4.1. Therapeutic indications

Elvanse is indicated as part of a comprehensive treatment programme for attention deficit/hyperactivity disorder (ADHD) in children aged 6 years and over when response to previous methylphenidate treatment is considered clinically inadequate.

Elvanse is also indicated as part of a comprehensive treatment programme for attention deficit/hyperactivity disorder (ADHD) in adults with pre-existing symptoms of ADHD in childhood.

Treatment must be under the supervision of a specialist in childhood and/or adolescent behavioural disorders (for paediatric patients) or a specialist in behavioural disorders (for adult patients). Diagnosis should be based on a complete history and evaluation of the patient according to current DSM criteria or ICD guidelines. Diagnosis cannot be made solely on the presence of one or more symptoms.

In adults, the presence of pre-existing symptoms of ADHD in childhood is required and should be confirmed retrospectively (according to the patient's medical record or, if not available, through appropriate and structured instruments or interviews). Based on clinical judgment, patients should have ADHD of at least moderate severity as indicated by at least moderate functional impairment in two or more settings (for example, social, academic, and/or occupational functioning), affecting several aspects of an individual's life.

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

Elvanse is not indicated in all patients with ADHD and the decision to use the medicinal product must take into consideration the profile of the patient, including a thorough assessment of the severity and chronicity of the patient's symptoms, the potential for abuse, misuse or diversion and clinical response to any previous pharmacotherapies for the treatment of ADHD.

A comprehensive treatment programme typically includes psychological, educational, behavioural, occupational and social measures as well as pharmacotherapy, as appropriate, and is aimed at stabilising the patient with a behavioural syndrome characterised by symptoms which may include chronic history of short attention span, distractibility, emotional lability, impulsivity, moderate to severe hyperactivity, minor neurological signs and abnormal EEG. Learning may or may not be impaired (for paediatric patients).

Appropriate educational placement is essential (for paediatric patients), and psychosocial intervention is generally necessary. The use of Elvanse should always be used in this way according to the licensed indication.

4.2. Posology and method of administration

Treatment must be initiated under the supervision of an appropriate specialist in behavioural disorders.

Pre-treatment evaluation

Prior to prescribing, it is necessary to conduct a baseline evaluation of a patient's cardiovascular status including blood pressure and heart rate. A comprehensive history should document concomitant medications, past and present co-morbid medical and psychiatric disorders or symptoms, family history of sudden cardiac/unexplained death, and accurate recording of pre‑treatment weight. For paediatric patients, height and weight should be recorded on a growth chart (see section 4.3 and section 4.4).

Consistent with other stimulants, the potential for abuse, misuse or diversion of Elvanse should be considered prior to prescribing (see section 4.4).

Ongoing monitoring

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

• Blood pressure and pulse should be recorded at each adjustment of dose and at least every six months. For paediatric patients this should be recorded on a centile chart.

• For paediatric patients: height, weight, and appetite should be recorded at least six-monthly with maintenance of a growth chart.

• Weight should be recorded in adults regularly.

• Development of de novo or worsening of pre-existing psychiatric disorders should be monitored at every adjustment of dose and then at least every six months and at every visit.

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

Posology

Dosage should be individualised according to the therapeutic needs and response of the patient. Careful dose titration is necessary at the start of treatment with Elvanse.

The starting dose is 30 mg taken once daily in the morning. When in the judgment of the clinician a lower initial dose is appropriate, patients may begin treatment with 20 mg once daily in the morning.

The dose may be increased by 10 or 20 mg increments, at approximately weekly intervals. Elvanse should be administered orally at the lowest effective dosage.

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

Treatment must be stopped if the symptoms do not improve after appropriate dosage adjustment over a 1‑month period. If paradoxical aggravation of symptoms or other intolerable adverse events occur, the dosage should be reduced or discontinued.

Method of administration

Elvanse may be taken with or without food.

