RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment Due to reduced clearance in patients with severe renal impairment (GFR 15 to 30 mL/min/1.73 m2), the maximum dose should not exceed 50 mg/day. The maximum recommended dose in ESRD (GFR 15 mL/min/1.73 m2) patients is 30 mg/day [see Clinical Pharmacology 12.3)].Lisdexamfetamine and d-amphetamine are not dialyzable.

SPL MEDGUIDE SECTION.

MEDICATION GUIDELISDEXAMFETAMINE DIMESYLATE(lis-DEX-am-FET-ah-meen) Capsules, CIIWhat is the most important information should know about lisdexamfetamine dimesylate capsules Lisdexamfetamine dimesylate capsules may cause serious side effects, including: oAbuse and dependence. Lisdexamfetamine dimesylate capsules, other amphetamine containing medicines, and methylphenidate have high chance for abuse and may cause physical and psychological dependence. Your healthcare provider should check you or your child for signs of abuse and dependence before and during treatment with lisdexamfetamine dimesylate capsules. oTell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs. oYour healthcare provider can tell you more about the differences between physical and psychological dependence and drug addiction. oHeart-related problems including: osudden death, stroke, and heart attack in adults osudden death in children who have heart problems or heart defectsoincreased blood pressure and heart rate Your healthcare provider should check you or your child carefully for heart problems before starting treatment with lisdexamfetamine dimesylate capsules. Tell your healthcare provider if you or your child have any heart problems, heart defects, high blood pressure, or family history of these problems. Your healthcare provider should check your or your childs blood pressure and heart rate regularly during treatment with lisdexamfetamine dimesylate capsules. Call your healthcare provider or go to the nearest hospital emergency room right away if you or your child have any signs of heart problems such as chest pain, shortness of breath, or fainting during treatment with lisdexamfetamine dimesylate capsules. oMental (psychiatric) problems, including: new or worse behavior and thought problems new or worse bipolar illness new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or new manic symptoms Tell your healthcare provider about any mental problems you or your child have or about family history of suicide, bipolar illness, or depression. Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems during treatment withlisdexamfetamine dimesylate capsules, especially hearing voices, seeing or believing things that are not real, or new manic symptoms. What are lisdexamfetamine dimesylate capsules Lisdexamfetamine dimesylate capsules are central nervous system (CNS) stimulant prescription medicine used for the treatment of: oAttention Deficit Hyperactivity Disorder (ADHD) in adults and children years of age and older. Lisdexamfetaminedimesylate capsules may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD. oModerate to severe binge eating disorder (BED) in adults. Lisdexamfetamine dimesylate capsules may help reduce the number of binge eating days in people with BED. Lisdexamfetamine dimesylate capsules are not for use in children under years of age with ADHD. Lisdexamfetamine dimesylate capsules are not for weight loss. It is not known if lisdexamfetamine dimesylate capsules are safe and effective for the treatment of obesity. It is not known if lisdexamfetamine dimesylate capsules are safe and effective for use in children with BED. Lisdexamfetamine dimesylate capsules are federally controlled substance (CII) because it contains lisdexamfetamine dimesylate that can be target for people who abuse prescription medicines or street drugs. Keep lisdexamfetamine dimesylate capsules in safe place to protect it from theft. Never give your lisdexamfetaminedimesylate capsules to anyone else because it may cause death or harm them. Selling or giving away lisdexamfetamine dimesylate capsules may harm others and is against the law. Do not take lisdexamfetamine dimesylate capsules if you or your child are: oallergic to amphetamine products or any of the ingredients in lisdexamfetamine dimesylate capsules. See the end of this Medication Guide for complete list of ingredients in lisdexamfetamine dimesylate capsules. otaking, or have stopped taking in the last 14 days, medicine called Monoamine Oxidase Inhibitor (MAOI). obeing treated with the antibiotic linezolid or intravenous methylene blue. Before taking lisdexamfetamine dimesylate capsules, tell your healthcare provider about all medical conditions, including if you or your child: ohave heart problems, heart defects, or high blood pressure ohave mental problems including psychosis, mania, bipolar illness, or depression or have family history of suicide, bipolar illness, or depression ohave circulation problems in fingers and toes oare pregnant or plan to become pregnant. Lisdexamfetamine dimesylate capsules may harm the unborn baby. There is pregnancy registry for females who are exposed to lisdexamfetamine dimesylate capsules during pregnancy. The purpose of the registry is to collect information about the health of females exposed to lisdexamfetamine dimesylate capsules and their baby. If you or your child becomes pregnant during treatment with lisdexamfetamine dimesylate capsules, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychostimulants at 1-866-961-2388 or visit online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/adhd-medications/. oare breastfeeding or plan to breastfeed. Lisdexamfetamine dimesylate capsules passes into breast milk. You should not breastfeed during treatment with lisdexamfetamine dimesylate capsules. Talk to your healthcare provider about the best way to feed the baby during treatment with lisdexamfetamine dimesylate capsules. Tell your healthcare provider about all the medicines that you or your child take, including prescription and over- the-counter medicines, vitamins, and herbal supplements. Lisdexamfetamine dimesylate capsules can affect the way other medicines work and other medicines may affect how lisdexamfetamine dimesylate capsules works. Taking lisdexamfetamine dimesylate capsules with other medicines can cause serious side effects. Sometimes the doses of other medicines will need to be changed while taking lisdexamfetamine dimesylate capsules. Especially tell your healthcare provider if you or your child take:oselective serotonin reuptake inhibitors (SSRIs)oserotonin norepinephrine reuptake inhibitors (SNRIs)omedicines used to treat migraine headaches called triptansotricyclic antidepressantsolithiumofentanylotramadolotryptophanobuspironeoSt. Johns WortKeep list of all medicines to show your healthcare provider and pharmacist when you get new medicine. Your healthcare provider will decide if lisdexamfetamine dimesylate capsules can be taken with other medicines. Do not start any new medicine during treatment with lisdexamfetamine dimesylate capsules without talking to your healthcare provider first. How should lisdexamfetamine dimesylate capsules be taken oTake lisdexamfetamine dimesylate capsules exactly as prescribed by your healthcare provider. oYour healthcare provider may change the dose if needed. oTake lisdexamfetamine dimesylate capsules time each day in the morning with or without food. oYour healthcare provider may sometimes stop lisdexamfetamine dimesylate capsules treatment for while to check ADHD or BED symptoms. oLisdexamfetamine dimesylate comes in capsules. Taking lisdexamfetamine dimesylate capsules: oLisdexamfetamine dimesylate capsules may be swallowed whole. oIf lisdexamfetamine dimesylate capsulescannot be swallowed whole, the capsule may be opened and the entire contents sprinkled onto yogurt, or poured into water or orange juice. oUsing spoon, break apart any powder that is stuck together. Stir the lisdexamfetamine dimesylate capsules powder and yogurt, water, or orange juice until they are completely mixed together. oSwallow all the yogurt, water, or orange juice mixture right away. Do not store the yogurt, water, or orange juice mixture. oIt is normal to see filmy coating on the inside of your glass or container after you eat or drink all the lisdexamfetamine dimesylate capsules mixture. If you or your child take too much lisdexamfetamine dimesylate, call your healthcare provider or poison control center at 1-800-222-1222 or go to the nearest hospital emergency room right away.What should avoid while takinglisdexamfetamine dimesylate capsules Do not drive, operate machinery, or do other dangerous activities until you know how lisdexamfetamine dimesylate capsules affects you. What are the possible side effects of lisdexamfetamine dimesylate capsules Lisdexamfetamine dimesylate capsules may cause serious side effects, including: oSee What is the most important information should know about lisdexamfetamine dimesylate capsules oSlowing of growth (height and weight) in children. Children should have their height and weight checked often during treatment with lisdexamfetamine dimesylate capsules. Lisdexamfetamine dimesylate capsules treatment may be stopped if your child is not growing or gaining weight. oCirculation problems in fingers and toes (Peripheral vasculopathy, including Raynauds phenomenon). Signs and symptoms may include: oFingers or toes may feel numb, cool, painfuloFingers or toes may change color from pale, to blue, to red Tell your healthcare provider if you or your child have numbness, pain, skin color change, or sensitivity to temperature in your fingers or toes. Call your healthcare provider right away if you or your child have any signs of unexplained wounds appearing on fingers or toes during treatment with lisdexamfetamine dimesylate capsules. oSerotonin Syndrome. potentially life-threatening problem called serotonin syndrome may happen when lisdexamfetamine dimesylate capsules are taken with certain other medicines. Stop taking lisdexamfetamine dimesylate capsules and call your healthcare provider or go to the nearest hospital emergency room right away if you or your child develop any of the following signs and symptoms of serotonin syndrome: oagitationofast heartbeatoflushingoseizuresocomaosweatingoloss of coordinationoconfusionodizzinessotremors, stiff muscles, or muscle twitching oseeing or hearing things that are not real (hallucination) ochanges in blood pressureohigh body temperature (hyperthermia)oNausea, vomiting, diarrheaThe most common side effects of lisdexamfetamine dimesylate capsules in children to 17 years old and adults with ADHD include: oloss of appetite (anorexia)oanxietyodecreased appetiteodiarrheaoweight lossodizzinessodry mouthoirritabilityotrouble sleeping onauseaostomach painovomitingThe most common side effects of lisdexamfetamine dimesylate capsulesin adults with BED include: odry mouthotrouble sleepingodecreased appetiteoincreased heart rateoconstipationofeeling jitteryoanxiety These are not all the possible side effects of lisdexamfetamine dimesylate capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store lisdexamfetamine dimesylate capsules oStore lisdexamfetamine dimesylate capsules in safe place (like locked cabinet) and in tightly closed container at room temperature between 68F to 77F (20C to 25C). oProtect lisdexamfetamine dimesylate capsules from light.o Dispose of remaining, unused, or expired lisdexamfetamine dimesylate capsules by medicine take-back program at authorized collection sites such as retail pharmacies, hospital or clinic pharmacies, and law enforcement locations. If no take-back program or authorized collector is available, mix lisdexamfetamine dimesylate capsules with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in container such as sealed plastic bag and throw away (discard) lisdexamfetamine dimesylate capsules in the household trash. Keep lisdexamfetamine dimesylate capsules and all medicines out of the reach of children. General information about the safe and effective use of lisdexamfetamine dimesylate capsules. Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use lisdexamfetamine dimesylate capsules for condition for which it was not prescribed. Do not give lisdexamfetamine dimesylate capsules to other people, even if they have the same symptoms that you have. It may harm them and it is against the law. You can ask your pharmacist or healthcare provider for information about lisdexamfetamine dimesylate capsules that is written for health professionals. What are the ingredients in lisdexamfetamine dimesylate capsules Active Ingredient: lisdexamfetamine dimesylate Inactive Ingredients: ammonium hydroxide, calcium phosphate, gelatin, iron oxide black, isopropyl alcohol, magnesium stearate, microcrystalline cellulose, n-butyl alcohol, propylene glycol, shellac glaze, sodium starch glycolate, and titanium dioxide. In addition, the 20 mg capsule also contains yellow iron oxide. The 30 mg capsule also contains FD&C yellow 6. The 40 mg capsule also contains FD&C blue and FD&C green 3. The 50 mg and 60 mg capsules also contains D&C red 28 and FD&C blue 1. The 70 mg capsule also contains D&C red 28, FD&C blue 1, and FD&C yellow 6. For more information about lisdexamfetamine dimesylate capsules, go to www.hikma.com or call 1-800-962-8364.This Medication Guide has been approved by the U.S. Food and Drug Administration. Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922C50001173/02 Revised June 2023. oAbuse and dependence. Lisdexamfetamine dimesylate capsules, other amphetamine containing medicines, and methylphenidate have high chance for abuse and may cause physical and psychological dependence. Your healthcare provider should check you or your child for signs of abuse and dependence before and during treatment with lisdexamfetamine dimesylate capsules. oTell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs. oYour healthcare provider can tell you more about the differences between physical and psychological dependence and drug addiction. oHeart-related problems including: osudden death, stroke, and heart attack in adults osudden death in children who have heart problems or heart defects. oincreased blood pressure and heart rate oMental (psychiatric) problems, including: new or worse behavior and thought problems new or worse bipolar illness new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or new manic symptoms oAttention Deficit Hyperactivity Disorder (ADHD) in adults and children years of age and older. Lisdexamfetaminedimesylate capsules may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD. oModerate to severe binge eating disorder (BED) in adults. Lisdexamfetamine dimesylate capsules may help reduce the number of binge eating days in people with BED. oallergic to amphetamine products or any of the ingredients in lisdexamfetamine dimesylate capsules. See the end of this Medication Guide for complete list of ingredients in lisdexamfetamine dimesylate capsules. otaking, or have stopped taking in the last 14 days, medicine called Monoamine Oxidase Inhibitor (MAOI). obeing treated with the antibiotic linezolid or intravenous methylene blue. ohave heart problems, heart defects, or high blood pressure ohave mental problems including psychosis, mania, bipolar illness, or depression or have family history of suicide, bipolar illness, or depression ohave circulation problems in fingers and toes oare pregnant or plan to become pregnant. Lisdexamfetamine dimesylate capsules may harm the unborn baby. o There is pregnancy registry for females who are exposed to lisdexamfetamine dimesylate capsules during pregnancy. The purpose of the registry is to collect information about the health of females exposed to lisdexamfetamine dimesylate capsules and their baby. If you or your child becomes pregnant during treatment with lisdexamfetamine dimesylate capsules, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychostimulants at 1-866-961-2388 or visit online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/adhd-medications/. oare breastfeeding or plan to breastfeed. Lisdexamfetamine dimesylate capsules passes into breast milk. You should not breastfeed during treatment with lisdexamfetamine dimesylate capsules. Talk to your healthcare provider about the best way to feed the baby during treatment with lisdexamfetamine dimesylate capsules. oselective serotonin reuptake inhibitors (SSRIs). oserotonin norepinephrine reuptake inhibitors (SNRIs). omedicines used to treat migraine headaches called triptans. otricyclic antidepressants. olithium. ofentanyl. otramadol. otryptophan. obuspirone. oSt. Johns Wort. oTake lisdexamfetamine dimesylate capsules exactly as prescribed by your healthcare provider. oYour healthcare provider may change the dose if needed. oTake lisdexamfetamine dimesylate capsules time each day in the morning with or without food. oYour healthcare provider may sometimes stop lisdexamfetamine dimesylate capsules treatment for while to check ADHD or BED symptoms. oLisdexamfetamine dimesylate comes in capsules. Taking lisdexamfetamine dimesylate capsules: oLisdexamfetamine dimesylate capsules may be swallowed whole. oIf lisdexamfetamine dimesylate capsulescannot be swallowed whole, the capsule may be opened and the entire contents sprinkled onto yogurt, or poured into water or orange juice. oUsing spoon, break apart any powder that is stuck together. Stir the lisdexamfetamine dimesylate capsules powder and yogurt, water, or orange juice until they are completely mixed together. oSwallow all the yogurt, water, or orange juice mixture right away. Do not store the yogurt, water, or orange juice mixture. oIt is normal to see filmy coating on the inside of your glass or container after you eat or drink all the lisdexamfetamine dimesylate capsules mixture. If you or your child take too much lisdexamfetamine dimesylate, call your healthcare provider or poison control center at 1-800-222-1222 or go to the nearest hospital emergency room right away.. oSee What is the most important information should know about lisdexamfetamine dimesylate capsules oSlowing of growth (height and weight) in children. Children should have their height and weight checked often during treatment with lisdexamfetamine dimesylate capsules. Lisdexamfetamine dimesylate capsules treatment may be stopped if your child is not growing or gaining weight. oCirculation problems in fingers and toes (Peripheral vasculopathy, including Raynauds phenomenon).. Signs and symptoms may include: oFingers or toes may feel numb, cool, painful. oFingers or toes may change color from pale, to blue, to red Tell your healthcare provider if you or your child have numbness, pain, skin color change, or sensitivity to temperature in your fingers or toes. Call your healthcare provider right away if you or your child have any signs of unexplained wounds appearing on fingers or toes during treatment with lisdexamfetamine dimesylate capsules. oSerotonin Syndrome. potentially life-threatening problem called serotonin syndrome may happen when lisdexamfetamine dimesylate capsules are taken with certain other medicines. Stop taking lisdexamfetamine dimesylate capsules and call your healthcare provider or go to the nearest hospital emergency room right away if you or your child develop any of the following signs and symptoms of serotonin syndrome: oagitation. ofast heartbeat. oflushing. oseizures. ocoma. osweating. oloss of coordination. oconfusion. odizziness. otremors, stiff muscles, or muscle twitching oseeing or hearing things that are not real (hallucination) ochanges in blood pressure. ohigh body temperature (hyperthermia). oNausea, vomiting, diarrhea. oloss of appetite (anorexia). oanxiety. odecreased appetite. odiarrhea. oweight loss. odizziness. odry mouth. oirritability. otrouble sleeping onausea. ostomach pain. ovomiting. odry mouth. otrouble sleeping. odecreased appetite. oincreased heart rate. oconstipation. ofeeling jittery. oanxiety oStore lisdexamfetamine dimesylate capsules in safe place (like locked cabinet) and in tightly closed container at room temperature between 68F to 77F (20C to 25C). oProtect lisdexamfetamine dimesylate capsules from light.. Dispose of remaining, unused, or expired lisdexamfetamine dimesylate capsules by medicine take-back program at authorized collection sites such as retail pharmacies, hospital or clinic pharmacies, and law enforcement locations. If no take-back program or authorized collector is available, mix lisdexamfetamine dimesylate capsules with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in container such as sealed plastic bag and throw away (discard) lisdexamfetamine dimesylate capsules in the household trash. For more information about lisdexamfetamine dimesylate capsules, go to www.hikma.com or call 1-800-962-8364.

