Elvanse 20 mg hard capsules - Summary of Product Characteristics (SPC) (2023)

20 mg capsules: Each capsule contains 20 mg of lisdexamfetamine dimesylate, equivalent to 5.9 mg of dexamphetamine.

For the full list of excipients, see section 6.1.

Haircut, sweetheart.

Elvanse 20 mg capsule: opaque ivory body and opaque ivory cap, printed with "S489" and "20 mg" in black ink.

Each capsule is approximately 16mm long and 6mm wide.

Elvanse is indicated as part of a comprehensive treatment program for attention deficit hyperactivity disorder (ADHD) in children 6 years of age and older when response to prior methylphenidate treatment is considered clinically inadequate.

Treatment must be under the supervision of a specialist in behavioral disorders of childhood and/or adolescence. Diagnosis must be made according to DSM criteria or ICD guidelines and must be based on a thorough history and evaluation of the patient. A diagnosis cannot be made based solely on the presence of one or more symptoms.

The specific etiology of this syndrome is unknown and there is no single diagnostic test. Proper diagnosis requires the use of specialized medical, psychological, educational, and social resources.

A comprehensive treatment program typically includes psychological, educational, and social interventions, as well as pharmacotherapy, and is aimed at stabilizing children with a behavioral syndrome characterized by symptoms that include a chronic history of poor attention span, distractibility, emotional lability, impulsivity and moderate. to severe May include hyperactivity, minor neurological signs, and abnormal EEG. Learning may or may not be affected.

Elvanse is not indicated in all children with ADHD and the decision to use the medication should be based on a very thorough assessment of the severity and chronicity of the child's symptoms in relation to the child's age and the potential for abuse, abuse, or distraction.

Appropriate school placement is essential and psychosocial intervention is usually required. Elvanse should always be used in this way, according to the authorized indication.

Treatment should be initiated under the supervision of an appropriate specialist in behavioral disorders of childhood and/or adolescence.

Evaluation before treatment

Before prescribing, an initial assessment of the patient's cardiovascular status, including blood pressure and heart rate, is necessary. A complete medical history should document concomitant medications, past and present comorbid medical and psychiatric disorders or symptoms, family history of sudden cardiac/unexplained death, and accurate recording of pretreatment height and weight on a chart. growth (see Section 4.3 and Section 4.3). ). 4.4).

As with other stimulants, the potential for misuse, abuse or misuse of Elvanse should be considered before prescribing (see section 4.4).

Continuous monitoring

Growth, psychiatric and cardiovascular status should be monitored continuously (see also section 4.4).

• Blood pressure and pulse should be recorded on a percentile curve at each dose adjustment and at least every six months.

• Height, weight, and appetite should be recorded at least every six months while maintaining a growth chart.

• Development ofone more timeor worsening of pre-existing psychiatric disorders should be monitored at each dose adjustment and then at least every 6 months and at each visit.

Patients should be monitored for the risk of diversion, misuse and abuse of Elvanse.

Dose

The dosage must be individualized according to the therapeutic needs and the response of the patient. Careful dose titration is required when initiating treatment with Elvanse.

The starting dose is 30 mg once a day in the morning. If the doctor decides that a lower starting dose is appropriate, patients can begin treatment with 20 mg once daily in the morning.

The dose can be increased in 10 or 20 mg increments at approximately weekly intervals. Elvanse should be administered orally at the lowest effective dose.

The maximum recommended dose is 70 mg/day; higher doses have not been studied.

Treatment should be discontinued if symptoms do not improve after appropriate dose adjustment over a period of 1 month. If paradoxical worsening of symptoms or other intolerable side effects occur, the dose should be reduced or discontinued.

type of administration

Elvanse can be taken with or without food.

Elvanse can be swallowed whole or the capsule can be opened and the entire contents emptied and mixed with soft food such as yoghurt or in a glass of water or orange juice. If the contents contain compressed powder, a spoon can be used to break the powder into the soft or liquid food. The contents must be shaken until completely dispersed. The patient should immediately consume the entire mixture of soft or liquid foods; should not be saved. The active ingredient is completely dissolved after dispersion; however, a film containing the inactive ingredients may remain in the jar or container after the mixture has been consumed.

The patient should not take less than one capsule per day and not split a single capsule.

If you miss a dose, you can take Elvanse again the next day. Evening doses should be avoided due to the possibility of insomnia.

long term use

Pharmacological treatment of ADHD may be necessary for a long period of time. The physician choosing to use Elvanse for a prolonged period (greater than 12 months) should reassess the benefit of Elvanse at least annually and consider drug-free trial periods to assess the patient's functioning without pharmacotherapy, preferably during the school holidays.

Adult

In adolescents whose symptoms persist into adulthood and who have demonstrated a clear benefit from treatment, it may be appropriate to continue treatment into adulthood (see sections 4.4 and 5.1).

Children under 6 years

Elvanse should not be used in children under 6 years of age. Safety and efficacy in this age group have not been established. Currently available data are described in sections 4.8, 5.1 and 5.2, but no recommendation on posology can be made.