Elvanse may be swallowed whole, or the capsule opened and the entire contents emptied and mixed with a soft food such as yogurt or in a glass of water or orange juice. If the contents include any compacted powder, a spoon may be used to break apart the powder in the soft food or liquid. The contents should be stirred until completely dispersed. The patient should consume the entire mixture of soft food or liquid immediately; it should not be stored. The active ingredient dissolves completely once dispersed; however, a film containing the inactive ingredients may remain in the glass or container once the mixture is consumed.

The patient should not take anything less than one capsule per day and a single capsule should not be divided.

In the event of a missed dose, Elvanse dosing can resume the next day. Afternoon doses should be avoided because of the potential for insomnia.

Long-term use

Pharmacological treatment of ADHD may be needed for extended periods. The physician who elects to use Elvanse for extended periods (over 12 months) should re-evaluate the usefulness of Elvanse at least yearly, and consider trial periods off medication to assess the patient's functioning without pharmacotherapy, preferably during times off from school or work.

Elderly population

Data is limited in elderly patients; therefore, a thorough pre-treatment evaluation and ongoing monitoring of blood pressure and cardiovascular status is required (see sections 4.3 and 4.4). Dexamfetamine clearance is reduced in the elderly, therefore dose adjustment may be required (see section 5.2).

Patients with renal impairment

Due to reduced clearance in patients with severe renal insufficiency (GFR 15 to < 30 mL/min/1.73 m2 or CrCl < 30 mL/min) the maximum dose should not exceed 50 mg/day. Further dosage reduction should be considered in patients undergoing dialysis. Lisdexamfetamine and dexamfetamine are not dialysable.

Patients with hepatic impairment

No studies have been conducted in patients with hepatic impairment.

Children under 6 years

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

4.3. Contraindications

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

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

Hyperthyroidism or thyrotoxicosis.

Agitated states.

Symptomatic cardiovascular disease.

Advanced arteriosclerosis.

Moderate to severe hypertension.

Glaucoma.

Phaeochromocytoma.

4.4. Special warnings and precautions for use

Abuse and dependence

Stimulants including lisdexamfetamine dimesylate have a potential for abuse, misuse, dependence, or diversion for non-therapeutic uses that physicians should consider when prescribing this product. The risk of misuse may be greater in adults (especially young adults) than in paediatric use. Stimulants should be prescribed cautiously to patients with a history of substance abuse or dependence.

Abuse of amfetamines can lead to tolerance, and psychological dependence with varying degrees of abnormal behaviour. Symptoms of amfetamine abuse may include dermatoses, insomnia, irritability, hyperactivity, emotional lability and psychosis. Withdrawal symptoms such as fatigue and depression have been reported.

Caregivers and/or patients should be advised on the proper storage and disposal of unused medicinal product to prevent diversion (e.g., through friends and relatives).

Cardiovascular adverse events

Sudden death in patients with pre-existing structural cardiac abnormalities 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 products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug.

Adults: Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs.

Hypertension and other cardiovascular conditions

Stimulant medications cause a modest increase in average blood pressure (about 2‑4 mmHg) and average heart rate (about 3‑6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia.

Lisdexamfetamine has shown to prolong the QTc interval in some patients. It should be used with caution in patients with prolongation of the QTc interval, in patients treated with drugs affecting the QTc interval, or in patients with relevant pre-existing cardiac disease or electrolyte disturbances.

The use of lisdexamfetamine dimesylate is contraindicated in patients with symptomatic cardiovascular disease and also in those patients with moderate to severe hypertension (see section 4.3). As the prevalence of hypertension increases with increasing age, a continued monitoring of blood pressure and cardiovascular status is required during treatment (see section 4.2).

Cardiomyopathy

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

Assessing cardiovascular status in patients being treated with stimulant medications

All patients who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram or echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.

Psychiatric adverse events

Pre‑existing psychosis

Administration of stimulants may exacerbate symptoms of behaviour disturbance and thought disorder in patients with pre‑existing psychotic disorders.

Bipolar illness

Particular care should be taken in using stimulants to treat ADHD patients with comorbid bipolar disorder because of concern for possible induction of mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

Emergence of new psychotic or manic symptoms

Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate.