SPL UNCLASSIFIED SECTION.

2.1 Pre-treatment Screening. Prior to treating patients with CNS stimulants, including lisdexamfetamine dimesylate capsules, assess for the presence of cardiac disease (e.g., careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)].To reduce the abuse of CNS stimulants including lisdexamfetamine dimesylate capsules, assess the risk of abuse, prior to prescribing. After prescribing, keep careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and re-evaluate the need for lisdexamfetamine dimesylate capsules use [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oPregnancy: May cause fetal harm (8.1) oLactation: Breastfeeding not recommended (8.2). oPregnancy: May cause fetal harm (8.1) oLactation: Breastfeeding not recommended (8.2). 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and researchprograms/pregnancyregistry/adhdmedications/. Risk SummaryThe limited available data from published literature and postmarketing reports on use of lisdexamfetamine dimesylate in pregnant women are not sufficient to inform drug-associated risk for major birth defects and miscarriage. Adverse pregnancy outcomes, including premature delivery and low birth weight, have been seen in infants born to mothers dependent on amphetamines [see Clinical Considerations]. In animal reproduction studies, lisdexamfetamine dimesylate (a prodrug of d-amphetamine) had no effects on embryo-fetal morphological development or survival when administered orally to pregnant rats and rabbits throughout the period of organogenesis. Pre-and postnatal studies were not conducted with lisdexamfetamine dimesylate. However, amphetamine (d-to l-ratio of 3:1) administration to pregnant rats during gestation and lactation caused decrease in pup survival and decrease in pup body weight that correlated with delay in developmental landmarks at clinically relevant doses of amphetamine. In addition, adverse effects on reproductive performance were observed in pups whose mothers were treated with amphetamine. Long-term neurochemical and behavioral effects have also been reported in animal developmental studies using clinically relevant doses of amphetamine [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 2-4% and 15-20%, respectively.Clinical Considerations Fetal/Neonatal Adverse Reactions Amphetamines, such as lisdexamfetamine dimesylate, cause vasoconstriction and thereby may decrease placental perfusion. In addition, amphetamines can stimulate uterine contractions increasing the risk of premature delivery. Infants born to amphetamine-dependent mothers have an increased risk of premature delivery and low birth weight. Monitor infants born to mothers taking amphetamines for symptoms of withdrawal such as feeding difficulties, irritability, agitation, and excessive drowsiness. Data Animal Data Lisdexamfetamine dimesylate had no apparent effects on embryo-fetal morphological development or survival when administered orally to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 40 and 120 mg/kg/day, respectively. These doses are approximately 5.5 and 33 times, respectively, the maximum recommended human dose (MRHD) of 70 mg/day given to adults, on mg/m2 body surface area basis. study was conducted with amphetamine (d-to l-enantiomer ratio of 3:1) in which pregnant rats received daily oral doses of 2, 6, and 10 mg/kg from gestation day to lactation day 20. All doses caused hyperactivity and decreased weight gain in the dams. decrease in pup survival was seen at all doses. decrease in pup body weight was seen at and 10 mg/kg which correlated with delays in developmental landmarks, such as preputial separation and vaginal opening. Increased pup locomotor activity was seen at 10 mg/kg on day 22 postpartum but not at weeks postweaning. When pups were tested for reproductive performance at maturation, gestational weight gain, number of implantations, and number of delivered pups were decreased in the group whose mothers had been given 10 mg/kg. number of studies from the literature in rodents indicate that prenatal or early postnatal exposure to amphetamine (d- or d, l-) at doses similar to those used clinically can result in long term neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function.. 8.2 Lactation Risk SummaryLisdexamfetamine is pro-drug of dextroamphetamine. Based on limited case reports in published literature, amphetamine (d-or d, l-) is present in human milk, at relative infant doses of 2% to 13.8% of the maternal weight-adjusted dosage and milk/plasma ratio ranging between 1.9 and 7.5. There are no reports of adverse effects on the breastfed infant. Long-term neurodevelopmental effects on infants from amphetamine exposure are unknown. It is possible that large dosages of dextroamphetamine might interfere with milk production, especially in women whose lactation is not well established. Because of the potential for serious adverse reactions in nursing infants, including serious cardiovascular reactions, blood pressure and heart rate increase, suppression of growth, and peripheral vasculopathy, advise patients that breastfeeding is not recommended during treatment with lisdexamfetamine dimesylate.. 8.4 Pediatric Use. ADHD Safety and effectiveness of lisdexamfetamine dimesylate have been established in pediatric patients with ADHD ages to 17 years [see Dosage and Administration 2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. Safety and effectiveness of lisdexamfetamine dimesylate have not been established in pediatric patients below the age of years. Safety and efficacy of lisdexamfetamine dimesylate were evaluated in double-blind, randomized, parallel-group, placebo-controlled, fixed-dose study in pediatric patients ages to years with ADHD, followed by 1-year open-label extension study. In these studies, patients experienced elevated rates of adverse reactions, including weight loss, decreased BMI, decreased appetite, insomnia, infections (upper respiratory and nasopharyngitis), irritability, and affect lability. With the same lisdexamfetamine dimesylate dose, mean steady state exposure of dextroamphetamine was approximately 44% higher in pediatric patients ages to years compared to the pediatric patients ages to 11 years.BED Safety and effectiveness of lisdexamfetamine dimesylate have not been established in patients less than 18 years of age. Growth Suppression Growth should be monitored during treatment with stimulants, including lisdexamfetamine dimesylate, and pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions 5.5) and Adverse Reactions (6.1)]. Juvenile Animal Data Studies conducted in juvenile rats and dogs at clinically relevant doses showed growth suppression that partially or fully reversed in dogs and female rats but not in male rats after four-week drug-free recovery period. study was conducted in which juvenile rats received oral doses of 4, 10, or 40 mg/kg/day of lisdexamfetamine dimesylate from day to day 63 of age. These doses are approximately 0.3, 0.7, and times the maximum recommended human daily dose of 70 mg on mg/m2 basis for child. Dose-related decreases in food consumption, bodyweight gain, and crown-rump length were seen; after four-week drug-free recovery period, bodyweights and crown-rump lengths had significantly recovered in females but were still substantially reduced in males. Time to vaginal opening was delayed in females at the highest dose, but there were no drug effects on fertility when the animals were mated beginning on day 85 of age. In study in which juvenile dogs received lisdexamfetamine dimesylate for months beginning at 10 weeks of age, decreased bodyweight gain was seen at all doses tested (2, 5, and 12 mg/kg/day, which are approximately 0.5, 1, and times the maximum recommended human daily dose on mg/m2 basis for child). This effect partially or fully reversed during four-week drug-free recovery period.. 8.5 Geriatric Use. Clinical studies of lisdexamfetamine dimesylate capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience and pharmacokinetic data [see Clinical Pharmacology (12.3)] have not identified differences in responses between the elderly and younger patients. 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.. 8.6 Renal Impairment Due to reduced clearance in patients with severe renal impairment (GFR 15 to 30 mL/min/1.73 m2), the maximum dose should not exceed 50 mg/day. The maximum recommended dose in ESRD (GFR 15 mL/min/1.73 m2) patients is 30 mg/day [see Clinical Pharmacology 12.3)].Lisdexamfetamine and d-amphetamine are not dialyzable.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oSerious Cardiovascular Reactions: Sudden death has been reported in association with CNS stimulant treatment at recommended doses in pediatric patients with structural cardiac abnormalities or other serious heart problems. In adults, sudden death, stroke, and myocardial infarction have been reported. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, or coronary artery disease (5.2) oBlood Pressure and Heart Rate Increases: Monitor blood pressure and pulse. Consider benefits and risks before use in patients for whom blood pressure increases may be problematic (5.3)oPsychiatric Adverse Reactions: May cause psychotic or manic symptoms in patients with no prior history, or exacerbation of symptoms in patients with pre-existing psychosis. Evaluate for bipolar disorder prior to stimulant use (5.4)oSuppression of Growth: Monitor height and weight in pediatric patients during treatment (5.5)oPeripheral Vasculopathy, including Raynauds phenomenon: Stimulants are associated with peripheral vasculopathy, including Raynauds phenomenon. Careful observation for digital changes is necessary during treatment with stimulants (5.6)oSerotonin Syndrome: Increased risk when co-administered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue lisdexamfetamine dimesylate capsules and initiate supportive treatment (4, 5.7, 10) oSerious Cardiovascular Reactions: Sudden death has been reported in association with CNS stimulant treatment at recommended doses in pediatric patients with structural cardiac abnormalities or other serious heart problems. In adults, sudden death, stroke, and myocardial infarction have been reported. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, or coronary artery disease (5.2) oBlood Pressure and Heart Rate Increases: Monitor blood pressure and pulse. Consider benefits and risks before use in patients for whom blood pressure increases may be problematic (5.3). oPsychiatric Adverse Reactions: May cause psychotic or manic symptoms in patients with no prior history, or exacerbation of symptoms in patients with pre-existing psychosis. Evaluate for bipolar disorder prior to stimulant use (5.4). oSuppression of Growth: Monitor height and weight in pediatric patients during treatment (5.5). oPeripheral Vasculopathy, including Raynauds phenomenon: Stimulants are associated with peripheral vasculopathy, including Raynauds phenomenon. Careful observation for digital changes is necessary during treatment with stimulants (5.6). oSerotonin Syndrome: Increased risk when co-administered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue lisdexamfetamine dimesylate capsules and initiate supportive treatment (4, 5.7, 10) 5.1 Potential for Abuse and Dependence. CNS stimulants, including lisdexamfetamine dimesylate capsules, other amphetamine-containing products and methylphenidate, have high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Drug Abuse and Dependence (9.2, 9.3)].. 5.2 Serious Cardiovascular Reactions. Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in pediatric patients with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during lisdexamfetamine dimesylate capsules treatment.. 5.3 Blood Pressure and Heart Rate Increases CNS stimulants cause an increase in blood pressure (mean increase about to mm Hg) and heart rate (mean increase about to bpm). Monitor all patients for potential tachycardia and hypertension.. 5.4 Psychiatric Adverse Reactions. Exacerbation of Pre-existing Psychosis: CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with pre-existing psychotic disorder.Induction of Manic Episode in Patients with Bipolar Disorder: CNS stimulants may induce mixed/manic episode in patients with bipolar disorder. Prior to initiating treatment, screen patients for risk factors for developing manic episode (e.g., comorbid or history of depressive symptoms or family history of suicide, bipolar disorder, and depression). New Psychotic or Manic Symptoms: CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing lisdexamfetamine dimesylate capsules. In pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in 0.1% of CNS stimulant-treated patients compared to 0% in placebo-treated patients.. 5.5 Suppression of Growth CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including lisdexamfetamine dimesylate capsules. In 4-week, placebo-controlled trial of lisdexamfetamine dimesylate capsules in pediatric patients ages to 12 years old with ADHD, there was dose-related decrease in weight in the lisdexamfetamine dimesylate capsules groups compared to weight gain in the placebo group. Additionally, in studies of another stimulant, there was slowing of the increase in height [see Adverse Reactions 6.1)].Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. Lisdexamfetamine dimesylate capsules are not approved for use in pediatric patients below years of age [see Use in Specific Populations (8.4)].. 5.6 Peripheral Vasculopathy, including Raynauds Phenomenon Stimulants, including lisdexamfetamine dimesylate capsules, are associated with peripheral vasculopathy, including Raynauds phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynauds phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.. 5.7 Serotonin Syndrome Serotonin syndrome, potentially life-threatening reaction, may occur when amphetamines are used in combination with other drugs that affect the serotonergic neurotransmitter systems such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. Johns Wort [see Drug Interactions 7.1)]. The co-administration with cytochrome P450 2D6 (CYP2D6) inhibitors may also increase the risk with increased exposure to the active metabolite of lisdexamfetamine dimesylate capsules (dextroamphetamine). In these situations, consider an alternative non-serotonergic drug or an alternative drug that does not inhibit CYP2D6 [see Drug Interactions 7.1)].Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Concomitant use of lisdexamfetamine dimesylate capsules with MAOI drugs is contraindicated [see Contraindications 4)]. Discontinue treatment with lisdexamfetamine dimesylate capsules and any concomitant serotonergic agents immediately if symptoms of serotonin syndrome occur, and initiate supportive symptomatic treatment. If concomitant use of lisdexamfetamine dimesylate capsules with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate lisdexamfetamine dimesylate capsules with lower doses, monitor patients for the emergence of serotonin syndrome during drug initiation or titration, and inform patients of the increased risk for serotonin syndrome.

