Lisdexamfetamine Dimesilate

Registered South African indications:

• Attention Deficit Hyperactivity Disorder
  - Diagnosed according to the most recent DSM diagnostic criteria where treatment with methylphenidate and atomoxetine has failed

Amfetamines have a high potential for abuse. Administration of amfetamines for prolonged periods of time may lead to medicine dependence. Misuse of amfetamine may cause sudden death and serious cardiovascular adverse events.

 

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Known hypersensitivity to sympathomimetic amines
• Advanced arteriosclerosis
• Symptomatic cardiovascular disease
• Moderate to severe hypertension
• Hyperthyroidism
• Glaucoma
• Agitated states
• Coadministration with monoamine oxidase inhibitors (MAOI) or within 14 days after MAOI treatment (hypertensive crisis may result)
• Phaeochromocytoma
• Tics or Tourette's syndrome
• Severe depression, anorexia nervosa, psychotic symptoms or suicidal tendency
• Known drug dependence or alcohol abuse
• Pregnancy
• Breastfeeding

South African recommendations

Caution in the following patient groups

• Mild to moderate (eGFR ≥30ml/min/1.73m²)
• Hepatic impairment

Abuse, misuse, and dependence

• Potential for abuse, misuse, dependence, or diversion; assess risk prior to prescribing and monitor for signs of abuse and dependence. Use with caution in patients with a history of substance abuse

Withdrawal and discontinuation

• Careful supervision is required during withdrawal; abrupt cessation after prolonged high dosage can cause extreme fatigue, mental depression, and sleep EEG changes. Withdrawal may unmask symptoms of underlying disorders or cause severe depression

Dosage and intoxication

• Caution patients against increasing the recommended dose. Chronic intoxication may manifest as severe dermatoses, insomnia, irritability, hyperactivity, personality changes, and psychosis indistinguishable from schizophrenia

Pre-treatment cardiac and psychiatric assessment

• Assess personal and family history for cardiac disease (including sudden death or ventricular dysrhythmia) and psychiatric disorders. Conduct physical exams and consider specialist review or cardiac evaluation (ECG/echocardiogram) if risk factors are identified

Cardiovascular events and structural abnormalities

• Serious events including sudden death, stroke, and myocardial infarction have been reported. Generally, do not use in patients (children, adolescents, or adults) with known serious structural cardiac abnormalities, cardiomyopathy, or serious heart rhythm abnormalities

Hypertension and heart rate

• Monitor all patients for increases in blood pressure and heart rate. Use with caution in patients with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular dysrhythmia

Psychiatric disorders and bipolar illness

• Stimulants may exacerbate pre-existing psychosis or induce mixed/manic episodes in patients with comorbid bipolar disorder; screen for bipolar risk (family history of suicide, depression, and bipolar disorder) before initiation

Emergence of new symptoms and aggression

• Psychotic or manic symptoms (hallucinations, delusions) in those without a prior history may be caused by usual doses; consider discontinuation. Monitor for the appearance or worsening of aggressive behaviour or hostility

Seizures

• May lower the convulsive threshold; discontinue lisdexamfetamine dimesilate in the presence of seizures

Visual disturbance

• Difficulties with accommodation and blurring of vision have been reported

Tics and tourette’s syndrome (see Contraindications)

• May exacerbate motor and phonic tics; clinical evaluation of children and their families for these conditions should precede use

Long-term growth suppression

• Associated with dose-related weight loss and potential suppression of height and weight in children. Carefully monitor growth during long-term therapy and interrupt treatment if growth is not as expected

Peripheral vasculopathy (Raynaud's Phenomenon)

• Associated with digital changes and, rarely, ulceration or tissue breakdown. Careful observation for digital changes is necessary; symptoms generally improve with dose reduction or discontinuation

Prescribing and dispensing

• Prescribe or dispense the least amount feasible to minimise overdosage risk. Consider risks when using concurrently with other sympathomimetic medicines

Paediatric and elderly use

• Should not be used in children under 13 years (formulations do not allow dose optimisation for ages 6–12); safety and efficacy are not established for children under 6 or adults over 55 years