Aggression

Aggressive behaviour or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the post-marketing experience of some medications indicated for the treatment of ADHD including lisdexamfetamine dimesylate. Stimulants may cause aggressive behaviour or hostility. Patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behaviour or hostility.

Tics

Stimulants have been reported to exacerbate motor and phonic tics and Tourette's syndrome. Therefore, clinical evaluation for tics and Tourette's syndrome in children and their families should precede use of stimulant medications.

Long-term effect on growth (height and weight)

In children and adolescents aged 6 to 17 years

Stimulants have been associated with a slowing of weight gain and a reduction in attained height. Growth should be monitored during treatment with stimulants, and patients who are not growing or gaining weight as expected may need to have their treatment interrupted. Height, weight, and appetite should be recorded at least 6‑monthly.

In a controlled study of patients aged 6 to 17 years the mean (SD) changes in body weight after seven weeks were -2.35 (2.084) kg for lisdexamfetamine dimesylate, +0.87 (1.102) kg for placebo, and -1.36 (1.552) kg for methylphenidate hydrochloride.

In adults

Stimulants have been associated with weight loss. Weight should be monitored during treatment with stimulants, and patients who are losing weight may need to have their treatment interrupted.

Seizures

There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizure, in patients with prior EEG abnormalities in absence of seizures, and very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of new onset or worsening seizures, the drug should be discontinued.

Visual disturbance

Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.

Prescribing and dispensing

The least amount of lisdexamfetamine dimesylate feasible should be prescribed or dispensed in order to minimise the risk of possible overdose by the patient.

Use with other sympathomimetic drugs

Lisdexamfetamine dimesylate should be used with caution in patients who use other sympathomimetic drugs (see section 4.5).

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

In vitro enzyme inhibition

Lisdexamfetamine dimesylate was not an in vitro inhibitor of the major human CYP450 isoforms (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) in human hepatic microsomal suspensions, nor was it an in vitro inducer of CYP1A2, CYP2B6 or CYP3A4/5 in cultured fresh human hepatocytes. Lisdexamfetamine dimesylate was not an in vitro substrate for P-gp in MDCKII cells nor an in vitro inhibitor of P-gp in Caco-2 cells and is therefore unlikely to be involved in clinical interactions with drugs transported by the P-gp pump. An in vivo human study of lisdexamfetamine dimesylate did not result in any clinically meaningful effect on the pharmacokinetics of drugs metabolised by CYP1A2, CYP2D6, CYP2C19, or CYP3A.

Agents whose blood levels may be impacted by lisdexamfetamine dimesylate

Extended release guanfacine: In a drug interaction study, administration of an extended release guanfacine in combination with lisdexamfetamine dimesylate induced a 19% increase in guanfacine maximum plasma concentrations (Cmax), whereas, exposure (area under the curve; AUC) was increased by 7%. These small changes are not expected to be clinically meaningful. In this study, no effect on dexamfetamine exposure was observed following co‑administration of extended release guanfacine and lisdexamfetamine dimesylate.

Extended release venlafaxine: In a drug interaction study, administration of 225 mg extended release venlafaxine, a CYP2D6 substrate, in combination with 70 mg lisdexamfetamine dimesylate induced a 9% decrease in the Cmax and 17% decrease in the AUC for the primary active metabolite o-desmethylvenlafaxine and a 10% increase in Cmax and 13% increase in AUC for venlafaxine. Dexamfetamine may be a weak inhibitor of CYP2D6. Lisdexamfetamine has no effect on the AUC and Cmax of the composite of venlafaxine and o-desmethylvenlafaxine. These small changes are not expected to be clinically meaningful. In this study, no effect on dexamfetamine exposure was observed following co-administration of extended release venlafaxine and lisdexamfetamine dimesylate.

Agents and conditions that alter urinary pH and impact the urinary excretion and half-life of amfetamine

Ascorbic acid and other agents and conditions (thiazide diuretics, diets high in animal protein, diabetes, respiratory acidosis) that acidify urine increase urinary excretion and decrease the half-life of amfetamine. Sodium bicarbonate and other agents and conditions (diets high in fruits and vegetables, urinary tract infections and vomiting) that alkalinise urine decrease urinary excretion and extend the half-life of amfetamine.