ABUSE SECTION.

9.2 Abuse. CNS stimulants, including lisdexamfetamine dimesylate capsules, other amphetamine-containing products, and methylphenidate have high potential for abuse. Abuse is the intentional non-therapeutic use of drug, even once, to achieve desired psychological or physiological effect. Abuse is characterized by impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is cluster of behavioral, cognitive, and physiological phenomena that may include strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Both abuse and misuse may lead to addiction, and some individuals may develop addiction even when taking lisdexamfetamine dimesylate capsules as prescribed.Signs and symptoms of amphetamine abuse may include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, suicidal or homicidal ideation have also been seen. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which can result in overdose and death [see Overdosage 10)].To reduce the abuse of CNS stimulants, including lisdexamfetamine dimesylate capsules, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants. Monitor for signs of abuse while on therapy, and re-evaluate the need for lisdexamfetamine dimesylate capsules use.Studies of Lisdexamfetamine Dimesylate Capsules in Drug Abusers: randomized, double-blind, placebo-control, cross-over, abuse liability study in 38 patients with history of drug abuse was conducted with single-doses of 50, 100, or 150 mg of lisdexamfetamine dimesylate capsules, 40 mg of immediate-release d-amphetamine sulphate (a controlled II substance), and 200 mg of diethylpropion hydrochloride (a controlled IV substance). Lisdexamfetamine dimesylate capsules 100 mg produced significantly less Drug Liking Effects as measured by the Drug Rating Questionnaire-Subject score, compared to d-amphetamine 40 mg; and 150 mg of lisdexamfetamine dimesylate capsules demonstrated similar Drug-Liking Effects compared to 40 mg of d-amphetamine and 200 mg of diethylpropion. Intravenous administration of 50 mg lisdexamfetamine dimesylate to individuals with history of drug abuse produced positive subjective responses on scales measuring Drug Liking, Euphoria, Amphetamine Effects, and Benzedrine Effects that were greater than placebo but less than those produced by an equivalent dose (20 mg) of intravenous d-amphetamine.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail in other sections of the labeling: oKnown hypersensitivity to amphetamine products or other ingredients of lisdexamfetamine dimesylate capsules [see Contraindications (4)] oHypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4) and Drug Interactions (7.1)] oDrug Dependence [see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9.2, 9.3)] oSerious Cardiovascular Reactions [see Warnings and Precautions (5.2)] oBlood Pressure and Heart Rate Increases [see Warnings and Precautions (5.3)] oPsychiatric Adverse Reactions [see Warnings and Precautions (5.4)] oSuppression of Growth [see Warnings and Precautions (5.5)] oPeripheral Vasculopathy, including Raynauds phenomenon [see Warnings and Precautions 5.6)] oSerotonin Syndrome [see Warnings and Precautions (5.7)] oKnown hypersensitivity to amphetamine products or other ingredients of lisdexamfetamine dimesylate capsules [see Contraindications (4)] oHypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4) and Drug Interactions (7.1)] oDrug Dependence [see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9.2, 9.3)] oSerious Cardiovascular Reactions [see Warnings and Precautions (5.2)] oBlood Pressure and Heart Rate Increases [see Warnings and Precautions (5.3)] oPsychiatric Adverse Reactions [see Warnings and Precautions (5.4)] oSuppression of Growth [see Warnings and Precautions (5.5)] oPeripheral Vasculopathy, including Raynauds phenomenon [see Warnings and Precautions 5.6)] oSerotonin Syndrome [see Warnings and Precautions (5.7)] Most common adverse reactions (incidence >=5% and at rate at least twice placebo) in pediatric patients ages to 17 years, and/or adults with ADHD were anorexia, anxiety, decreased appetite, decreased weight, diarrhea, dizziness, dry mouth, irritability, insomnia, nausea, upper abdominal pain, and vomiting (6.1)Most common adverse reactions (incidence >= 5% and at rate at least twice placebo) in adults with BED were dry mouth, insomnia, decreased appetite, increased heart rate, constipation, feeling jittery, and anxiety (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Attention Deficit Hyperactivity DisorderThe safety data in this section is based on data from the 4-week controlled parallel-group clinical studies of lisdexamfetamine dimesylate in pediatric and adult patients with ADHD [see Clinical Studies 14.1)].Adverse Reactions Associated with Discontinuation of Treatment in ADHD Clinical Trials: In the controlled trial in pediatric patients ages to 12 years (Study 1), 8% (18/218) of lisdexamfetamine dimesylate-treated patients discontinued due to adverse reactions compared to 0% (0/72) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate of placebo) were ECG voltage criteria for ventricular hypertrophy, tic, vomiting, psychomotor hyperactivity, insomnia, decreased appetite and rash [2 instances for each adverse reaction, i.e., 2/218 (1%)]. Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included abdominal pain upper, dry mouth, weight decreased, dizziness, somnolence, logorrhea, chest pain, anger and hypertension. In the controlled trial in pediatric patients ages 13 to 17 years (Study 4), 3% (7/233) of lisdexamfetamine dimesylate-treated patients discontinued due to adverse reactions compared to 1% (1/77) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate of placebo) were decreased appetite (2/233; 1%) and insomnia (2/233; 1%). Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included irritability, dermatillomania, mood swings, and dyspnea. In the controlled adult trial (Study 7), 6% (21/358) of lisdexamfetamine dimesylate -treated patients discontinued due to adverse reactions compared to 2% (1/62) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate of placebo) were insomnia (8/358; 2%), tachycardia (3/358; 1%), irritability (2/358; 1%), hypertension (4/358; 1%), headache (2/358; 1%), anxiety (2/358; 1%), and dyspnea (3/358; 1%). Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included palpitations, diarrhea, nausea, decreased appetite, dizziness, agitation, depression, paranoia and restlessness.Adverse Reactions Occurring at an Incidence of >=5% or More Among Lisdexamfetamine dimesylate Treated Patients with ADHD in Clinical Trials: The most common adverse reactions (incidence >=5% and at rate at least twice placebo) reported in pediatric patients ages to 17 years, and/or adults were anorexia, anxiety, decreased appetite, decreased weight, diarrhea, dizziness, dry mouth, irritability, insomnia, nausea, upper abdominal pain, and vomiting. Adverse Reactions Occurring at an Incidence of 2% or More Among Lisdexamfetamine dimesylate Treated Patients with ADHD in Clinical Trials:Adverse reactions reported in the controlled trials in pediatric patients ages, to 12 years (Study 1), pediatric patients ages 13 to 17 years (Study 4), and adult patients (Study 7) treated with lisdexamfetamine dimesylate or placebo are presented in Tables 1, and below. Table Adverse Reactions Reported by 2% or More of Pediatric Patients Ages to 12 Years with ADHD Taking Lisdexamfetamine Dimesylate and Greater than or Equal to Twice the Incidence in Patients Taking Placebo in 4-Week Clinical Trial (Study 1)Lisdexamfetamine DimesylatePlacebo(n=218)(n=72)Decreased Appetite39%4%Insomnia22%3%Abdominal Pain Upper12%6%Irritability10%0%Vomiting9%4%Weight Decreased9%1%Nausea6%3%Dry Mouth5%0%Dizziness5%0%Affect Lability3%0%Rash3%0%Pyrexia2%1%Somnolence2%1%Tic2%0%Anorexia2%0%Table Adverse Reactions Reported by 2% or More of Pediatric Patients Ages 13 to 17 Years with ADHD Taking Lisdexamfetamine Dimesylate and Greater than or Equal to Twice the Incidence in Patients Taking Placebo in 4-Week Clinical Trial (Study 4)Lisdexamfetamine DimesylatePlacebo(n=233)(n=77)Decreased Appetite34%3%Insomnia13%4%Weight Decreased9%0%Dry Mouth4%1%Palpitations 2% 1% Anorexia 2% 0% Tremor 2% 0% Table Adverse Reactions Reported by 2% or More of Adult Patients with ADHD Taking Lisdexamfetamine Dimesylate and Greater than or Equal to Twice the Incidence in Patients Taking Placebo in 4-Week Clinical Trial (Study 7)Lisdexamfetamine DimesylatePlacebo(n=358)(n=62)Decreased Appetite27%2%Insomnia27%8%Dry Mouth26%3%Diarrhea7%0%Nausea7%0%Anxiety6%0%Anorexia5%0%Feeling Jittery4%0%Agitation3%0%Increased Blood Pressure 3%0%Hyperhidrosis3%0%Restlessness3%0%Decreased Weight3%0%Dyspnea2%0%Increased Heart Rate 2%0%Tremor2%0%Palpitations2%0%In addition, in the adult population erectile dysfunction was observed in 2.6% of males on lisdexamfetamine dimesylate and 0% on placebo; decreased libido was observed in 1.4% of subjects on lisdexamfetamine dimesylate and 0% on placebo.Weight Loss and Slowing Growth Rate in Pediatric Patients with ADHD: In controlled trial of lisdexamfetamine dimesylate capsules in pediatric patients ages to 12 years (Study 1), mean weight loss from baseline after weeks of therapy was -0.9, -1.9, and -2.5 pounds, respectively, for patients receiving 30 mg, 50 mg, and 70 mg of lisdexamfetamine dimesylate, compared to 1 pound weight gain for patients receiving placebo. Higher doses were associated with greater weight loss with weeks of treatment. Careful follow-up for weight in pediatric patients ages to 12 years who received lisdexamfetamine dimesylate capsules over 12 months suggests that consistently medicated pediatric patients (i.e., treatment for days per week throughout the year) have slowing in growth rate, measured by body weight as demonstrated by an age-and sex-normalized mean change from baseline in percentile, of -13.4 over year (average percentiles at baseline and 12 months were 60.9 and 47.2, respectively). In 4-week controlled trial of lisdexamfetamine dimesylate in pediatric patients ages 13 to 17 years, mean weight loss from baseline to endpoint was -2.7, -4.3, and -4.8 lbs., respectively, for patients receiving 30 mg, 50 mg, and 70 mg of lisdexamfetamine dimesylate, compared to 2.0 pound weight gain for patients receiving placebo. Careful follow-up of weight and height in pediatric patients ages to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated pediatric patients ages to 13 years (i.e., treatment for days per week throughout the year) have temporary slowing in growth rate (on average, total of about cm less growth in height and 2.7 kg less growth in weight over years), without evidence of growth rebound during this period of development. In controlled trial of amphetamine (d- to l-enantiomer ratio of 3:1) in pediatric patients ages 13 to 17 years, mean weight change from baseline within the initial weeks of therapy was -1.1 pounds and -2.8 pounds, respectively, for patients receiving 10 mg and 20 mg of amphetamine. Higher doses were associated with greater weight loss within the initial weeks of treatment [see Warnings and Precautions 5.5)]. Weight Loss in Adults with ADHD:In the controlled adult trial (Study 7), mean weight loss after weeks of therapy was 2.8 pounds, 3.1 pounds, and 4.3 pounds, for patients receiving final doses of 30 mg, 50 mg, and 70 mg of lisdexamfetamine dimesylate capsules, respectively, compared to mean weight gain of 0.5 pounds for patients receiving placebo.Binge Eating Disorder The safety data in this section is based on data from two 12-week parallel group, flexible-dose, placebo-controlled studies in adults with BED [see Clinical Studies 14.2]. Patients with cardiovascular risk factors other than obesity and smoking were excluded. Adverse Reactions Associated with Discontinuation of Treatment in BED Clinical Trials: In controlled trials of patients ages 18 to 55 years, 5.1% (19/373) of lisdexamfetamine dimesylate-treated patients discontinued due to adverse reactions compared to 2.4% (9/372) of placebo-treated patients. No single adverse reaction led to discontinuation in 1% or more of lisdexamfetamine dimesylate-treated patients. Less commonly reported adverse reactions (less than 1% or less than twice rate of placebo) included increased heart rate, headache, abdominal pain upper, dyspnea, rash, insomnia, irritability, feeling jittery and anxiety. Adverse Reactions Occurring at an Incidence of 5% or More and At Least Twice Placebo Among Lisdexamfetamine dimesylate Treated Patients with BED in Clinical Trials: The most common adverse reactions (incidence >=5% and at rate at least twice placebo) reported in adults were dry mouth, insomnia, decreased appetite, increased heart rate, constipation, feeling jittery, and anxiety. Adverse Reactions Occurring at an Incidence of 2% or More and At Least Twice Placebo Among Lisdexamfetamine dimesylate Treated Patients with BED in Clinical Trials:Adverse reactions reported in the pooled controlled trials in adult patients (Study 11 and 12) treated with lisdexamfetamine dimesylate or placebo are presented in Table below.Table Adverse Reactions Reported by 2% or More of Adult Patients with BED Taking Lisdexamfetamine Dimesylate and Greater than or Equal to Twice the Incidence in Patients Taking Placebo in 12-Week Clinical Trials (Study 11 and 12)Lisdexamfetamine DimesylatePlacebo(N=373)(N=372)Dry Mouth36%7%InsomniaIncludes all preferred terms containing the word insomnia. 20%8%Decreased Appetite 8%2%Increased Heart RateIncludes the preferred terms heart rate increased and tachycardia. 7%1%Feeling Jittery 6%1%Constipation 6%1%Anxiety 5%1%Diarrhea 4%2%Decreased Weight 4%0%Hyperhidrosis 4%0%Vomiting 2%1%Gastroenteritis 2%1%Paresthesia 2%1%Pruritus 2%1%Upper Abdominal Pain 2%0%Energy Increased 2%0%Urinary Tract Infection 2%0%Nightmare 2%0%Restlessness 2%0%Oropharyngeal Pain 2%0%. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of lisdexamfetamine dimesylate capsules. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. These events are as follows: cardiomyopathy, mydriasis, diplopia, difficulties with visual accommodation, blurred vision, eosinophilic hepatitis, anaphylactic reaction, hypersensitivity, dyskinesia, dysgeusia, tics, bruxism, depression, dermatillomania, alopecia, aggression, Stevens-Johnson Syndrome, chest pain, angioedema, urticaria, seizures, libido changes, frequent or prolonged erections, constipation, rhabdomyolysis, and intestinal ischemia.

BOXED WARNING SECTION.