Laboratory test interference

• May cause significant elevation in plasma corticosteroid levels (greatest in the evening) and interfere with urinary steroid determinations

Effects on ability to drive and use machines

• Lisdexamfetamine dimesilate may affect the ability of patients to drive or use machinery. Patients should not drive or use machinery until they know how treatment with lisdexamfetamine dimesilate affects them. Lisdexamfetamine dimesilate can cause dizziness, drowsiness and visual disturbances including difficulties with accommodation, diplopia and blurred vision

Forms avail. in SA and covered in this monograph: cap

South African registered indications and dosages

Attention Deficit Hyperactivity Disorder (ADHD)
- Diagnosed according to the most recent DSM diagnostic criteria where treatment with methylphenidate and atomoxetine has failed

Treatment should be initiated and supervised by a medical practitioner experienced in treatment of patients with ADHD 

Younger than 55 years

• Oral (cap): Initial: 30mg, dly in the morning; Titrate by 20mg, weekly; Max: 70mg/24hrs 

Older than 55 years

• Not established for use

---

Treatment with lisdexamfetamine dimesilate should be part of a comprehensive treatment program for ADHD

---

Patients should be reviewed at least every 6 months to assess if there is an on-going need for treatment. Blood 
pressure and cardiovascular status should also be regularly reviewed

---

Lisdexamfetamine dimesilate should be administered orally at the lowest possible dosage and should then 
be slowly adjusted to the lowest effective dose for each individual. Doses greater than 70mg/day have not been studied

---

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 lisdexamfetamine dimesilate

---

Avoid afternoon doses because of the potential for insomnia

---

Method of administration

Lisdexamfetamine dimesilate capsules may be taken whole, or the capsule may be 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 of the capsule include any compacted powder, a spoon may be used to break apart the powder in the soft food or liquid
The contents should be mixed 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

Forms avail. in SA and covered in this monograph: cap

South African registered indications and dosages

Attention Deficit Hyperactivity Disorder (ADHD)
- Diagnosed according to the most recent DSM diagnostic criteria where treatment with methylphenidate and atomoxetine has failed

Treatment should be initiated and supervised by a medical practitioner experienced in treatment of patients with ADHD 

Younger than 13 years

• Not established for use

---

Lisdexamfetamine dimesilate should not be used in children under the age of 13 years, as the available formulations are not appropriate for up or down titration to find an optimal dose in children aged 6 to 12 years. Safety and efficacy in children under the age of 6 years have not been established

---

Older than 13 years

• Oral (cap): 30mg, dly in the morning; Titrate by 20mg weekly; Max: 70mg/24hrs 

---

Treatment with lisdexamfetamine dimesilate should be part of a comprehensive treatment program for ADHD

---

Patients should be reviewed at least every 6 months to assess if there is an on-going need for treatment. Blood 
pressure and cardiovascular status should also be regularly reviewed

---

Lisdexamfetamine dimesilate should be administered orally at the lowest possible dosage and should then 
be slowly adjusted to the lowest effective dose for each individual. Doses greater than 70mg/day have not been studied

---

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 lisdexamfetamine dimesilate

---

Avoid afternoon doses because of the potential for insomnia

---

Method of administration

Lisdexamfetamine dimesilate capsules may be taken whole, or the capsule may be 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 of the capsule include any compacted powder, a spoon may be used to break apart the powder in the soft food or liquid
The contents should be mixed 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

