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 )] .

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.

ients 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 )] .

orted 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.

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 )] .

s 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 potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed infants, advise patients that breastfeeding is not recommended during treatment with loreev xr. 8.4 pediatric use the safety and effectiveness of loreev xr has not been established in pediatric patients. 8.5 geriatric use clinical studies of lorazepam tablets were not adequate to determine whether patients age 65 years and older responded differently than younger patients; however, the incidence of sedation and unsteadiness was observed to increase with age [see adverse reactions ( 6 )] . age does not appear to have a significant effect on lorazepam pharmacokinetics [see clinical pharmacology ( 12.3 )] . in general, dose selection for an elderly patient should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. greater sensitivity (e.g., sedation) of some older individuals cannot be ruled out [see warnings and precautions ( 5.6 )] . 8.6 hepatic impairment as with all benzodiazepines, the use of lorazepam, including loreev xr, may worsen hepatic encephalopathy. therefore, loreev xr should be used with caution in patients with severe hepatic insufficiency and/or encephalopathy.

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.

conditions, the median time to attain c max (t max ) 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 t max 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 t max 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 ( 2.5 ), drug interactions ( 7 )] . 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 half-life and decreased total clearance [see dosage and administration ( 2.5 ), drug interactions ( 7 )] . 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 ( 7 )] . 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.

elayed 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 t max 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 ( 2.5 ), drug interactions ( 7 )] . 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 half-life and decreased total clearance [see dosage and administration ( 2.5 ), drug interactions ( 7 )] . 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 ( 7 )] . 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.

stant 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.

medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see warnings and precautions ( 5.2 ), drug abuse and dependence ( 9.2 )] . withdrawal reactions inform patients that the continued use of loreev xr may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of loreev xr may precipitate acute withdrawal reactions, which can be life-threatening. inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. instruct patients that discontinuation or dosage reduction of loreev xr may require a slow taper [see warnings and precautions ( 5.3 ), drug abuse and dependence ( 9.3 )] . cns depression advise patients about the risks of cns depression. instruct patients to avoid the consumption of alcohol during treatment with loreev xr. advise patients to not drive a car or operate heavy machinery until they know how loreev xr affects them [see warnings and precautions ( 5.4 ), drug interactions ( 7 )] . patients with depression or psychosis advise patients, their families, and caregivers to look for signs of suicidal ideation or worsening depression, and to inform the patient’s healthcare provider immediately [see warnings and precautions ( 5.5 )] . concomitant medications advise patients to inform their healthcare provider of all medicines they take, including prescription and nonprescription medicines, vitamins and herbal supplements [see drug interactions ( 7 )] . administration information advise patients to take loreev xr capsules whole or open the capsule and sprinkle the entire contents over a tablespoon of applesauce, followed by drinking water. advise patients to consume the mixture immediately, without chewing, within 2 hours; do not store for future use [see dosage and administration ( 2.2 )] . pregnancy advise pregnant females that 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 newborns [see warnings and precautions ( 5.8 ), use in specific populations ( 8.1 )] . instruct patients to inform their healthcare provider if they are pregnant. advise pregnant women that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to loreev xr [see use in specific populations ( 8.1 )] . lactation advise patients that breastfeeding is not recommended during treatment with loreev xr [see use in specific populations ( 8.2 )] .