Monoamine oxidase inhibitors

Amfetamine should not be administered during or within 14 days following the administration of monoamine oxidase inhibitors (MAOI) because it can increase the release of norepinephrine and other monoamines. This can cause severe headaches and other signs of hypertensive crisis. A variety of toxic neurological effects and malignant hyperpyrexia can occur, sometimes with fatal outcomes (see section 4.3).

Serotonergic drugs

Serotonin syndrome has rarely occurred in association with the use of amfetamines such as lisdexamfetamine dimesylate, when given in conjunction with serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). It has also been reported in association with overdose of amfetamines, including lisdexamfetamine dimesylate (see section 4.9).

Agents whose effects may be reduced by amfetamines

Antihypertensives: Amfetamines may decrease the effectiveness of guanethidine or other antihypertensive medications.

Agents whose effects may be potentiated by amfetamines

Amfetamines potentiate the analgesic effect of narcotic analgesics.

Agents that may reduce the effects of amfetamines

Chlorpromazine: Chlorpromazine blocks dopamine and norepinephrine receptors, thus inhibiting the central stimulant effects of amfetamines.

Haloperidol: Haloperidol blocks dopamine receptors, thus inhibiting the central stimulant effects of amfetamines.

Lithium carbonate: The anorectic and stimulatory effects of amfetamines may be inhibited by lithium carbonate.

Use with alcohol

There are limited data on the possible interaction with alcohol.

Drug/laboratory test interactions

Amfetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amfetamine may interfere with urinary steroid determinations.

4.6. Fertility, pregnancy and lactation

Pregnancy

Dexamfetamine, the active metabolite of lisdexamfetamine, crosses the placenta. Data from a cohort study of in total approximately 5 570 pregnancies exposed to amfetamine in the first trimester do not suggest an increased risk of congenital malformation. Data from another cohort study in approximately 3 100 pregnancies exposed to amfetamine during the first 20 weeks of pregnancy, suggest an increased risk of preeclampsia, and preterm birth. Newborns exposed to amfetamine during pregnancy may experience withdrawal symptoms.

In animal reproduction studies, lisdexamfetamine dimesylate had no effect on embryofoetal development or survival when administered orally to pregnant rats and rabbits (see section 5.3). Administration of lisdexamfetamine dimesylate to juvenile rats was associated with reductions in growth measurements at clinically relevant exposures.

The physician should discuss lisdexamfetamine dimesylate treatment with female patients of child-bearing potential. Lisdexamfetamine dimesylate should only be used during pregnancy if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

Amfetamines are excreted in human milk. Lisdexamfetamine dimesylate should not be used during breast-feeding.

Fertility

The effects of lisdexamfetamine dimesylate on fertility and early embryonic development have not been investigated in animal reproductive studies. Amfetamine has shown no harmful effects on fertility in a rat study (see section 5.3). The effect of lisdexamfetamine dimesylate on human fertility has not been investigated.

4.7. Effects on ability to drive and use machines

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

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

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

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

• It is an offence to drive while under the influence of this medicine.

• However, you would not be committing an offence (called 'statutory defence') if:

o The medicine has been prescribed to treat a medical problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely.

4.8. Undesirable effects

Summary of the safety profile

Adverse reactions observed with lisdexamfetamine dimesylate treatment mainly reflect side effects commonly associated with stimulant use. Very common adverse reactions include decreased appetite, insomnia, dry mouth, headache, upper abdominal pain, and weight decreased.

Tabulated summary of adverse reactions

The following table presents all adverse reactions based on clinical trials and spontaneous reporting.

The following definitions apply to the frequency terminology used hereafter:

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)

Frequency not known (cannot be estimated from the available data).

An asterisk (*) indicates that additional information on the respective adverse reaction is provided below the table.