Patients with renal failure

Due to reduced clearance in patients with severe renal impairment (GFR 15 to < 30 ml/min/1.73 m²or CrCl < 30 mL/min) the maximum dose should not exceed 50 mg/day. A further dose reduction should be considered in patients undergoing dialysis. Lisdexamfetamine and dexamphetamine are not dialyzable.

Patients with liver failure

No studies have been performed in patients with hepatic impairment.

Hypersensitivity to sympathomimetic amines or to any of the excipients listed in section 6.1.

Concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI treatment (may lead to hypertensive crisis; see section 4.5).

Hyperthyroidism or thyrotoxicosis.

excited states.

symptomatic cardiovascular disease.

Advanced arteriosclerosis.

Moderate to severe high blood pressure.

Glaucoma.

Abuse and Addiction

Stimulants, including lisdexamfetamine dimesylate, have a potential for abuse, misuse, dependence, or diversion for non-therapeutic purposes that clinicians should be aware of when prescribing this product. Stimulants should be prescribed with caution to patients with a history of drug abuse or dependence.

Tolerance, extreme psychological dependence, and severe social disability have occurred with stimulant abuse. There have been reports of patients increasing their dose of amphetamine to many times the recommended dose; abrupt discontinuation after prolonged administration of high doses leads to extreme fatigue and mental depression. Changes in the sleep EEG are also noted. Manifestations of chronic amphetamine intoxication may include severe dermatoses, pronounced insomnia, irritability, hyperactivity, and personality changes. The most serious manifestation of chronic intoxication is psychosis, which is often clinically indistinguishable from schizophrenia.

cardiovascular side effects

Sudden death in patients with pre-existing structural heart defects or other serious heart problems

Children and adolescents Sudden death has been reported in children and adolescents taking CNS stimulants, including those with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant medications generally should not be used in children or adolescents with known severe structural heart abnormalities, cardiomyopathy, severe heart rhythm disorders, or other serious heart problems that may increase their susceptibility to the sympathomimetic effect of a stimulant.

Adults: Sudden death, stroke, and heart attack have been reported in adults taking stimulant medications at the usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults are more likely than children to have severe structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious heart problems. Adults with such abnormalities generally should also not be treated with stimulants.

Hypertension and other cardiovascular diseases

Stimulants cause mild increases in average blood pressure (about 2 to 4 mmHg) and heart rate (about 3 to 6 bpm), and people may experience larger increases. While average changes alone should not have short-term consequences, all patients should be monitored for significant changes in heart rate and blood pressure. Caution should be exercised when treating patients whose underlying conditions could be compromised by increases in blood pressure or heart rate, e.g. B. those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia.

Lisdexamfetamine has been shown to prolong QT_Cinterval in some patients. It should be used with caution in patients with prolongation of the QT interval._CInterval, in patients treated with drugs that affect QT_Cinterval or in patients with relevant pre-existing cardiac disease or electrolyte imbalances.

The use of lisdexamfetamine dimesylate is contraindicated in patients with symptomatic cardiovascular disease and in patients with moderate to severe hypertension (see section 4.3).

cardiomyopathy

Cardiomyopathy has been reported with chronic amphetamine use. It has also been reported with lisdexamfetamine dimesylate.

Assessment of cardiovascular status in patients treated with stimulants

All patients being considered for stimulant treatment should have a careful medical history (including evaluation of a family history of sudden death or ventricular arrhythmia) and physical examination to assess for the presence of cardiac disease and should be evaluated for findings of additional cardiac tests. suggestive of such a condition (for example, electrocardiogram or echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease while receiving stimulant therapy should have immediate cardiac evaluation.

Psychiatric side effects

pre-existing psychosis

The administration of stimulants may worsen the symptoms of thought and behavior disorders in patients with pre-existing psychotic disorders.

Bipolar disorder

Special caution should be exercised when using stimulants to treat patients with ADHD and comorbid bipolar disorder due to concerns about the possible induction of mixed/manic episodes in such patients. Before initiating treatment with a stimulant, patients with comorbid depressive symptoms should be appropriately evaluated to determine if they are at risk for bipolar disorder; Such evaluation should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

Appearance of new psychotic or manic symptoms

Treatment Emerging psychotic or manic symptoms, e.g. B. Stimulants in usual doses may cause hallucinations, delusions, or mania in children and adolescents without a history of psychotic illness or mania. If such symptoms occur, a possible causal role of the stimulant should be considered and discontinuation of treatment may be appropriate.

Assault

Aggressive behavior or hostility is commonly seen in children and adolescents with ADHD and has been reported in clinical trials and post-marketing experience with some medications indicated for the treatment of ADHD, including lisdexamfetamine dimesylate. Stimulants can provoke aggressive behavior or hostility. Patients beginning ADHD treatment should be monitored for the development or worsening of aggressive or hostile behaviors.

tics

Stimulants have been reported to aggravate motor and phonic tics and Tourette's syndrome. Therefore, clinical evaluation of tics and Tourette syndrome in children and their families should precede the use of stimulants.

Long-term suppression of growth (height and weight)

Stimulants have been associated with decreased weight gain and decreased height attained. Growth should be monitored during treatment with stimulants, and discontinuation of treatment may be necessary in patients who do not grow or gain weight as expected. Height, weight and appetite must be recorded at least every 6 months.