Pregnancy

South African recommendations

• Contraindicated
• Lisdexamfetamine dimesilate should not be used in pregnancy as harm to the foetus cannot be excluded
• Dexamfetamine, the active metabolite of lisdexamfetamine, crosses the placenta. Amfetamines such as lisdexamfetamine dimesilate cause vasoconstriction and may decrease placental perfusion which may affect the developing foetus. It also stimulates uterine contractions increasing the risk of premature delivery and low birth weight babies. There is some evidence, although inconclusive, that amfetamine use in early pregnancy, may be associated with an increased risk of pre-eclampsia
• Women of childbearing age being treated with lisdexamfetamine dimesilate should be advised not to become pregnant
• Effects on infants: Infants born to mothers taking amfetamines should be monitored for symptoms of withdrawal such as feeding difficulties, irritability, agitation and excessive drowsiness
• Effects on embryo-foetal development: Lisdexamfetamine dimesilate had no apparent effects on embryo-foetal development or survival when administered orally to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 40 and 120mg/kg/day respectively. These doses resulted in respective plasma dexamfetamine AUC values which were 5 and 2 fold the AUC expected in adults at the maximum recommended dose of 70mg, and respective plasma lisdexamfetamine AUC values which were 12 and 40 fold the AUC expected in adults at the maximum recommended dose
• A study of lisdexamfetamine dimesilate has not been conducted in rats treated throughout gestation and lactation. Amfetamine sulphate (d- to l- enantiomer ratio of 3:1), when given orally to rats from early gestation through to weaning at doses of 2, 6 and 10mg total amfetamine base/kg/day, reduced the number of live born pups and pup viability during lactation. Body weight gain of offspring was reduced during lactation and after weaning, development was delayed, and increases in locomotor activity were observed. The reproductive performance of the offspring was also reduced. Some effects were observed at the 2mg/kg/day dose, which was associated with a plasma amfetamine AUC about half that expected in adults at the maximum recommended dose of 70mg

Breastfeeding

South African recommendations

• Contraindicated
• Women on treatment with lisdexamfetamine dimesilate should not breastfeed their infants. Amfetamines are excreted in human milk. There is a risk of severe adverse reactions in the infant including cardiovascular reactions, blood pressure and heart rate increases, suppression of growth and peripheral vasculopathy. Long term neurodevelopmental effects on infants from amfetamine exposure are unknown

Fertility

South African recommendations

• The effect of lisdexamfetamine dimesilate on human fertility has not been investigated

South African recommendations

• Mild to moderate (eGFR ≥30ml/min/1.73m²): Caution; no dose adjustment recommended
  Severe (eGFR 15-<30ml/min/1.73m²): Caution; dose adjustment recommended
  Max: 50mg/24hrs
  Further dosage reduction should be considered in patients undergoing dialysis. Lisdexamfetamine and dexamfetamine are not dialysable

South African recommendations

• Caution; no information available
  No studies have been conducted in patients with hepatic impairment

South African recommendations

• Not indicated for use in geriatric patients
  Safety and efficacy have not been established in adult patients over the age of 55 years

Immune System Disorders

Less frequent

• Hypersensitivity (Adults and Adolescents)

Frequency unknown

• Anaphylactic reaction (Adults and Adolescents)

Metabolism and Nutrition Disorders

Frequent

• Decreased appetite (Adults and Adolescents)

Psychiatric Disorders

Frequent

• Insomnia (Adults and Adolescents)
• Agitation (Adults)
• Anxiety (Adults and Adolescents)
• Libido decreased (Adults)
• Depression (Adolescents)
• Affect lability (Adults)
• Psychomotor hyperactivity (Adults)
• Bruxism (Adults)

Less frequent

• Agitation (Adolescents)
• Logorrhoea (Adults and Adolescents)
• Depression (Adults)
• Tic (Adults and Adolescents)
• Affect lability (Adolescents)
• Dysphoria (Adults and Adolescents)
• Euphoria (Adults and Adolescents)
• Psychomotor hyperactivity (Adolescents)
• Bruxism (Adolescents)
• Dermatillomania (Adults and Adolescents)
• Mania (Adults and Adolescents)
• Hallucination (Adolescents)
• Aggression (Adolescents)

Frequency unknown

• Psychotic episodes (Adults and Adolescents)
• Hallucination (Adults)
• Aggression (Adults)

Nervous System Disorders

Frequent

• Headache (Adults and Adolescents)
• Dizziness (Adults and Adolescents)
• Restlessness (Adults and Adolescents)
• Tremor (Adults and Adolescents)
• Somnolence (Adolescents)

Less frequent

• Somnolence (Adults)
• Dyskinesia (Adults and Adolescents)
• Dysgeusia (Adults and Adolescents)
• Syncope (Adults and Adolescents)

Frequency unknown

• Seizure (Adults and Adolescents)

Eye Disorders

Less frequent

• Blurred vision (Adults)
• Mydriasis (Adolescents)