WARNING: ABUSE AND DEPENDENCE. CNS stimulants, including lisdexamfetamine dimesylate, other amphetamine-containing products, and methylphenidate, have high potential for abuse and dependence. Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy [see Warnings and Precautions (5.1), and Drug Abuse and Dependence (9.2, 9.3)] .. WARNING: ABUSE AND DEPENDENCESee full prescribing information for complete boxed warning.oCNS stimulants, including lisdexamfetamine dimesylate, other amphetamine-containing products, and methylphenidate have high potential for abuse and dependence (5.1, 9.3) oAssess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy (5.1, 9.2). oCNS stimulants, including lisdexamfetamine dimesylate, other amphetamine-containing products, and methylphenidate have high potential for abuse and dependence (5.1, 9.3) oAssess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy (5.1, 9.2).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Lisdexamfetamine is prodrug of dextroamphetamine. Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The exact mode of therapeutic action in ADHD and BED is not known.. 12.2 Pharmacodynamics Amphetamines block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. The parent drug, lisdexamfetamine, does not bind to the sites responsible for the reuptake of norepinephrine and dopamine in vitro.. 12.3 Pharmacokinetics Pharmacokinetic studies after oral administration of lisdexamfetamine dimesylate have been conducted in healthy adult (capsule and chewable tablet formulations) and pediatric (6 to 12 years) patients with ADHD (capsule formulation). After single dose administration of lisdexamfetamine dimesylate, pharmacokinetics of dextroamphetamine was found to be linear between 30 mg and 70 mg in pediatric study (6 to 12 years), and between 50 mg and 250 mg in an adult study. Dextroamphetamine pharmacokinetic parameters following administration of lisdexamfetamine dimesylate in adults exhibited low inter-subject (<25%) and intra-subject (<8%) variability. There is no accumulation of lisdexamfetamine and dextroamphetamine at steady state in healthy adults.Absorption Capsule formulation Following single-dose oral administration of lisdexamfetamine dimesylate capsule (30 mg, 50 mg, or 70 mg) in patients ages to 12 years with ADHD under fasted conditions, Tmax of lisdexamfetamine and dextroamphetamine was reached at approximately hour and 3.5 hours post dose, respectively. Weight/Dose normalized AUC and Cmax values were the same in pediatric patients ages to 12 years as the adults following single doses of 30 mg to 70 mg lisdexamfetamine dimesylate capsule.Effect of food on capsule formulation Neither food (a high fat meal or yogurt) nor orange juice affects the observed AUC and Cmax of dextroamphetamine in healthy adults after single-dose oral administration of 70 mg of lisdexamfetamine dimesylate capsules. Food prolongs Tmax by approximately hour (from 3.8 hours at fasted state to 4.7 hours after high fat meal or to 4.2 hours with yogurt). After an 8-hour fast, the AUC for dextroamphetamine following oral administration of lisdexamfetamine dimesylate in solution and as intact capsules were equivalent.Elimination Plasma concentrations of unconverted lisdexamfetamine are low and transient, generally becoming non-quantifiable by hours after administration. The plasma elimination half-life of lisdexamfetamine typically averaged less than one hour in volunteers ages years and older. The plasma elimination half-life of dextroamphetamine was approximately 8.6 to 9.5 hours in pediatric patients to 12 years and 10 to 11.3 hours in healthy adults.Metabolism Lisdexamfetamine is converted to dextroamphetamine and l-lysine primarily in blood due to the hydrolytic activity of red blood cells after oral administration of lisdexamfetamine dimesylate. In vitro data demonstrated that red blood cells have high capacity for metabolism of lisdexamfetamine; substantial hydrolysis occurred even at low hematocrit levels (33% of normal). Lisdexamfetamine is not metabolized by cytochrome P450 enzymes. Excretion Following oral administration of 70 mg dose of radiolabeled lisdexamfetamine dimesylate to healthy subjects, approximately 96% of the oral dose radioactivity was recovered in the urine and only 0.3% recovered in the feces over period of 120 hours. Of the radioactivity recovered in the urine, 42% of the dose was related to amphetamine, 25% to hippuric acid, and 2% to intact lisdexamfetamine.Specific Populations Exposures of dextroamphetamine in specific populations are summarized in Figure 1. Figure 1: Specific Populations: Figure shows the geometric mean ratios and the 90% confidence limits for Cmax and AUC of d-amphetamine. Comparison for gender uses males as the reference. Comparison for age uses 55-64 years as the reference.Drug Interaction Studies Effects of other drugs on the exposures of dextroamphetamine are summarized in Figure 2. Figure 2: Effect of Other Drugs on Lisdexamfetamine Dimesylate: The effects of Lisdexamfetamine dimesylate on the exposures of other drugs are summarized in Figure 3. Figure 3: Effect of Lisdexamfetamine Dimesylate on Other Drugs:. figure-1.jpg. figure-2.jpg. figure-3.jpg.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Attention Deficit Hyperactivity Disorder (ADHD) Pediatric Patients Ages to 12 Years with ADHD: double-blind, randomized, placebo-controlled, parallel-group study (Study 1) was conducted in pediatric patients ages to 12 years (N=290) who met DSM-IV criteria for ADHD (either the combined type or the hyperactive-impulsive type). Patients were randomized to receive final doses of 30 mg, 50 mg, or 70 mg of lisdexamfetamine dimesylate or placebo once daily in the morning for total of four weeks of treatment. All patients receiving lisdexamfetamine dimesylate were initiated on 30 mg for the first week of treatment. Patients assigned to the 50 mg and 70 mg dose groups were titrated by 20 mg per week until they achieved their assigned dose. The primary efficacy outcome was change in Total Score from baseline to endpoint in investigator ratings on the ADHD Rating Scale (ADHD-RS), an 18-text questionnaire with score range of 0-54 points that measures the core symptoms of ADHD which includes both hyperactive/impulsive and inattentive subscales. Endpoint was defined as the last post-randomization treatment week (i.e., Weeks through 4) for which valid score was obtained. All lisdexamfetamine dimesylate dose groups were superior to placebo in the primary efficacy outcome. Mean effects at all doses were similar; however, the highest dose (70 mg/day) was numerically superior to both lower doses (Study in Table 6). The effects were maintained throughout the day based on parent ratings (Conners Parent Rating Scale) in the morning (approximately 10 am), afternoon (approximately pm), and early evening (approximately pm).A double-blind, placebo-controlled, randomized, crossover design, analog classroom study (Study 2) was conducted in pediatric patients ages to 12 years (N=52) who met DSM-IV criteria for ADHD (either the combined type or the hyperactive-impulsive type). Following 3-week open-label dose optimization with Adderall XR(R), patients were randomly assigned to continue their optimized dose of Adderall XR (10 mg, 20 mg, or 30 mg), lisdexamfetamine dimesylate (30 mg, 50 mg, or 70 mg), or placebo once daily in the morning for week each treatment. Efficacy assessments were conducted at 1, 2, 3, 4.5, 6, 8, 10, and 12 hours post-dose using the Swanson, Kotkin, Agler, M. Flynn, and Pelham Deportment scores (SKAMP-DS), 4-text subscale of the SKAMP with scores ranging from to 24 points that measures deportment problems leading to classroom disruptions. significant difference in patient behavior, based upon the average of investigator ratings on the SKAMP-DS across the assessments were observed between patients when they received lisdexamfetamine dimesylate compared to patients when they received placebo (Study in Table 6). The drug effect reached statistical significance from hours to 12 post-dose, but was not significant at hour.A second double-blind, placebo-controlled, randomized, crossover design, analog classroom study (Study 3) was conducted in pediatric patients ages to 12 years (N=129) who met DSMIV criteria for ADHD (either the combined type or the hyperactive-impulsive type). Following 4-week open-label dose optimization with lisdexamfetamine dimesylate (30 mg, 50 mg, 70 mg), patients were randomly assigned to continue their optimized dose of lisdexamfetamine dimesylate or placebo once daily in the morning for week each treatment. significant difference in patient behavior, based upon the average of investigator ratings on the SKAMP-Deportment scores across all assessments conducted at 1.5, 2.5, 5.0, 7.5, 10.0, 12.0, and 13.0 hours post-dose, were observed between patients when they received lisdexamfetamine dimesylate compared to patients when they received placebo (Study in Table 6, Figure 4).Pediatric Patients Ages 13 to 17 Years with ADHD: double-blind, randomized, placebo-controlled, parallel-group study (Study 4) was conducted in pediatric patients ages 13 to 17 years (N=314) who met DSM-IV criteria for ADHD. In this study, patients were randomized in 1:1:1:1 ratio to daily morning dose of lisdexamfetamine dimesylate (30 mg/day, 50 mg/day or 70 mg/day) or placebo for total of four weeks of treatment. All patients receiving lisdexamfetamine dimesylate were initiated on 30 mg for the first week of treatment. Patients assigned to the 50 mg and 70 mg dose groups were titrated by 20 mg per week until they achieved their assigned dose. The primary efficacy outcome was change in Total Score from baseline to endpoint in investigator ratings on the ADHD Rating Scale (ADHD-RS). Endpoint was defined as the last post-randomization treatment week (i.e., Weeks through 4) for which valid score was obtained. All lisdexamfetamine dimesylate dose groups were superior to placebo in the primary efficacy outcome (Study in Table 6).Pediatric Patients Ages to 17 Years: Short-Term Treatment in ADHD: double-blind, randomized, placebo- and active-controlled parallel-group, dose-optimization study (Study 5) was conducted in pediatric patients ages to 17 years (n=336) who met DSM-IV criteria for ADHD. In this eight-week study, patients were randomized to daily morning dose of lisdexamfetamine dimesylate (30, 50 or 70 mg/day), an active control, or placebo (1:1:1). The study consisted of Screening and Washout Period (up to 42 days), 7-week Double-blind Evaluation Period (consisting of 4-week Dose-Optimization Period followed by 3-week Dose-Maintenance Period), and 1-week Washout and Follow-up Period. During the Dose Optimization Period, subjects were titrated until an optimal dose, based on tolerability and investigators judgment, was reached. Lisdexamfetamine dimesylate showed significantly greater efficacy than placebo. The placebo-adjusted mean reduction from baseline in the ADHD-RS-IV total score was 18.6. Subjects on lisdexamfetamine dimesylate also showed greater improvement on the Clinical Global Impression-Improvement (CGI-I) rating scale compared to subjects on placebo (Study in Table 6). Pediatric Patients Ages to 17 Years: Maintenance Treatment in ADHD:Maintenance of Efficacy Study (Study 6) A double-blind, placebo-controlled, randomized withdrawal study was conducted in pediatric patients ages to 17 years (N=276) who met the diagnosis of ADHD (DSM-IV criteria). total of 276 patients were enrolled into the study, 236 patients participated in Study and 40 subjects directly enrolled. Subjects were treated with open-label lisdexamfetamine dimesylate for at least 26 weeks prior to being assessed for entry into the randomized withdrawal period. Eligible patients had to demonstrate treatment response as defined by CGI-S <3 and Total Score on the ADHD-RS <=22. Patients that maintained treatment response for weeks at the end of the open label treatment period were eligible to be randomized to ongoing treatment with the same dose of lisdexamfetamine dimesylate (N=78) or switched to placebo (N=79) during the double-blind phase. Patients were observed for relapse (treatment failure) during the week double blind phase. significantly lower proportion of treatment failures occurred among lisdexamfetamine dimesylate subjects (15.8%) compared to placebo (67.5%) at endpoint of the randomized withdrawal period. The endpoint measurement was defined as the last post-randomization treatment week at which valid ADHD-RS Total Score and CGI-S were observed. Treatment failure was defined as >=50% increase (worsening) in the ADHD-RS Total Score and >=2-point increase in the CGI-S score compared to scores at entry into the double-blind randomized withdrawal phase. Subjects who withdrew from the randomized withdrawal period and who did not provide efficacy data at their last on-treatment visit were classified as treatment failures (Study 6, Figure 5).Adults: Short-Term Treatment in ADHD: double-blind, randomized, placebo-controlled, parallel-group study (Study 7) was conducted in adults ages 18 to 55 (N=420) who met DSM-IV criteria for ADHD. In this study, patients were randomized to receive final doses of 30 mg, 