System/Organ Class

Adverse Reaction

Children

(6 to 12 years)

Adolescents

(13 to 17 years)

Adults

Immune System Disorders

Anaphylactic reaction

Frequency not known

Frequency not known

Frequency not known

Hypersensitivity

Uncommon

Uncommon

Uncommon

Metabolism and Nutrition Disorders

Decreased appetite

Very common

Very common

Very common

Psychiatric Disorders

*Insomnia

Very common

Very common

Very common

Agitation

Uncommon

Uncommon

Common

Anxiety

Uncommon

Common

Common

Logorrhoea

Uncommon

Uncommon

Uncommon

Libido decreased

Not applicable

Not reported

Common

Depression

Uncommon

Common

Uncommon

Tic

Common

Uncommon

Uncommon

Affect lability

Common

Uncommon

Common

Dysphoria

Uncommon

Uncommon

Uncommon

Euphoria

Frequency not known

Uncommon

Uncommon

Psychomotor hyperactivity

Uncommon

Uncommon

Common

Bruxism

Uncommon

Uncommon

Common

Dermatillomania

Uncommon

Uncommon

Uncommon

Psychotic episodes

Frequency not known

Frequency not known

Frequency not known

Mania

Uncommon

Uncommon

Uncommon

Hallucination

Uncommon

Uncommon

Frequency not known

Aggression

Common

Uncommon

Frequency not known

Tourette's Disorder aggravated

Frequency not known

Frequency not known

Frequency not known

Nervous System Disorders

Headache

Very common

Very common

Very common

Dizziness

Common

Common

Common

Restlessness

Uncommon

Common

Common

Tremor

Uncommon

Common

Common

Somnolence

Common

Common

Uncommon

Seizure

Frequency not known

Frequency not known

Frequency not known

Dyskinesia

Uncommon

Uncommon

Uncommon

Dysgeusia

Uncommon

Uncommon

Uncommon

Syncope

Uncommon

Uncommon

Uncommon

Eye Disorders

Vision blurred

Uncommon

Frequency not known

Uncommon

Mydriasis

Uncommon

Uncommon

Frequency not known

Cardiac Disorders

Tachycardia

Common

Common

Common

Palpitation

Uncommon

Common

Common

QTc prolongation

Frequency not known

Frequency not known

Frequency not known

Cardiomyopathy

Frequency not known

Uncommon

Frequency not known

Vascular disorders

Raynaud's phenomenon

Uncommon

Frequency not known

Frequency not known

Epistaxis

Uncommon

Uncommon

Uncommon

Respiratory, Thoracic and Mediastinal Disorders

Dyspnoea

Uncommon

Common

Common

Gastrointestinal Disorders

Dry mouth

Common

Common

Very common

Diarrhoea

Common

Common

Common

Constipation

Common

Uncommon

Common

Upper abdominal pain

Very common

Common

Common

Nausea

Common

Common

Common

Vomiting

Common

Common

Uncommon

Hepatobiliary Disorders

*Eosinophilic Hepatitis

Frequency not known

Frequency not known

Frequency not known

Skin and Subcutaneous Tissue Disorders

Hyperhidrosis

Uncommon

Uncommon

Common

Urticaria

Uncommon

Uncommon

Uncommon

Rash

Common

Uncommon

Uncommon

*Angioedema

Frequency not known

Frequency not known

Frequency not known

*Stevens-Johnson Syndrome

Frequency not known

Frequency not known

Frequency not known

Reproductive System and Breast Disorders

Erectile dysfunction

Not applicable

Uncommon

Common

General Disorders and Administration Site Conditions

Chest pain

Uncommon

Uncommon

Common

Irritability

Common

Common

Common

Fatigue

Common

Common

Common

Feeling jittery

Uncommon

Common

Common

Pyrexia

Common

Common

Uncommon

Investigations

Blood pressure increased

Uncommon

Uncommon

Common

*Weight decreased

Very Common

Very Common

Common

Description of selected adverse reactions

Insomnia

Includes insomnia, initial insomnia, middle insomnia, and terminal insomnia.