In a controlled study of patients 6 to 17 years of age, the mean (SD) change in body weight after seven weeks was -2.35 (2,084) kg for lisdexamfetamine dimesylate, +0.87 (1,102) kg for the placebo and -1.36 (1.552) kg for the ) kg of methylphenidate hydrochloride.

seizures

There is some clinical evidence that stimulants may lower the seizure threshold in patients with a history of seizures, in patients with a history of EEG abnormalities without a history of seizures, and, very rarely, in patients with no history of seizures and no prior evidence in the clinical setting. Seizure EEG The drug should be discontinued if seizures begin or worsen.

visual disturbance

Accommodation difficulties and blurred vision have been reported with stimulant treatment.

Prescription and Dispensation

The lowest possible amount of lisdexamfetamine dimesylate should be prescribed or dispensed to minimize the risk of possible overdose by the patient.

Use with other sympathomimetics

Lisdexamfetamine dimesylate should be used with caution in patients using other sympathomimetics (see section 4.5).

use in adults

If discontinuation of treatment has not been successful in an adolescent who has reached the age of 18, it may be necessary to continue treatment into adulthood. The need for further treatment of these adults should be reviewed periodically and performed annually.

excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule and is therefore considered essentially 'sodium-free'. h is almost "sodium free".

in vitroenzyme inhibition

in vitroExperiments with human microsomes indicate minor inhibition of CYP2D6 by amphetamine and minor inhibition of CYP1A2, 2D6, and 3A4 by one or more metabolites. Although the clinical significance of this interaction is likely to be minimal, administration of drugs metabolized by these routes should be considered.

Active substances whose blood levels may be affected by lisdexamfetamine dimesylate

Guanfacine Extended-Release: In an interaction study, administration of a guanfacine extended-release in combination with lisdexamfetamine dimesylate resulted in a 19% increase in maximum guanfacine plasma concentrations (Cmax)._maximum), while exposure (area under the curve; AUC) increased by 7%. These small changes are not expected to be clinically significant. In this study, no effect on dexamphetamine exposure was observed after co-administration of sustained-release guanfacine and lisdexamfetamine dimesylate.

Venlafaxine Extended-Release: In an interaction study, administration of venlafaxine extended-release 225 mg, a CYP2D6 substrate, in combination with lisdexamfetamine dimesylate 70 mg induced a 9% decrease in Cmax._maximumand a 17% decrease in AUC for the primary active metabolite O-desmethylvenlafaxine and a 10% increase in Cmax_maximumand a 13% increase in AUC for venlafaxine. Dexamphetamine may be a weak inhibitor of CYP2D6. Lisdexamfetamine has no effect on AUC and Cmax_maximumthe composition of venlafaxine and o-desmethylvenlafaxine. These small changes are not expected to be clinically significant. In this study, no effect on dexamphetamine exposure was observed after co-administration of extended-release venlafaxine and lisdexamfetamine dimesylate.

Agents and conditions that alter urinary pH and affect urinary excretion and half-life of amphetamine

Ascorbic acid and other agents and conditions (thiazide diuretics, diets high in animal protein, diabetes, respiratory acidosis) that acidify the urine increase urine output and shorten the half-life of amphetamine. Sodium bicarbonate and other agents and conditions (diet high in fruits and vegetables, urinary tract infections, and vomiting) that alkalize the urine decrease urine output and prolong the half-life of amphetamine.

monoamine oxidase inhibitor

Amphetamine should not be administered during or within 14 days of monoamine oxidase inhibitor (MAOI) administration because it may increase the release of norepinephrine and other monoamines. This can cause severe headaches and other signs of a hypertensive crisis. Various toxic neurological effects and malignant hyperpyrexia can occur, sometimes with fatal outcome (see section 4.3).

serotonergic drugs

Serotonin syndrome has been rarely associated with the use of amphetamines such as lisdexamfetamine dimesylate when co-administered with serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors ( SNRI). It has also been reported in association with overdose of amphetamines, including lisdexamfetamine dimesylate (see section 4.9).

Drugs whose effects can be weakened by amphetamines

Antihypertensive drugs: Amphetamines may decrease the effectiveness of guanethidine or other antihypertensive drugs.

Means, the effect of which can be enhanced by amphetamines.

Amphetamines potentiate the analgesic effect of narcotic pain relievers.

Substances that can reduce the effects of amphetamines

Chlorpromazine: Chlorpromazine blocks dopamine and norepinephrine receptors, thus inhibiting the central stimulatory effects of amphetamines.

Haloperidol: Haloperidol blocks dopamine receptors, thereby inhibiting the central stimulatory effects of amphetamines.

Lithium Carbonate: Lithium carbonate can inhibit the anorexic and stimulant effects of amphetamines.

use with alcohol

There are limited data on possible interactions with alcohol.