50 mg, or 70 mg of lisdexamfetamine dimesylate or placebo for total of four weeks of treatment. All patients receiving lisdexamfetamine dimesylate were initiated on 30 mg for the first week of treatment. Patients assigned to the 50 mg and 70 mg dose groups were titrated by 20 mg per week until they achieved their assigned dose. The primary efficacy outcome was change in Total Score from baseline to endpoint in investigator ratings on the ADHD Rating Scale (ADHD-RS). Endpoint was defined as the last post-randomization treatment week (i.e., Weeks through 4) for which valid score was obtained. All lisdexamfetamine dimesylate dose groups were superior to placebo in the primary efficacy outcome (Study in Table 6).The second study was multi-center, randomized, double-blind, placebo-controlled, cross-over, modified analog classroom study (Study 8) of lisdexamfetamine dimesylate to simulate workplace environment in 142 adults ages 18 to 55 who met DSM-IV-TR criteria for ADHD. There was 4-week open-label, dose optimization phase with lisdexamfetamine dimesylate (30 mg/day, 50 mg/day, or 70 mg/day in the morning). Patients were then randomized to one of two treatment sequences: 1) lisdexamfetamine dimesylate (optimized dose) followed by placebo, each for one week, or 2) placebo followed by lisdexamfetamine dimesylate, each for one week. Efficacy assessments occurred at the end of each week, using the Permanent Product Measure of Performance (PERMP), skill-adjusted math test that measures attention in ADHD. PERMP total score results from the sum of the number of math problems attempted plus the number of math problems answered correctly. Lisdexamfetamine dimesylate treatment, compared to placebo, resulted in statistically significant improvement in attention across all post-dose time points, as measured by average PERMP total scores over the course of one assessment day, as well as at each time point measured. The PERMP assessments were administered at pre-dose (-0.5 hours) and at 2, 4, 8, 10, 12, and 14 hours post-dose (Study in Table 6, Figure 6).Adults: Maintenance Treatment in ADHD: double-blind, placebo-controlled, randomized withdrawal design study (Study 9) was conducted in adults ages 18 to 55 (N=123) who had documented diagnosis of ADHD or met DSM-IV criteria for ADHD. At study entry, patients must have had documentation of treatment with lisdexamfetamine dimesylate for minimum of months and had to demonstrate treatment response as defined by Clinical Global Impression Severity (CGI-S) <=3 and Total Score on the ADHD-RS <22. ADHD-RS Total Score is measure of core symptoms of ADHD. The CGI-S score assesses the clinicians impression of the patients current illness state and ranges from (not at all ill) to (extremely ill). Patients that maintained treatment response at Week of the open label treatment phase (N=116) were eligible to be randomized to ongoing treatment with the same dose of lisdexamfetamine dimesylate (N=56) or switched to placebo (N=60) during the double-blind phase. Patients were observed for relapse (treatment failure) during the 6-week double-blind phase. The efficacy endpoint was the proportion of patients with treatment failure during the double-blind phase. Treatment failure was defined as >=50% increase (worsening) in the ADHD-RS Total Score and >=2-point increase in the CGI-S score compared to scores at entry into the double-blind phase. Maintenance of efficacy for patients treated with lisdexamfetamine dimesylate was demonstrated by the significantly lower proportion of patients with treatment failure (9%) compared to patients receiving placebo (75%) at endpoint during the double-blind phase (Study 9, Figure 7).Table 6: Summary of Primary Efficacy Results from Short-term Studies of Lisdexamfetamine dimesylate in Pediatric Patients (Ages to 17) and Adults with ADHDStudy No.(Age range)Primary EndpointTreatment Group Mean Baseline Score(SD)LS Mean Changefrom Baseline (SE)Placebo-subtractedDifferencea (95% CI)Study (6 -12 years) ADHD-RSIV lisdexamfetamine dimesylate (30 mg/day)Doses statistically significantly superior to placebo. 43.2 (6.7)-21.8 (1.6)-15.6 (-19.9, -11.2)lisdexamfetamine dimesylate (50 mg/day) 43.3 (6.7)-23.4 (1.6)-17.2 (-21.5, -12.9)lisdexamfetamine dimesylate (70 mg/day) 45.1(6.8)-26.7 (1.5)-20.5 (-24.8, -16.2)Placebo 42.4 (7.1)-6.2 (1.6)--Study (6 -12 years) Average SKAMP-DS lisdexamfetamine dimesylate (30, 50 or 70 mg/day) --b 0.8 (0.1)d -0.9 (-1.1, -0.7)Placebo--b 1.7 (0.1)d --Study (6 -12 years) Average SKAMP-DS lisdexamfetamine dimesylate (30, 50 or 70 mg/day) 0.9 (1.0)c 0.7 (0.1)d -0.7 (-0.9, -0.6)Placebo0.7 (0.9)c 1.4 (0.1)d --Study (13 -17 years) ADHD-RS-IV lisdexamfetamine dimesylate (30 mg/day) 38.3 (6.7) -18.3 (1.2)-5.5 (-9.0, -2.0) lisdexamfetamine dimesylate (50 mg/day) 37.3 (6.3)-21.1 (1.3)-8.3 (-11.8, -4.8) lisdexamfetamine dimesylate (70 mg/day) 37.0 (7.3)-20.7 (1.3)-7.9 (-11.4, -4.5) Placebo38.5 (7.1)-12.8 (1.2)--Study (6 -17 years) ADHD-RS-IV lisdexamfetamine dimesylate (30, 50 or 70 mg/day) 40.7 (7.3)-24.3 (1.2)-18.6 (-21.5, -15.7)Placebo41.0 (7.1)-5.7 (1.1)--Study (18 -55 years) ADHD-RS-IV lisdexamfetamine dimesylate (30 mg/day) 40.5 (6.2)-16.2 (1.1)-8.0 (-11.5, -4.6) lisdexamfetamine dimesylate (50 mg/day) 40.8 (7.3)-17.4 (1.0)-9.2 (-12.6, -5.7) lisdexamfetamine dimesylate (70 mg/day) 41.0 (6.0)-18.6 (1.0)-10.4 (-13.9, -6.9) Placebo39.4 (6.4)-8.2 (1.4)--Study (18 -55 years) Average PERMP lisdexamfetamine dimesylate (30, 50 or 70 mg/day) 260.1 (86.2)c 312.9 (8.6)d 23.4 (15.6, 31.2)Placebo261.4 (75.0)c 289.5 (8.6)d --SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.a Difference (drug minus placebo) in least-squares mean change from baseline.b Pre-dose SKAMP-DS was not collected.c Pre-dose SKAMP-DS (Study 3) or PERMP (Study 8) total score, averaged over both periods.d LS Mean for SKAMP-DS (Study and 3) or PERMP (Study 8) is post-dose average score over all sessions of the treatment day, rather than change from baseline.Figure LS Mean SKAMP Deportment Subscale Score by Treatment and Time-point for Pediatric Patients Ages to 12 with ADHD after Week of Double Blind Treatment (Study 3) Higher score on the SKAMP-Deportment scale indicates more severe symptoms.Figure Kaplan-Meier Estimated Proportion of Patients with Treatment Failure for Pediatric Patients Ages to 17 (Study 6)Figure LS Mean (SE) PERMP Total Score by Treatment and Time-point for Adults Ages 18 to 55 with ADHD after Week of Double Blind Treatment (Study 8)Higher score on the PERMP scale indicates less severe symptoms.Figure Kaplan-Meier Estimated Proportion of Subjects with Relapse in Adults with ADHD (Study 9) figure 4.jpg. figure-5.jpg. image-6.jpg. image-7.jpg. 14.2 Binge Eating Disorder (BED) A phase study evaluated the efficacy of lisdexamfetamine dimesylate 30, 50 and 70 mg/day compared to placebo in reducing the number of binge days/week in adults with at least moderate to severe BED. This randomized, double-blind, parallel-group, placebo-controlled, forced-dose titration study (Study 10) consisted of an 11-week double-blind treatment period (3 weeks of forced-dose titration followed by weeks of dose maintenance). Lisdexamfetamine dimesylate 30 mg/day was not statistically different from placebo on the primary endpoint. The 50 and 70 mg/day doses were statistically superior to placebo on the primary endpoint. The efficacy of lisdexamfetamine dimesylate in the treatment of BED was demonstrated in two 12-week randomized, double-blind, multi-center, parallel-group, placebo-controlled, dose-optimization studies (Study 11 and Study 12) in adults aged 18-55 years (Study 11: N=374, Study 12: N=350) with moderate to severe BED. diagnosis of BED was confirmed using DSM-IV criteria for BED. Severity of BED was determined based on having at least binge days per week for weeks prior to the baseline visit and on having Clinical Global Impression Severity (CGI-S) score of >=4 at the baseline visit. For both studies, binge day was defined as day with at least binge episode, as determined from the subjects daily binge diary. Both 12-week studies consisted of 4-week dose-optimization period and an 8-week dose-maintenance period. During dose-optimization, subjects assigned to lisdexamfetamine dimesylate began treatment at the titration dose of 30 mg/day and, after week of treatment, were subsequently titrated to 50 mg/day. Additional increases to 70 mg/day were made as tolerated and clinically indicated. Following the dose-optimization period, subjects continued on their optimized dose for the duration of the dose-maintenance period. The primary efficacy outcome for the two studies was defined as the change from baseline at Week 12 in the number of binge days per week. Baseline is defined as the weekly average of the number of binge days per week for the 14 days prior to the baseline visit. Subjects from both studies on lisdexamfetamine dimesylate had statistically significantly greater reduction from baseline in mean number of binge days per week at Week 12. In addition, subjects on lisdexamfetamine dimesylate showed greater improvement as compared to placebo across key secondary outcomes with higher proportion of subjects rated improved on the CGI-I rating scale, higher proportion of subjects with 4-week binge cessation, and greater reduction in the Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (Y-BOCS-BE) total score.Table 7: Summary of Primary Efficacy Results in BEDStudyNumberTreatment GroupPrimary Efficacy Measure: Binge Days per Week at Week 12Mean Baseline Score (SD)LS Mean Change from Baseline (SE)Placebo-subtracted Differencea (95% CI) Study 11 lisdexamfetamine dimesylate (50 or 70 mg/day)Doses statistically significantly superior to placebo. Placebo4.79 (1.27)4.60 (1.21)-3.87 (0.12)-2.51 (0.13)-1.35 (-1.70, -1.01)--Study 12 lisdexamfetamine dimesylate (50 or 70 mg/day) Placebo4.66 (1.27)4.82 (1.42)-3.92 (0.14)-2.26 (0.14)-1.66 (-2.04, -1.28)--SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.a Difference (drug minus placebo) in least-squares mean change from baseline. double-blind, placebo controlled, randomized withdrawal design study (Study 13) was conducted to evaluate maintenance of efficacy based on time to relapse between lisdexamfetamine dimesylate and placebo in adults aged 18 to 55 (N=267) with moderate to severe BED. In this longer-term study patients who had responded to lisdexamfetamine dimesylate in the preceding 12-week open-label treatment phase were randomized to continuation of lisdexamfetamine dimesylate or placebo for up to 26 weeks of observation for relapse. Response in the open-label phase was defined as or fewer binge days each week for four consecutive weeks prior to the last visit at the end of the 12-week open-label phase and CGIS score of or less at the same visit. Relapse during the double-blind phase was defined as having or more binge days each week for two consecutive weeks (14 days) prior to any visit and having an increase in CGI-S score of or more points compared to the randomized-withdrawal baseline. Maintenance of efficacy for patients who had an initial response during the open-label period and then continued on lisdexamfetamine dimesylate during the 26-week double-blind randomized-withdrawal phase was demonstrated with lisdexamfetamine dimesylate being superior over placebo as measured by time to relapse.Figure Kaplan-Meier Estimated Proportions of Subjects with Relapse in Adults with BED (Study 13)Examination of population subgroups based on age (there were no patients over 65), gender, and race did not reveal any clear evidence of differential responsiveness in the treatment of BED.. figure-8.jpg.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Lisdexamfetamine dimesylate capsules are contraindicated in patients with:oKnown hypersensitivity to amphetamine products or other ingredients of lisdexamfetamine dimesylate capsules. Anaphylactic reactions, Stevens-Johnson Syndrome, angioedema, and urticaria have been observed in postmarketing reports [see Adverse Reactions (6.2)].oPatients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping MAOIs (including MAOIs such as linezolid or intravenous methylene blue), because of an increased risk of hypertensive crisis [see Warnings and Precautions (5.7) and Drug Interactions (7.1)]. oKnown hypersensitivity to amphetamine products or other ingredients of lisdexamfetamine dimesylate capsules. Anaphylactic reactions, Stevens-Johnson Syndrome, angioedema, and urticaria have been observed in postmarketing reports [see Adverse Reactions (6.2)].. oPatients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping MAOIs (including MAOIs such as linezolid or intravenous methylene blue), because of an increased risk of hypertensive crisis [see Warnings and Precautions (5.7) and Drug Interactions (7.1)]. oKnown hypersensitivity to amphetamine products or other ingredients in lisdexamfetamine dimesylate capsules (4) oUse with monoamine oxidase (MAO) inhibitor, or within 14 days of the last MAO inhibitor dose (4, 7.2). oKnown hypersensitivity to amphetamine products or other ingredients in lisdexamfetamine dimesylate capsules (4) oUse with monoamine oxidase (MAO) inhibitor, or within 14 days of the last MAO inhibitor dose (4, 7.2).

