica Pharma LLC Morristown, NJ 07960 USA Revised: Aug 2021

 

Side Effects

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

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

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.

 

Drug Interactions

Table 1 presents clinically significant interactions with LOREEV XR.

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 ) 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	InterventionAvoid co-administration of alcohol with LOREEV XR. Use caution if LOREEV XR is co-administered with other CNS-depressants [see WARNINGS AND PRECAUTIONS].
Inhibitors of UGT
Clinical Impact	Concomitant use of LOREEV XR with UGT inhibitors may increase lorazepam exposure [see CLINICAL PHARMACOLOGY], 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].

Drug Abuse And Dependence

Controlled Substance

LOREEV XR contains lorazepam, a Schedule IV controlled substance.

Abuse

LOREEV XR is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction.

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. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see WARNINGS AND PRECAUTIONS].

The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.

The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

Dependence

Physical Dependence

LOREEV XR may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see WARNINGS AND PRECAUTIONS].

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue LOREEV XR or reduce the dosage [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].

Acute Withdrawal Signs and Symptoms

Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures and suicidality.

Protracted Withdrawal Syndrome

Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential reemergence or continuation of symptoms for which the benzodiazepine was being used.

Tolerance

Tolerance to LOREEV XR may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of LOREEV XR may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

 

Overdosage & Contraindications

OVERDOSE

Clinical Experience

In postmarketing experience, overdose with lorazepam has occurred predominantly in combination with alcohol and/or other drugs.

Manifestations of benzodiazepine overdose include varying degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion, paradoxical reactions, dysarthria and lethargy. In more serious cases, and especially when other drugs or alcohol were ingested, symptoms may include ataxia, hypotonia, hypotension, cardiovascular depression, respiratory depression, hypnotic state, coma, and death.

Management Of Overdose

General supportive measures should be employed, with consideration that multiple agents may have been taken in combination with lorazepam. Vital signs must be monitored and the patient closely observed. When there is a risk of aspiration, induction of emesis is not recommended. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Administration of activated charcoal may also limit drug absorption. Hypotension, though unlikely, may be controlled with norepinephrine bitartrate injection. Lorazepam is poorly dialyzable. Lorazepam glucuronide, the inactive metabolite, may be highly dialyzable.

Flumazenil, a benzodiazepine antagonist, may be used in hospitalized patients as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including Contraindications, Warnings, and Precautions should be consulted prior to use.

In case of an overdosage, consult a Certified Poison Control Center at 1-800-222-1222 for latest recommendations.

 

CONTRAINDICATIONS

LOREEV XR is contraindicated in patients with:

• hypersensitivity to benzodiazepines or to any of the ingredients in LOREEV XR [see WARNINGS AND PRECAUTIONS].
• acute narrow-angle glaucoma

 

Clinical Pharmacology

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.

Pharmacokinetics

LOREEV XR pharmacokinetics are dose proportional over the dose range of 1 mg to 3 mg. Steady-state plasma concentrations are typically achieved after 5 days of once-daily administration.

At steady-state, the mean area under concentration curve (AUCTau ), the mean peak plasma concentration (Cmax ), and the mean minimum plasma concentration (Cmin ) of lorazepam following LOREEV XR 3 mg once-daily administration was 694 ng*h/mL, 35 ng/mL and 25 ng/mL, respectively. AUCTau, Cmax, and Cmin of lorazepam from lorazepam tablets following 1 mg, three-times daily administration were 765 ng*h/mL, 41 ng/mL and 29 ng/mL, respectively.

Absorption

Following a single 3 mg dose of LOREEV XR under fasted conditions, the median time to attain Cmax (Tmax ) is 14 hours, with a range of 7 to 24 hours.

Effect of Food

Administration of LOREEV XR with a high-fat and high calorie meal did not have a significant effect on exposure of LOREEV XR. However, median Tmax of lorazepam delayed by approximately 2 hours.

LOREEV XR administered under fasted conditions after sprinkling the entire contents onto one-tablespoon (15 mL) of applesauce did not significantly affect exposure and Tmax of lorazepam.

Distribution

Following a single 3 mg dose of LOREEV XR under fasted conditions, the mean apparent volume of distribution is approximately 117 L. At clinically relevant concentrations, lorazepam is approximately 85% bound to plasma proteins.

Elimination

Oral mean plasma clearance (CL/F) is about 72 mL/min in adults following a single 3 mg dose of LOREEV XR and the mean elimination half-life of lorazepam is approximately 20.2 ± 7.2 hours.

Metabolism

Lorazepam is conjugated at its 3-hydroxy group in the liver into lorazepam glucuronide, which has no demonstratable CNS activity in animals.

Excretion

Lorazepam glucuronide is excreted in the urine.

Specific Populations

Geriatric Patients

Studies comparing young and elderly subjects have shown that advancing age does not have a significant effect on the pharmacokinetics of lorazepam tablets. However, a study involving single intravenous doses of 1.5 to 3 mg of lorazepam injection, mean total body clearance of lorazepam decreased by 20% in 15 elderly subjects of 60 to 84 years of age compared to that in 15 younger subjects of 19 to 38 years of age. The clinical significance of the decrease in mean total body clearance of lorazepam injection in geriatric patients is unknown.

Patients With Hepatic Impairment

No pharmacokinetic studies were conducted with LOREEV XR in patients with hepatic impairment.

Patients With Renal Impairment

No pharmacokinetic studies were conducted with LOREEV XR in patients with renal impairment. Lorazepam is poorly dialyzable. Lorazepam glucuronide, the inactive metabolite, may be highly dialyzable.

Drug Interaction Studies

Concurrent administration of lorazepam with valproate, an inhibitor of UGT, results in increased plasma concentrations and reduced clearance of lorazepam [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].

Concurrent administration of lorazepam with probenecid, an inhibitor of UGT, may result in a more rapid onset or prolonged effect of lorazepam due to increased halflife and decreased total clearance [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].

Alcohol

An in vitro study showed significant increases of lorazepam release from LOREEV XR capsules at 2 hours with approximately 91-95% and 37-42% of the drug release in the presence of 40% and 20% alcohol, respectively [see DRUG INTERACTIONS]. Effects of 5% and 10% alcohol on drug release were not significant at 2 hours. There is no in vivo study conducted for the effect of alcohol on drug exposure.

Animal Toxicology And/Or Pharmacology

Esophageal dilation occurred in rats treated with lorazepam for more than one year at 6 mg/kg/day. The no-effect dose was 1.25 mg/kg/day (approximately 1.2 times the maximum recommended human dose of 10 mg/day based on mg/m² body surface area). The effect was reversible only when the treatment was withdrawn within two months of first observation of the phenomenon. The clinical significance of this is unknown.