Drug/Laboratory Test Interactions

Amphetamines can cause significant increases in plasma corticosteroid levels. This increase is greater at night. Amphetamine can interfere with the determination of urinary steroids.

the pregnancy

Dexamphetamine, the active metabolite of lisdexamfetamine, crosses the placenta. Data from a cohort study that included a total of approximately 5570 pregnancies exposed to amphetamine in the first trimester do not indicate an increased risk of birth defects. Data from another cohort study of approximately 3,100 pregnancies exposed to amphetamine during the first 20 weeks of pregnancy suggest an increased risk of preeclampsia and preterm birth. Newborns exposed to amphetamine during pregnancy may experience withdrawal symptoms.

In animal reproduction studies. Lisdexamfetamine dimesylate had no effect on embryo-foetal development or survival when administered orally to pregnant rats and rabbits (see section 5.3). Administration of lisdexamfetamine dimesylate to young rats was associated with reduced growth measures at clinically relevant exposures.

The physician should discuss lisdexamfetamine dimesylate treatment with patients who have started menstruation. Lisdexamfetamine dimesylate should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

breast-feeding

Amphetamines are excreted in breast milk. Lisdexamfetamine dimesylate should not be used during lactation.

Fertility

The effects of lisdexamfetamine dimesylate on fertility and early embryonic development have not been evaluated in animal reproduction studies. Amphetamine has not shown adverse effects on fertility in a study in rats (see section 5.3). The effect of lisdexamfetamine dimesylate on human fertility has not been studied.

Lisdexamfetamine dimesylate may cause dizziness, drowsiness, and visual disturbances, including accommodation difficulties and blurred vision. These may have a moderate influence on the ability to drive and use machines. Patients should be warned of these potential effects and advised to avoid potentially hazardous activities, such as driving or operating machinery, if affected.

This medication may impair cognitive function and affect the patient's ability to drive. This class of drugs is included in the list of drugs contained in the Regulations under Section 5a of the Road Traffic Act of 1988. When prescribing this drug, patients must be informed about:

• The medicine is likely to affect your ability to drive.

• Do not drive until you know how the medicine affects you.

• It is a criminal offense to drive under the influence of this medication.

• However, you are not committing a criminal offense (so-called “legal defense”) if:

o The drug was prescribed to treat a medical problem and

o You have taken it according to the instructions of the prescribing doctor and the information that came with the medicine

o Has not affected your ability to drive safely.

Security Profile Summary

Side effects seen with lisdexamfetamine dimesylate treatment primarily reflect side effects commonly associated with stimulant use. Very common side effects are decreased appetite, insomnia, dry mouth, headache, upper abdominal pain, and weight loss.

Tabulated Summary of Side Effects

The following table shows all adverse reactions based on clinical studies and spontaneous reports.

The following definitions apply to the frequency terminology used below:

Very common (≥ 1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000)

Very rare (< 1/10,000)

Not known (frequency cannot be estimated from the available data).

An asterisk (*) indicates that additional information is provided below the table for that side effect.

Description of selected side effects

insomnia

It includes insomnia, initial insomnia, intermediate insomnia, and terminal insomnia.

the weight has decreased

In a 4-week controlled study of lisdexamfetamine dimesylate in children 6 to 12 years of age, the mean weight loss from baseline to completion was 0.4, 0.9, and 1.1 kg in patients receiving 30 mg. , 50 mg and 70 mg of lisdexamfetamine. assigned to dimesylate compared with a 0.5 kg weight gain in patients receiving placebo. Higher doses were associated with greater weight loss after 4 weeks of treatment. Careful weight control in children 6 to 12 years of age who received lisdexamfetamine dimesylate for 12 months suggests that continuous treatment (ie, treatment 7 days a week throughout the year) reduces the rate of growth as measured by weight. body, as determined by age and age. sex-normalized mean change from baseline at the -13.4 percentile over 1 year. The mean percentiles at baseline (n=271) and at 12 months (n=146) were 60.9 and 47.2, respectively.

In a 4-week controlled study of lisdexamfetamine dimesylate in adolescents 13 to 17 years of age, the mean weight loss from baseline to completion was 1.2, 1.9, and 2.3 kg in patients taking 30 mg. , 50 mg, and 70 mg, respectively, lisdexamfetamine dimesylate compared with a 0.9 kg weight gain in patients receiving placebo. Careful monitoring of weight in adolescents 13 to 17 years of age who received lisdexamfetamine dimesylate for 12 months suggests that continuous treatment (ie, treatment 7 days a week throughout the year) increased the rate of growth, as measured by the body weight, decreased, as indicated by an age- and sex-normalized mean change from baseline at the -6.5th percentile over 1 year. The median percentiles at baseline (n=265) and at 12 months (n=156) were 66.0 and 61.5, respectively.

In children and adolescents (6 to 17 years) who received lisdexamfetamine dimesylate for two years, careful weight control indicated that constant medication (ie, treatment 7 days a week for the two years) resulted in increased growth. slow measured in the body that led to weight. In children and adolescents, the mean weight percentiles and standard deviations (SD) at baseline (n=314) and at 24 months (week 104, n=189) were 65.4 (SD 27.11) and 48.2 (DE 29, 94). The age and sex normalized mean change from baseline in percentile over 2 years was -16.9 (SD 17.33).