CONTROLLED SUBSTANCE SECTION.

9.1 Controlled Substance. Lisdexamfetamine dimesylate capsules contain lisdexamfetamine, prodrug of amphetamine, Schedule II controlled substance.

DESCRIPTION SECTION.

11 DESCRIPTION. Lisdexamfetamine dimesylate capsules, CNS stimulant, are capsules for once-a-day oral administration. The chemical designation for lisdexamfetamine dimesylate is (2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl] hexanamide dimethanesulfonate. The molecular formula is C15H25N3Oo(CH4O3S)2, which corresponds to molecular weight of 455.60. The chemical structure is: Lisdexamfetamine dimesylate is white to off-white powder that is soluble in water (792 mg/mL). Lisdexamfetamine dimesylate capsules contain 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg of lisdexamfetamine dimesylate (equivalent to 11.6 mg, 17.3 mg, 23.1 mg, 28.9 mg, 34.7 mg, and 40.5 mg of lisdexamfetamine) and the following inactive ingredients: ammonium hydroxide, calcium phosphate, gelatin, iron oxide black, isopropyl alcohol, magnesium stearate, microcrystalline cellulose, n-butyl alcohol, propylene glycol, shellac glaze, sodium starch glycolate, and titanium dioxide. In addition, the 20 mg capsule also contains yellow iron oxide. The 30 mg capsule also contains FD&C yellow 6. The 40 mg capsule also contains FD&C blue and FD&C green 3. The 50 mg and 60 mg capsules also contain D&C red 28 and FD&C blue 1. The 70 mg capsule also contains D&C red 28, FD&C blue 1, and FD&C yellow 6.. Lisdexamfetamine pan black.jpg.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Indicated Population Initial Dose Titration Schedule Recommended Dose Maximum Dose ADHD (Adults and pediatric patients years and older) (2.2) 30 mg every morning 10 mg or 20 mg weekly 30 mg to 70 mg per day 70 mg per day BED (Adults) (2.3) 30 mg every morning 20 mg weekly 50 mg to 70 mg per day 70 mg per dayoPrior to treatment, assess for presence of cardiac disease (2.4)oSevere renal impairment: Maximum dose is 50 mg/day (2.5)oEnd stage renal disease (ESRD): Maximum dose is 30 mg/day (2.5). Indicated Population. Initial Dose. Titration Schedule. Recommended Dose. Maximum Dose. ADHD. (Adults and pediatric patients years and older) (2.2). 30 mg every morning. 10 mg or 20 mg weekly. 30 mg to 70 mg per day. 70 mg per day. BED (Adults) (2.3). 30 mg every morning. 20 mg weekly. 50 mg to 70 mg per day. 70 mg per day. oPrior to treatment, assess for presence of cardiac disease (2.4). oSevere renal impairment: Maximum dose is 50 mg/day (2.5). oEnd stage renal disease (ESRD): Maximum dose is 30 mg/day (2.5). 2.1 Pre-treatment Screening. Prior to treating patients with CNS stimulants, including lisdexamfetamine dimesylate capsules, assess for the presence of cardiac disease (e.g., careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)].To reduce the abuse of CNS stimulants including lisdexamfetamine dimesylate capsules, assess the risk of abuse, prior to prescribing. After prescribing, keep careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and re-evaluate the need for lisdexamfetamine dimesylate capsules use [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9)].. 2.2 General Instructions for Use. Take lisdexamfetamine dimesylate capsules by mouth in the morning with or without food; avoid afternoon doses because of the potential for insomnia. Lisdexamfetamine dimesylate capsules may be administered in one of the following ways:Information for lisdexamfetamine dimesylate capsules:oSwallow lisdexamfetamine dimesylate capsules whole, oroOpen capsules, empty and mix the entire contents with yogurt, water, or orange juice. If the contents of the capsule include any compacted powder, spoon may be used to break apart the powder. The contents should be mixed until completely dispersed. Consume the entire mixture immediately. It should not be stored. The active ingredient dissolves completely once dispersed; however, film containing the inactive ingredients may remain in the glass or container once the mixture is consumed. Do not take anything less than one capsule per day. single dose should not be divided.. oSwallow lisdexamfetamine dimesylate capsules whole, or. oOpen capsules, empty and mix the entire contents with yogurt, water, or orange juice. If the contents of the capsule include any compacted powder, spoon may be used to break apart the powder. The contents should be mixed until completely dispersed. Consume the entire mixture immediately. It should not be stored. The active ingredient dissolves completely once dispersed; however, film containing the inactive ingredients may remain in the glass or container once the mixture is consumed. Do not take anything less than one capsule per day. single dose should not be divided.. 2.3 Dosage for Treatment of ADHD. The recommended starting dosage in adults and pediatric patients years and older is 30 mg once daily in the morning. Dosage may be adjusted in increments of 10 mg or 20 mg at approximately weekly intervals up to maximum recommended dosage of 70 mg once daily [see Clinical Studies 14.1)].. 2.4 Dosage for Treatment of Moderate to Severe BED in Adults. The recommended starting dosage in adults is 30 mg once daily to be titrated in increments of 20 mg at approximately weekly intervals to achieve the recommended target dose of 50 mg to 70 mg once daily. The maximum recommended dosage is 70 mg once daily [see Clinical Studies (14.2)]. Discontinue lisdexamfetamine dimesylate if binge eating does not improve.. 2.5 Dosage in Patients with Renal Impairment In patients with severe renal impairment (GFR 15 to 30 mL/min/1.73 m2), the maximum dosage should not exceed 50 mg once daily. In patients with end stage renal disease (ESRD, GFR 15 mL/min/1.73 m2), the maximum recommended dosage is 30 mg once daily [see Use in Specific Populations (8.6)]. 2.6 Dosage Modifications due to Drug Interactions Agents that alter urinary pH can impact urinary excretion and alter blood levels of amphetamine. Acidifying agents (e.g., ascorbic acid) decrease blood levels, while alkalinizing agents (e.g., sodium bicarbonate) increase blood levels. Adjust lisdexamfetamine dimesylate dosage accordingly [see Drug Interactions 7.1)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Lisdexamfetamine dimesylate capsules 20 mg: ivory body/ivory cap (imprinted with 54 990)Lisdexamfetamine dimesylate capsules 30 mg: white body/orange cap (imprinted with 54 682)Lisdexamfetamine dimesylate capsules 40 mg: white body/light green cap (imprinted with 54 098)Lisdexamfetamine dimesylate capsules 50 mg: white body/blue cap (imprinted with 54 296)Lisdexamfetamine dimesylate capsules 60 mg: blue body/blue cap (imprinted with 54 338)Lisdexamfetamine dimesylate capsules 70 mg: orange body/blue cap (imprinted with 54 818). oCapsules: 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg (3). oCapsules: 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg (3).

DRUG ABUSE AND DEPENDENCE SECTION.

9 DRUG ABUSE AND DEPENDENCE. 9.1 Controlled Substance. Lisdexamfetamine dimesylate capsules contain lisdexamfetamine, prodrug of amphetamine, Schedule II controlled substance.. 9.2 Abuse. CNS stimulants, including lisdexamfetamine dimesylate capsules, other amphetamine-containing products, and methylphenidate have high potential for abuse. Abuse is the intentional non-therapeutic use of drug, even once, to achieve desired psychological or physiological effect. Abuse is characterized by impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is cluster of behavioral, cognitive, and physiological phenomena that may include strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Both abuse and misuse may lead to addiction, and some individuals may develop addiction even when taking lisdexamfetamine dimesylate capsules as prescribed.Signs and symptoms of amphetamine abuse may include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, suicidal or homicidal ideation have also been seen. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which can result in overdose and death [see Overdosage 10)].To reduce the abuse of CNS stimulants, including lisdexamfetamine dimesylate capsules, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants. Monitor for signs of abuse while on therapy, and re-evaluate the need for lisdexamfetamine dimesylate capsules use.Studies of Lisdexamfetamine Dimesylate Capsules in Drug Abusers: randomized, double-blind, placebo-control, cross-over, abuse liability study in 38 patients with history of drug abuse was conducted with single-doses of 50, 100, or 150 mg of lisdexamfetamine dimesylate capsules, 40 mg of immediate-release d-amphetamine sulphate (a controlled II substance), and 200 mg of diethylpropion hydrochloride (a controlled IV substance). Lisdexamfetamine dimesylate capsules 100 mg produced significantly less Drug Liking Effects as measured by the Drug Rating Questionnaire-Subject score, compared to d-amphetamine 40 mg; and 150 mg of lisdexamfetamine dimesylate capsules demonstrated similar Drug-Liking Effects compared to 40 mg of d-amphetamine and 200 mg of diethylpropion. Intravenous administration of 50 mg lisdexamfetamine dimesylate to individuals with history of drug abuse produced positive subjective responses on scales measuring Drug Liking, Euphoria, Amphetamine Effects, and Benzedrine Effects that were greater than placebo but less than those produced by an equivalent dose (20 mg) of intravenous d-amphetamine.. 9.3 Dependence Physical Dependence: Lisdexamfetamine dimesylate capsules may produce physical dependence from continued therapy. Physical dependence is state of adaptation manifested by withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include extreme fatigue and depression. Tolerance: lisdexamfetamine dimesylate capsules may produce tolerance from continued therapy. Tolerance is state of adaptation in which exposure to specific dose of drug results in reduction of the drugs desired and/or undesired effects over time.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Acidifying and Alkalinizing Agents: Agents that alter urinary pH can alter blood levels of amphetamine. Acidifying agents decrease amphetamine blood levels, while alkalinizing agents increase amphetamine blood levels. Adjust lisdexamfetamine dimesylate dosage accordingly (2.6, 7.1). 