Weight decreased

In a 4‑week controlled trial of lisdexamfetamine dimesylate in children aged 6 to 12 years, mean weight loss from baseline to endpoint was 0.4, 0.9, and 1.1 kg, for patients assigned to receive 30 mg, 50 mg, and 70 mg of lisdexamfetamine dimesylate respectively, compared to a 0.5 kg weight gain for patients receiving placebo. Higher doses were associated with greater weight loss with 4 weeks of treatment. Careful follow-up for weight in children aged 6 to 12 years who received lisdexamfetamine dimesylate over 12 months suggests that continuous treatment (i.e., treatment for 7 days per week throughout the year) slows growth rate measured by body weight as demonstrated by an age- and sex‑normalised mean change from baseline in percentile of -13.4 over 1 year. The average percentiles at baseline (n=271) and 12 months (n=146) were 60.9 and 47.2, respectively.

In a 4‑week controlled trial of lisdexamfetamine dimesylate in adolescents aged 13 to 17 years, mean weight loss from baseline to endpoint was 1.2, 1.9, and 2.3 kg for patients assigned to receive 30 mg, 50 mg, and 70 mg of lisdexamfetamine dimesylate respectively, compared to a 0.9 kg weight gain for patients receiving placebo. Careful follow-up for weight in adolescents aged 13 to 17 years who received lisdexamfetamine dimesylate over 12 months suggests that continuous treatment (i.e., treatment for 7 days per week throughout the year) slows growth rate measured by body weight as demonstrated by an age- and sex‑normalised mean change from baseline in percentile of -6.5 over 1 year. The average percentiles at baseline (n=265) and 12 months (n=156) were 66.0 and 61.5, respectively.

In children and adolescents (aged 6-17) who received lisdexamfetamine dimesylate over two years, careful monitoring of weight suggested that consistent medication (i.e, treatment for 7 days per week throughout the two years) resulted in a slowing of growth as measured by body weight. In children and adolescents, the average weight percentiles and standard deviations (SD) at baseline (n=314) and 24 months (Week 104, n=189), were 65.4 (SD 27.11) and 48.2 (SD 29.94), respectively. The age- and sex‑normalized mean change from baseline in percentile over 2 years was -16.9 (SD 17.33).

In a controlled clinical trial of lisdexamfetamine dimesylate in children ages 4 to 5 years who received 5 – 30 mg of lisdexamfetamine dimesylate, there were no clinically meaningful changes in weight from baseline after 6 weeks of follow-up. Careful follow-up for weight in children aged 4 to 5 years who received lisdexamfetamine dimesylate over 12 months in an open-label extension study suggests that continuous treatment (i.e., treatment for 7 days per week throughout the year) slows growth rate measured by body weight as demonstrated by an age- and sex‑normalised mean change from baseline in percentile of -17.92 (SD=13.767) over 1 year. The average percentiles at baseline (n=113) and 12 months (n=69) were 66.51 (SD=25.173) and 47.45 (SD=26.144), respectively.

Eosinophilic hepatitis

No cases were reported in the clinical studies.

Angioedema

No cases were reported in the clinical studies.

Stevens-Johnson syndrome

No cases were reported in the clinical studies.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (Website: www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The prolonged release of dexamfetamine after administration of lisdexamfetamine dimesylate should be considered when treating patients with overdose.

Manifestations of acute overdosage with amfetamines include restlessness, tremor, hyperreflexia, rapid respiration, confusion, aggression, hallucinations, panic states, hyperpyrexia, and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhoea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma.

Posterior reversible encephalopathy syndrome (PRES) has been reported in association with amfetamine overdose. Symptoms indicating PRES include headache, altered mental status, seizures and visual disturbances. Diagnosis should be confirmed by radiological procedure (e.g., MRI). Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral haemorrhage.

There is no specific antidote to amfetamine overdose. Management of acute amfetamine intoxication is largely symptomatic and may include administration of activated charcoal, administration of a cathartic, and sedation.

Lisdexamfetamine and dexamfetamine are not dialysable.

In case of amfetamine overdose, consult a poison control centre for guidance or treat as clinically indicated. The prolonged duration of action of amfetamine should be considered when treating patients with overdose.