In a controlled clinical study with lisdexamfetamine dimesylatein children 4 to 5 years of age who received 5-30 mglisdexamfetamine dimesylate, there were no clinically significant weight changes from baseline after 6 weeks of follow-up. Careful monitoring of weight in children 4 to 5 years of age who received lisdexamfetamine dimesylate for 12 months in an open-label extension study suggests that continuous treatment (ie, treatment 7 days a week throughout the year) reduced the rate of growth, measured in the body. , slower weight demonstrated by age and sex normalized mean change from baseline in percentile of -17.92 (SD = 13.767) over 1 year. The mean percentiles at baseline (n=113) and at 12 months (n=69) were 66.51 (SD=25.173) and 47.45 (SD=26.144), respectively.

Eosinophilic Hepatitis

No cases were reported in clinical studies.

angioedema

No cases were reported in clinical studies.

Stevens Johnson Syndrome

No cases were reported in clinical studies.

Report suspected side effects

It is important to report suspected side effects after the drug has been approved. It allows continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are requested to report any suspected adverse reaction via the Yellow Card Scheme (website: www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card on Google Play or the Apple App Store .

Extended-release dexamphetamine following administration of lisdexamfetamine dimesylate should be considered when treating patients with overdose.

Manifestations of acute amphetamine overdose include agitation, tremor, hyperreflexia, rapid breathing, confusion, aggression, hallucinations, panic, hyperpyrexia, and rhabdomyolysis. Fatigue and depression often follow central nervous system stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is often preceded by seizures and coma.

Treatment of acute amphetamine poisoning is largely symptomatic and includes gastric lavage, administration of activated charcoal, administration of a laxative, and sedation. Acidification of the urine increases amphetamine excretion but is thought to increase the risk of acute renal failure if myoglobinuria is present. When acute severe hypertension complicates amphetamine overdose, intravenous administration of phentolamine has been suggested. However, there is usually a gradual drop in blood pressure once adequate sedation has been achieved.

Lisdexamfetamine and dexamphetamine are not dialyzable.

Pharmacotherapeutic group: Centrally acting sympathomimetics, ATC code: N06 BA12.

mechanism of action

Lisdexamfetamine dimesylate is a pharmacologically inactive prodrug. After oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract and is mainly hydrolyzed by red blood cells to dexamphetamine, which is responsible for the drug's action.

Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant effects. The nature of the therapeutic action of amphetamine in ADHD is not fully understood but is believed to be due to its ability to block the reuptake of norepinephrine and dopamine in the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. . The prodrug lisdexamfetamine does not bind to the sites responsible for the reuptake of norepinephrine and dopamine.in vitro.

Clinical efficacy and safety

The effect of lisdexamfetamine dimesylate in the treatment of ADHD has been evaluated in three controlled studies in children 6 to 12 years of age, three controlled studies in adolescents 13 to 17 years of age, three controlled studies in children and adolescents (6 to 17 years of age ), and four controlled studies in adults meeting DSM-IV-TR criteria for ADHD.

In clinical studies conducted in children and adults, the effects of lisdexamfetamine dimesylate lasted 13 hours after ingestion in children and 14 hours after ingestion of the product in adults when the product was taken once daily in the morning.

Pediatric population

336 patients 6 to 17 years of age were evaluated in the pivotal European Phase 3 study SPD489-325. In this seven-week, randomized, double-blind, dose-optimized, placebo-controlled, active study, lisdexamfetamine dimesylate demonstrated significantly greater efficacy than placebo.

The ADHD Rating Scale is a measure of the core symptoms of ADHD. The placebo-adjusted mean reduction from baseline in ADHD-RS-IV total score in patients treated with lisdexamfetamine dimesylate was 18.6 (p<0.001). At each treatment visit and at endpoint, the percentage of subjects who met predefined response criteria (a ≥ 30 percent reduction from baseline in ADHD-RS-IV total score and a CGI-I score of 1 or 2) significantly higher (p < 0.001) for lisdexamfetamine dimesylate compared to placebo. The endpoint of this study is defined in Table 1. Results were also significantly higher for lisdexamfetamine dimesylate compared to placebo when individual component response criteria were assessed. Furthermore, mean ADHD symptom scores after treatment discontinuation did not exceed baseline pre-treatment scores, indicating that no rebound effect was occurring.

In addition to reducing symptoms, clinical studies have shown that lisdexamfetamine dimesylate significantly improves functional outcomes. Specifically, in study SPD489-325, 75.0% of patients treated with lisdexamfetamine dimesylate showed improvement (defined as "much improved" or "greatly improved") on the CGI-I (Clinical Impression) rating scale. overall-improvement), compared to 14.2% on the placebo scale (p<0.001).

Lisdexamfetamine dimesylate demonstrated significant improvement in children's academic performance as measured by the Health-Related Quality of Life instrument, Child Health and Illness Profile Parent Report Form - Children's Edition (CHIP-CE: PRF) Performance domain. Lisdexamfetamine dimesylate demonstrated a significant improvement from baseline compared to placebo (lisdexamfetamine dimesylate: 9.4 vs. placebo -1.1) with a mean difference between the two treatment groups of 10.5 (p<0.001 ).