7.1 Drugs Having Clinically Important Interactions with Amphetamines. Table Drugs having clinically important interactions with amphetamines.MAO Inhibitors (MAOI)Clinical Impact MAOI antidepressants slow amphetamine metabolism, increasing amphetamines effect on the release of norepinephrine and other monoamines from adrenergic nerve endings causing headaches and other signs of hypertensive crisis. Toxic neurological effects and malignant hyperpyrexia can occur, sometimes with fatal results. Intervention Do not administer lisdexamfetamine dimesylate during or within 14 days following the administration of MAOI [see Contraindications (4)]. Serotonergic Drugs Clinical Impact The concomitant use of lisdexamfetamine dimesylate and serotonergic drugs increases the risk of serotonin syndrome. Intervention Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during lisdexamfetamine dimesylate initiation or dosage increase. If serotonin syndrome occurs, discontinue lisdexamfetamine dimesylate and the concomitant serotonergic drug(s) [see Warnings and Precautions (5.7)]. CYP2D6 Inhibitors Clinical Impact The concomitant use of lisdexamfetamine dimesylate and CYP2D6 inhibitors may increase the exposure of dextroamphetamine, the active metabolite of lisdexamfetamine dimesylate compared to the use of the drug alone and increase the risk of serotonin syndrome. Intervention Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during lisdexamfetamine dimesylate initiation and after dosage increase. If serotonin syndrome occurs, discontinue lisdexamfetamine dimesylate and the CYP2D6 inhibitor [see Warnings and Precautions (5.7) and Overdosage (10)]. Alkalinizing Agents Clinical Impact Urinary alkalinizing agents can increase blood levels and potentiate the action of amphetamine. Intervention Co-administration of lisdexamfetamine dimesylate and urinary alkalinizing agents should be avoided. Acidifying Agents Clinical Impact Urinary acidifying agents can lower blood levels and efficacy of amphetamines. Intervention Increase dose based on clinical response. Tricyclic AntidepressantsClinical Impact May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. Intervention Monitor frequently and adjust or use alternative therapy based on clinical response. 7.2 Drugs Having No Clinically Important Interactions with Lisdexamfetamine Dimesylate. From pharmacokinetic perspective, no dose adjustment of lisdexamfetamine dimesylate is necessary when lisdexamfetamine dimesylate is co-administered with guanfacine, venlafaxine, or omeprazole. In addition, no dose adjustment of guanfacine or venlafaxine is needed when lisdexamfetamine dimesylate is co-administered [see Clinical Pharmacology 12.3)]. From pharmacokinetic perspective, no dose adjustment for drugs that are substrates of CYP1A2 (e.g., theophylline, duloxetine, melatonin), CYP2D6 (e.g., atomoxetine, desipramine, venlafaxine), CYP2C19 (e.g., omeprazole, lansoprazole, clobazam), and CYP3A4 (e.g., midazolam, pimozide, simvastatin) is necessary when lisdexamfetamine dimesylate is co-administered [see Clinical Pharmacology 12.3)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of lisdexamfetamine dimesylate capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience and pharmacokinetic data [see Clinical Pharmacology (12.3)] have not identified differences in responses between the elderly and younger patients. 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. Lisdexamfetamine dimesylate capsules 20 mg: ivory body/ivory cap (imprinted with 54 990) Bottle of 30, NDC 0054-0370-13; Bottle of 100, NDC 0054-0370-25Lisdexamfetamine dimesylate capsules 30 mg: white body/orange cap (imprinted with 54 682) Bottle of 30, NDC 0054-0371-13; Bottle of 100, NDC 0054-0371-25Lisdexamfetamine dimesylate capsules 40 mg: white body/light green cap (imprinted with 54 098) Bottle of 30, NDC 0054-0372-13; Bottle of 100, NDC 0054-0372-25Lisdexamfetamine dimesylate capsules 50 mg: white body/blue cap (imprinted with 54 296) Bottle of 30, NDC 0054-0373-13; Bottle of 100, NDC 0054-0373-25Lisdexamfetamine dimesylate capsules 60 mg: blue body/blue cap (imprinted with 54 338) Bottle of 30, NDC 0054-0374-13; Bottle of 100, NDC 0054-0374-25Lisdexamfetamine dimesylate capsules 70 mg: orange body/blue cap (imprinted with 54 818) Bottle of 30, NDC 0054-0375-13; Bottle of 100, NDC 0054-0375-25. 16.2 Storage and Handling. Dispense in tight, light-resistant container as defined in the USP.Store at 20 to 25C (68 to 77F). Excursions permitted between 15o to 30oC (59 to 86oF) [See USP Controlled Room Temperature].Disposal: Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired lisdexamfetamine dimesylate capsules by medicine take-back program.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Lisdexamfetamine Dimesylate Capsules are indicated for the treatment of: oAttention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients years and older [see Clinical Studies (14.1)] oModerate to severe binge eating disorder (BED) in adults [see Clinical Studies (14.2)]Limitations of Use:oPediatric patients with ADHD younger than years of age experienced more long-term weight loss than patients years and older[see Use in Specific Populations (8.4)].oLisdexamfetamine dimesylate capsules are not indicated or recommended for weight loss. Use of other sympathomimetic drugs for weight loss has been associated with serious cardiovascular adverse events. The safety and effectiveness of lisdexamfetamine dimesylate capsules for the treatment of obesity have not been established [see Warnings and Precautions (5.2)].. oAttention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients years and older [see Clinical Studies (14.1)] oModerate to severe binge eating disorder (BED) in adults [see Clinical Studies (14.2)]Limitations of Use:. oPediatric patients with ADHD younger than years of age experienced more long-term weight loss than patients years and older[see Use in Specific Populations (8.4)].. oLisdexamfetamine dimesylate capsules are not indicated or recommended for weight loss. Use of other sympathomimetic drugs for weight loss has been associated with serious cardiovascular adverse events. The safety and effectiveness of lisdexamfetamine dimesylate capsules for the treatment of obesity have not been established [see Warnings and Precautions (5.2)].. Lisdexamfetamine dimesylate capsules are central nervous system (CNS) stimulant indicated for the treatment of (1): oAttention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients years and olderoModerate to severe binge eating disorder (BED) in adultsLimitations of Use:oPediatric patients with ADHD younger than years of age experienced more long-term weight loss than patients years and older (8.4)oLisdexamfetamine dimesylate capsules are not indicated for weight loss. Use of other sympathomimetic drugs for weight loss has been associated with serious cardiovascular adverse events. The safety and effectiveness of lisdexamfetamine dimesylate capsules for the treatment of obesity have not been established (5.2). oAttention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients years and olderoModerate to severe binge eating disorder (BED) in adultsLimitations of Use:. oAttention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients years and older. oModerate to severe binge eating disorder (BED) in adultsLimitations of Use:. oPediatric patients with ADHD younger than years of age experienced more long-term weight loss than patients years and older (8.4). oLisdexamfetamine dimesylate capsules are not indicated for weight loss. Use of other sympathomimetic drugs for weight loss has been associated with serious cardiovascular adverse events. The safety and effectiveness of lisdexamfetamine dimesylate capsules for the treatment of obesity have not been established (5.2).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide). Controlled Substance Status/High Potential for Abuse and Dependence: Advise patients that lisdexamfetamine dimesylate is controlled substance and it can be abused and lead to dependence and not to give lisdexamfetamine dimesylate to anyone else [see Drug Abuse and Dependence (9.1, 9.2, and 9.3)]. Advise patients to store lisdexamfetamine dimesylate in safe place, preferably locked, to prevent abuse. Advise patients to dispose of remaining, unused, or expired lisdexamfetamine dimesylate by medicine take-back program. Serious Cardiovascular Risks: Advise patients that there is potential serious cardiovascular risk including sudden death, myocardial infarction, stroke, and hypertension with lisdexamfetamine dimesylate use. Instruct patients to contact healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2)]. Hypertension and Tachycardia: Instruct patients that lisdexamfetamine dimesylate can cause elevations of their blood pressure and pulse rate and they should be monitored for such effects. Psychiatric Risks: Advise patients that lisdexamfetamine dimesylate at recommended doses may cause psychotic or manic symptoms even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4)]. Suppression of Growth: Advise patients that lisdexamfetamine dimesylate may cause slowing of growth including weight loss [see Warnings and Precautions (5.5)].Impairment in Ability to Operate Machinery or Vehicles: Advise patients that lisdexamfetamine dimesylate may impair their ability to engage in potentially dangerous activities such as operating machinery or vehicles. Instruct patients to find out how lisdexamfetamine dimesylate will affect them before engaging in potentially dangerous activities [see Adverse Reactions (6.1, 6.2)]. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynauds phenomenon]: Instruct patients beginning treatment with lisdexamfetamine dimesylate about the risk of peripheral vasculopathy, including Raynauds phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking lisdexamfetamine dimesylate. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions 5.6)]. Serotonin Syndrome: Caution patients about the risk of serotonin syndrome with concomitant use of lisdexamfetamine dimesylate and other serotonergic drugs including SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. Johns Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others such as linezolid [see Contraindications 4), Warnings and Precautions (5.7) and Drug Interactions (7.1)]. Advise patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome. Concomitant Medications: Advise patients to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs because there is potential for interactions [see Drug Interactions (7.1)].Pregnancy: Advise patients of the potential fetal effects from the use of lisdexamfetamine dimesylate during pregnancy. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with lisdexamfetamine dimesylate [see Use in Specific Populations (8.1)]. Lactation: Advise women not to breastfeed if they are taking lisdexamfetamine dimesylate [see Use in Specific Populations (8.2)]. Administration Instructions oCapsules: Advise patients to take the capsules whole or empty and mix the entire contents with yogurt, water, or orange juice. Advise patients to consume the mixture immediately and not to store for future use [see Dosage and Administration (2.2)]. Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922C50001173/02Revised June 2023. oCapsules: Advise patients to take the capsules whole or empty and mix the entire contents with yogurt, water, or orange juice. Advise patients to consume the mixture immediately and not to store for future use [see Dosage and Administration (2.2)].