Frequency unknown

• Blurred vision (Adolescents)
• Mydriasis (Adults)

Cardiac Disorders

Frequent

• Tachycardia (Adults and Adolescents)
• Palpitation (Adults and Adolescents)

Less frequent

• Cardiomyopathy (Adolescents)

Frequency unknown

• QTc prolongation (Adults and Adolescents)
• Cardiomyopathy (Adults)

Vascular Disorders

Frequency unknown

• Raynaud’s phenomenon (Adults and Adolescents)

Respiratory, Thoracic and Mediastinal Disorders

Frequent

• Dyspnoea (Adults and Adolescents)

Gastrointestinal Disorders

Frequent

• Dry mouth (Adults and Adolescents)
• Diarrhoea (Adults and Adolescents)
• Constipation (Adults)
• Upper abdominal pain (Adults and Adolescents)
• Nausea (Adults and Adolescents)
• Vomiting (Adolescents)

Less frequent

• Constipation (Adolescents)
• Vomiting (Adults)

Hepatobiliary Disorders

Frequency unknown

• Eosinophilic hepatitis (Adults and Adolescents)

Skin and Subcutaneous Tissue Disorders

Frequent

• Hyperhidrosis (Adults)

Less frequent

• Hyperhidrosis (Adolescents)
• Urticaria (Adults and Adolescents)
• Rash (Adults and Adolescents)

Frequency unknown

• Angioedema (Adults and Adolescents)
• Stevens-Johnson Syndrome (Adults and Adolescents)

Reproductive System and Breast Disorders

Frequent

• Erectile dysfunction (Adults)

Less frequent

• Erectile dysfunction (Adolescents)

General Disorders and Administration Site Conditions

Frequent

• Chest pain (Adults)
• Irritability (Adults and Adolescents)
• Fatigue (Adults and Adolescents)
• Feeling jittery (Adults and Adolescents)
• Pyrexia (Adolescents)

Less frequent

• Chest pain (Adolescents)
• Pyrexia (Adults)

Investigations

Frequent

• Increased blood pressure (Adults)
• Weight decreased (Adults and Adolescents)

Less frequent

• Increased blood pressure (Adolescents)

• Monoamine oxidase inhibitors (MAOIs)
• Serotonergic drugs
• Selective serotonin reuptake inhibitors (SSRls)
• Serotonin and norepinephrine (noradrenaline) reuptake inhibitors (SNRls)
• Ascorbic acid
• Sodium bicarbonate
• Agents that acidify urine
• Agents that alkalinise urine
• Antihypertensives
• Narcotic analgesics
• Haloperidol
• Lithium carbonate

Other interactions

• Laboratory tests
  - Urinary steroid determinations

• Physical exam
• Cardiac history and evaluation
• Psychiatric history
• Blood pressure
• Heart rate
• Weight

Some cases may require

• Growth rate (height and weight in children)
• Electrocardiogram
• Echocardiogram

Additional observations

• Personal and family cardiac history
• Personal and family psychiatric history
• Assessment of family history of sudden death or ventricular dysrhythmia
• Assess the risk of abuse prior to prescribing
• Signs and symptoms of withdrawal such as feeding difficulties, irritability, agitation and excessive drowsiness (in infants born to mothers taking amfetamines)
• Appearance of or worsening of aggressive behaviour or hostility
• Signs of abuse and dependance while on therapy

After oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract and hydrolysed primarily in whole blood to dexamfetamine, which is responsible for the medicine’s activity. Amfetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action of amfetamine in Attention Deficit Hyperactivity Disorder (ADHD) is not fully established, however it is thought to be due to its ability to block the reuptake of norepinephrine (noradrenaline) and dopamine into the presynaptic neuron and increase the release of these monoamines into the extra neuronal space. The parent active ingredient, lisdexamfetamine, does not bind to the sites responsible for the reuptake of noradrenaline and dopamine in vitro.

Capsule 30mg

• Vyvanse (Takeda) (originator)

Capsule 50mg

• Vyvanse (Takeda) (originator)

Capsule 70mg

• Vyvanse (Takeda) (originator)