Table 1: Results of the SPD489-325 study at the end¹(Full analysis set)

¹Endpoint = the last treatment visit after baseline in the dose optimization or dose maintenance period (Visits 1-7) with a valid value

²Response is defined as a percentage reduction in ADHD-RS-IV total score of ≥ 30% from baseline.

³Improvement ("much improved" or "much improved")

Similar results for ADHD-RS and CGI-I were shown in two placebo-controlled studies, one in children (n=297) and one in adolescents (n=314), both conducted in the United States.

A double-blind, randomized, active-controlled, dose-optimizing study was conducted in children and adolescents 6 to 17 years of age (n=267) who met DSM-IV criteria for ADHD. In this nine-week study, patients were randomly assigned (1:1) to a daily morning dose of lisdexamfetamine dimesylate (30, 50, or 70 mg/day) or atomoxetine (doses up to 100 mg depending on subject weight). . During a 4-week dose optimization period, patients were titrated until an optimal dose was reached based on treatment-emergent adverse events and clinical judgment. Patients treated with lisdexamfetamine dimesylate had a shorter time to first response compared with patients treated with atomoxetine (median 13.0 vs 21.0 days; p = 0.003), with a response associated with a CGI I -Score of 1 (significant improvement). or 2 (much better) at one of the double-blind treatment visits. At all double-blind treatment visits, the proportion of responders in the lisdexamfetamine dimesylate group was consistently higher than the proportion of responders in the atomoxetine group. The difference was between 16 and 24 percentage points. At the end of the study, the least-squares mean changes from baseline in the ADHD-RS-IV total score for lisdexamfetamine dimesylate and atomoxetine were -26.1 and -19.7, respectively, with a difference between the treatment groups. -6.4.

Two active-controlled, double-blind, parallel-group studies (OROS-MPH [Concerta]) were conducted in adolescents 13 to 17 years of age with ADHD. Both studies also included a placebo control arm. The 8-week dose optimization study (SPD489-405) had a 5-week dose optimization period and a 3-week dose maintenance period. During the dose optimization phase, subjects were reintroduced once weekly based on treatment-emergent adverse events (TEAEs) and clinical response to an optimal dose of 30, 50, or 70 mg/day (for SPD489 subjects) or 18, 36, 54, or 72 mg/day (for OROS-MPH subjects) maintained over a 3-week maintenance dosing period. The mean doses at the end of the study were 57.9 mg and 55.8 mg for SPD489 and OROS-MPH, respectively. In this study, neither SPD489 nor OROS-MPH was statistically superior to the other product over the 8-week maintenance-dose period. At the higher doses of SPD489 (70 mg) and OROS-MPH (72 mg), treatment with SPD489 was shown to be superior to OROS-MPH as measured by the primary efficacy analysis (change from baseline at week 6 in ADHD-RS total score) and the primary secondary efficacy analysis (at the last study visit on the CGI-I) (see Table 2).

Table 2: Change from Baseline in ADHD-RS-IV Total Score and Endpoint in CGI-I (Full Analysis Set)

[a] From a mixed-effects repeated measures (MMRM) model including treatment group, nominal visit, treatment group interaction with visit as factors, baseline ADHD-RS-IV total score as a covariate, and an adjustment that includes the interaction of baseline ADHD - RS-IV Total Score with visit. The model is based on a REML estimation method and uses an unstructured covariance type.

[b] The effect size is the difference in the mean LS divided by the estimated standard deviation of the unstructured covariance matrix.

[c] The category "Improved" includes the responses "Very improved" and "Very improved".

[d] The category "Not improved" includes the responses "Slightly improved", "No change", "Slightly worse", "Much worse" and "Much worse".

[e] From a reference CGI-S stratified CMH assay.

Note: N = number of subjects in each treatment group, n = number of subjects tested.

A 2-year open-label safety study in children and adolescents (6-17 years) with ADHD enrolled 314 patients. Of these, 191 patients completed the study.

In addition, maintenance of effect was demonstrated in a randomized, double-blind, placebo-controlled withdrawal study conducted in children and adolescents aged 6 to 17 years (n=157) who met the diagnosis of ADHD (DSM-IV criteria). . Patients were optimized on open-label lisdexamfetamine dimesylate for a prolonged period (at least 26 weeks) before entering the 6-week randomized withdrawal phase. Eligible patients were randomized to remain on their optimized dose of lisdexamfetamine dimesylate or to switch to placebo. Patients were observed for relapse (treatment failure) during the 6-week double-blind period. Treatment failure was defined as a ≥50% increase (worsening) in the ADHD-RS total score and a ≥2 point increase in the CGI-S score compared to scores at the start of the randomized withdrawal period. and double blind. Treatment failure was significantly lower (p<0.001) in subjects receiving lisdexamfetamine dimesylate (15.8%) compared to placebo (67.5%). The majority of subjects (70.3%) who experienced treatment failure, regardless of treatment, experienced worsening of ADHD symptoms at or before the Week 2 post-randomization visit.