LACTATION SECTION.

8.2 Lactation Risk SummaryLisdexamfetamine is pro-drug of dextroamphetamine. Based on limited case reports in published literature, amphetamine (d-or d, l-) is present in human milk, at relative infant doses of 2% to 13.8% of the maternal weight-adjusted dosage and milk/plasma ratio ranging between 1.9 and 7.5. There are no reports of adverse effects on the breastfed infant. Long-term neurodevelopmental effects on infants from amphetamine exposure are unknown. It is possible that large dosages of dextroamphetamine might interfere with milk production, especially in women whose lactation is not well established. Because of the potential for serious adverse reactions in nursing infants, including serious cardiovascular reactions, blood pressure and heart rate increase, suppression of growth, and peripheral vasculopathy, advise patients that breastfeeding is not recommended during treatment with lisdexamfetamine dimesylate.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis: Carcinogenicity studies of lisdexamfetamine dimesylate have not been performed. No evidence of carcinogenicity was found in studies in which d-, 1-amphetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and mg/kg/day in male and female rats.Mutagenesis: Lisdexamfetamine dimesylate was not clastogenic in the mouse bone marrow micronucleus test in vivo and was negative when tested in the E. coli and S. typhimurium components of the Ames test and in the L5178Y/TK+/- mouse lymphoma assay in vitro.Impairment of Fertility: Amphetamine (d- to 1-enantiomer ratio of 3:1) did not adversely affect fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day.. 13.2 Animal Toxicology and/or Pharmacology Acute administration of high doses of amphetamine (d- or d,1-) has been shown to produce long-lasting neurotoxic effects, including irreversible nerve fiber damage, in rodents. The significance of these findings to humans is unknown.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Consult with Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice for treatment of overdosage. Individual patient response to amphetamines varies widely. Toxic symptoms may occur idiosyncratically at low doses.Manifestations of amphetamine overdose include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation. Serotonin syndrome has been reported with amphetamine use, including lisdexamfetamine dimesylate. Cardiovascular effects include arrhythmias, hypertension or hypotension and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma. Lisdexamfetamine and d-amphetamine are not dialyzable.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL . 20mg-100tabs.jpg.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. ADHD Safety and effectiveness of lisdexamfetamine dimesylate have been established in pediatric patients with ADHD ages to 17 years [see Dosage and Administration 2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. Safety and effectiveness of lisdexamfetamine dimesylate have not been established in pediatric patients below the age of years. Safety and efficacy of lisdexamfetamine dimesylate were evaluated in double-blind, randomized, parallel-group, placebo-controlled, fixed-dose study in pediatric patients ages to years with ADHD, followed by 1-year open-label extension study. In these studies, patients experienced elevated rates of adverse reactions, including weight loss, decreased BMI, decreased appetite, insomnia, infections (upper respiratory and nasopharyngitis), irritability, and affect lability. With the same lisdexamfetamine dimesylate dose, mean steady state exposure of dextroamphetamine was approximately 44% higher in pediatric patients ages to years compared to the pediatric patients ages to 11 years.BED Safety and effectiveness of lisdexamfetamine dimesylate have not been established in patients less than 18 years of age. Growth Suppression Growth should be monitored during treatment with stimulants, including lisdexamfetamine dimesylate, and pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions 5.5) and Adverse Reactions (6.1)]. Juvenile Animal Data Studies conducted in juvenile rats and dogs at clinically relevant doses showed growth suppression that partially or fully reversed in dogs and female rats but not in male rats after four-week drug-free recovery period. study was conducted in which juvenile rats received oral doses of 4, 10, or 40 mg/kg/day of lisdexamfetamine dimesylate from day to day 63 of age. These doses are approximately 0.3, 0.7, and times the maximum recommended human daily dose of 70 mg on mg/m2 basis for child. Dose-related decreases in food consumption, bodyweight gain, and crown-rump length were seen; after four-week drug-free recovery period, bodyweights and crown-rump lengths had significantly recovered in females but were still substantially reduced in males. Time to vaginal opening was delayed in females at the highest dose, but there were no drug effects on fertility when the animals were mated beginning on day 85 of age. In study in which juvenile dogs received lisdexamfetamine dimesylate for months beginning at 10 weeks of age, decreased bodyweight gain was seen at all doses tested (2, 5, and 12 mg/kg/day, which are approximately 0.5, 1, and times the maximum recommended human daily dose on mg/m2 basis for child). This effect partially or fully reversed during four-week drug-free recovery period.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and researchprograms/pregnancyregistry/adhdmedications/. Risk SummaryThe limited available data from published literature and postmarketing reports on use of lisdexamfetamine dimesylate in pregnant women are not sufficient to inform drug-associated risk for major birth defects and miscarriage. Adverse pregnancy outcomes, including premature delivery and low birth weight, have been seen in infants born to mothers dependent on amphetamines [see Clinical Considerations]. In animal reproduction studies, lisdexamfetamine dimesylate (a prodrug of d-amphetamine) had no effects on embryo-fetal morphological development or survival when administered orally to pregnant rats and rabbits throughout the period of organogenesis. Pre-and postnatal studies were not conducted with lisdexamfetamine dimesylate. However, amphetamine (d-to l-ratio of 3:1) administration to pregnant rats during gestation and lactation caused decrease in pup survival and decrease in pup body weight that correlated with delay in developmental landmarks at clinically relevant doses of amphetamine. In addition, adverse effects on reproductive performance were observed in pups whose mothers were treated with amphetamine. Long-term neurochemical and behavioral effects have also been reported in animal developmental studies using clinically relevant doses of amphetamine [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 2-4% and 15-20%, respectively.Clinical Considerations Fetal/Neonatal Adverse Reactions Amphetamines, such as lisdexamfetamine dimesylate, cause vasoconstriction and thereby may decrease placental perfusion. In addition, amphetamines can stimulate uterine contractions increasing the risk of premature delivery. Infants born to amphetamine-dependent mothers have an increased risk of premature delivery and low birth weight. Monitor infants born to mothers taking amphetamines for symptoms of withdrawal such as feeding difficulties, irritability, agitation, and excessive drowsiness. Data Animal Data Lisdexamfetamine dimesylate had no apparent effects on embryo-fetal morphological development or survival when administered orally to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 40 and 120 mg/kg/day, respectively. These doses are approximately 5.5 and 33 times, respectively, the maximum recommended human dose (MRHD) of 70 mg/day given to adults, on mg/m2 body surface area basis. study was conducted with amphetamine (d-to l-enantiomer ratio of 3:1) in which pregnant rats received daily oral doses of 2, 6, and 10 mg/kg from gestation day to lactation day 20. All doses caused hyperactivity and decreased weight gain in the dams. decrease in pup survival was seen at all doses. decrease in pup body weight was seen at and 10 mg/kg which correlated with delays in developmental landmarks, such as preputial separation and vaginal opening. Increased pup locomotor activity was seen at 10 mg/kg on day 22 postpartum but not at weeks postweaning. When pups were tested for reproductive performance at maturation, gestational weight gain, number of implantations, and number of delivered pups were decreased in the group whose mothers had been given 10 mg/kg. number of studies from the literature in rodents indicate that prenatal or early postnatal exposure to amphetamine (d- or d, l-) at doses similar to those used clinically can result in long term neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1)7/2021Warnings and Precautions (5.5)7/2021.