A fixed-dose safety and efficacy study was conducted in 4- to 5-year-old preschool children with ADHD. Subjects were randomized in a 5:5:5:5:6 ratio to lisdexamfetamine dimesylate (5, 10, 20, 30 mg doses) or placebo (see also section 5.2). The duration of the double-blind evaluation period was 6 weeks. In this study, the most frequently reported TEAEs in patients receiving Elvanse were decreased appetite (13.7% of patients), irritability (9.6% of patients), and affective lability and cough (4.8% of patients). patients each). In a 52-week open-label study, the most common TEAE was decreased appetite (15.9%) (see section 4.8).

adult population

The efficacy of lisdexamfetamine dimesylate in the treatment of ADHD was demonstrated in a randomized, placebo-controlled, double-blind, parallel-group study conducted in 420 adult patients 18 to 55 years of age who met DSM-IV criteria for ADHD. ADHD. Significant improvements in ADHD symptoms, as rated by investigators on the ADHD-RS using the Adult Rapid Total Score, were observed for all doses of lisdexamfetamine dimesylate compared with placebo. Treatment with lisdexamfetamine dimesylate significantly reduced the degree of functional impairment, as measured by improvement on the CGI-I rating scale, compared with placebo.

In addition, maintenance of effect was demonstrated in a randomized, double-blind, placebo-controlled withdrawal study enrolling adults (n=123) meeting DSM-IV criteria for ADHD who had been treated with dimesylate. lisdexamfetamine at study entry for at least 6 months. In the randomized, double-blind withdrawal period, a significantly lower proportion of patients treated with lisdexamfetamine dimesylate met the criteria for relapse (8.9%) compared with placebo-treated patients (75.0%). Relapse was defined as a ≥50% increase in the ADHD-RS-IV total score since randomization and a ≥2 point increase in the CGI-S score compared to the CGI-S score at randomization. .

Abuse Liability Studies

In a human risk of abuse study in which equivalent oral doses of 100 mg lisdexamfetamine dimesylate and 40 mg immediate-release dexamphetamine sulfate were administered to subjects with a history of drug abuse, 100 mg lisdexamfetamine dimesylate gave as a result subjective responses in a scale of effects of liking for drugs” (primary variable), which were significantly lower than those of immediate-release dexamfetamine 40 mg. However, oral administration of 150 mg lisdexamfetamine dimesylate resulted in increased positive subjective responses on this scale. comparable to the positive subjective responses elicited by immediate-release oral dexamphetamine 40 mg and diethylpropion 200 mg.

Intravenous administration of 50 mg lisdexamfetamine dimesylate to subjects with a history of substance abuse resulted in positive subjective responses on scales measuring drug likeness, euphoria, amphetamine effects, and benzedrine effects, which were greater than placebo, but less than those produced by an equivalent dose (20 mg) of intravenous dexamfetamine.

Absorption

Following oral administration, lisdexamfetamine dimesylate is rapidly absorbed from the gastrointestinal tract of healthy adults and children (6 to 12 years) with ADHD, thought to be mediated by the high-capacity PEPT1 transporter.

Food has no effect on the observed AUC and Cmax_maximumof dexamphetamine in healthy adults after a single 70-mg oral dose of lisdexamfetamine dimesylate capsules, but prolongs T_maximumin about 1 hour (from 3.8 hours fasting to 4.7 hours after a high-fat meal). After an 8-hour fast, the AUCs of dexamphetamine after oral administration of lisdexamfetamine dimesylate in solution and as intact capsules were equivalent.

distribution

In 18 children (6 to 12 years) with ADHD, T_maximumof dexamphetamine was approximately 3.5 hours after a single oral dose of lisdexamfetamine dimesylate, either 30 mg, 50 mg, or 70 mg, given after an 8-hour overnight fast. The t_maximumof lisdexamfetamine dimesylate was approximately 1 hour. The linear pharmacokinetics of dexamphetamine following a single oral dose of lisdexamfetamine dimesylate have been determined over the 30 mg to 70 mg dose range in children 6 to 12 years of age.

AUC and Cmax normalized by weight/dose_maximumDexamphetamine levels were 22% and 12% lower in adult women than in men on day 7 after a 70-mg/day dose of lisdexamfetamine for 7 days, respectively. AUC and Cmax normalized by weight/dose_maximumvalues ​​were the same in girls and boys after single doses of 30-70 mg.

In healthy adults, there is no steady-state accumulation of dexamphetamine and no accumulation of lisdexamfetamine dimesylate after once-daily dosing for 7 consecutive days.

biotransformation

Lisdexamfetamine dimesylate is converted to dexamphetamine and L-lysine, which are metabolized in the blood primarily due to the hydrolytic activity of red blood cells. Red blood cells have a high capacity for the metabolism of lisdexamfetamine.in vitroThe data showed that significant hydrolysis occurs even at low hematocrit levels. Lisdexamfetamine is not metabolized by cytochrome P450 enzymes.

Amphetamine is oxidized at position 4 of the benzene ring to form 4-hydroxyamphetamine or at the α or β carbon atoms of the side chain to form alpha-hydroxyamphetamine and norephedrine, respectively. Norephedrine and 4-hydroxyamphetamine are active and are subsequently oxidized to form 4-hydroxynorephedrine. Alpha-hydroxyamphetamine undergoes deamination to form phenylacetone, which eventually forms benzoic acid and its glucuronide and glycine-conjugated hippuric acid. Although the enzymes involved in the metabolism of amphetamine have not been clearly defined, CYP2D6 is known to be involved in the formation of 4-hydroxy-amphetamine.

elimination

Following oral administration of a 70 mg dose of radiolabeled lisdexamfetamine dimesylate to 6 healthy volunteers, approximately 96% of the radioactivity from the oral dose was recovered in the urine and only 0.3% in the feces over a period of 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. Unconverted lisdexamfetamine plasma concentrations are low and transient and generally unquantifiable 8 hours after dosing. The plasma elimination half-life of lisdexamfetamine averaged less than one hour in volunteer studies of lisdexamfetamine dimesylate. The half-life of dexamphetamine is 11 hours.

special populations

Dexamfetamine pharmacokinetics, determined by clearance, are similar in children (6 to 12 years) and adolescents (13 to 17 years), ADHD patients, and healthy adult subjects after correcting for body weight.

Systemic exposure to dexamphetamine is similar in men and women receiving the same mg/kg dose.

Formal race pharmacokinetic studies have not been performed. There is no evidence of an influence of race on the pharmacokinetics of lisdexamfetamine dimesylate.

In a pharmacokinetic study in 40 subjects (8 subjects in each of five renal function groups: normal, mildly impaired, moderately impaired, severely impaired renal function, and end-stage renal disease), dexamfetamine clearance was reduced from 0.7 l/ h/kg in normal subjects to 0.4 l/h/kg in patients with severe renal insufficiency (GFR 15 to <30 ml/min1.73m²o CrCl < 30 mL/min).

Based on a population pharmacokinetic analysis, the mean steady-state exposure of dexamfetamine in pediatric patients 4 to 5 years of age was approximately 44% higher than in pediatric patients 6 to 11 years of age receiving the same dose (30 mg/ day) received .

In a study of 47 subjects 55 years of age or older, dexamfetamine clearance was approximately 0.7 L/h/kg for subjects 55 to 74 years of age and 0.55 L/h/kg for subjects 55 to 74 years of age. years ≥ 75 years. This is slightly reduced compared to younger adults (approximately 1 L/h/kg for subjects 18-45 years).

Nonclinical studies of risk of abuse indicate that lisdexamfetamine dimesylate in rats and monkeys may produce subjective effects similar to those of the CNS stimulant dexamphetamine, but they are delayed and transient, while the rewarding effects observed in self-administration studies are less. than those of methylphenidate or cocaine.

In repeat-dose toxicity studies, the most important findings were behavioral changes, such as B. Increased activity typical of stimulant administration, with associated reductions in body weight gain, measures of growth, and drug intake. food, which is considered to result from an exaggerated pharmacological response.

Lisdexamfetamine dimesylate was not genotoxic in the testin vitroin the Ames test and in the mouse lymphoma assay orlivein the mouse bone marrow micronucleus test. No carcinogenicity studies have been performed with lisdexamfetamine dimesylate. In studies whered-, l-Amphetamine (1:1 enantiomeric ratio) was administered to mice and rats in the diet for 2 years at doses up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/day. kg/day in male and female rats.

Lisdexamfetamine dimesylate had no effect on embryo-foetal development or survival when administered orally to pregnant rats at doses up to 40 mg/kg/day and to rabbits at doses up to 120 mg/kg/day.

Acute administration of high doses of amphetamine (d- or d,l-) in rodents has been shown to produce long-lasting neurotoxic effects, including irreversible damage to nerve fibers. However, no adverse central nervous system changes were observed in definitive adolescent toxicity studies with lisdexamfetamine dimesylate in rats and dogs. The relevance of these findings to humans is unknown.

amphetamine (d- a l-Enantiomeric ratio of 3:1) had no adverse effects on fertility or early embryonic development in rats at doses up to 20 mg/kg/day.

Several rodent studies indicate that prenatal or early postnatal exposure to amphetamine (D- od, l-) in doses similar to those used clinically can cause long-term neurochemical and behavioral changes. Reported behavioral effects include learning and memory deficits, impaired physical activity, and changes in sexual function. Similar studies have not been performed for lisdexamfetamine dimesylate. However, an evaluation of fertility after discontinuation of lisdexamfetamine dimesylate treatment was included in a toxicity study in juvenile rats, with no adverse effects on fertility observed.

Microcrystalline cellulose.

Croscarmellose-Natrium.

magnesium stearate

capsule shells

Jelly.

Black ink (shellac and black iron oxide E172).

Capsule shell dyes:

20 mg: titanium dioxide (E171) and yellow iron oxide (E172).

High-density polyethylene bottle and child-resistant polypropylene closure with inner foil seal.

Package sizes: 28 or 30.

Not all pack sizes may be marketed.

Takeda UK Limited

1 Kingdom Street

London

W2 6BD

BRITAIN

20 milligrams

Date of first registration: July 31, 2015

Date of last renewal: 3^rdmayo 2020