Esketamine

Registered South African indications:

• Treatment-resistant depression (TRD)

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients 
• Hypersensitivity to ketamine
• Patients for whom an increase in blood pressure or intracranial pressure poses a serious risk
• Known aneurysmal vascular disease (incl. intracranial, thoracic, or abdominal aorta, or peripheral arterial blood vessels)
• History of intracerebral haemorrhage
• Arteriovenous malformation

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients 
• Hypersensitivity to ketamine
• Patients for whom an increase in blood pressure or intracranial pressure poses a serious risk
  - Aneurysmal vascular disease (incl. intracranial, thoracic, or abdominal aorta, or peripheral arterial blood vessels) 
  - History of intracerebral haemorrhage
  - Recent (within 6 weeks) cardiovascular event, including myocardial infarction

Cautions

South African manufacturer recommendations

• Pregnancy
• Breastfeeding
• Women of reproductive potential
• Renal impairment
• Severe hepatic impairment
• Elderly
• History of drug abuse or dependence
• Presence or history of psychosis
• Presence of history of mania or bipolar disorder
• Hyperthyroidism that has not been sufficiently treated
• Significant pulmonary insufficiency
• Known uncontrolled brady- or tachydysrhythmias that lead to haemodynamic instability
• History of brain injury, hypertensive encephalopathy, intrathecal therapy with ventricular shunts, or any other condition associated with increased intracranial pressure
• History of suicide-related events
• Significant degree of suicidal ideation
• Suicidal behaviour or thoughts
• Unusual changes in behaviour 
• High blood pressure
• Prolonged use of ketamine
• Cardiovascular and cerebrovascular conditions
  - Unstable or poorly controlled hypertension
  - History (within 6 weeks) of cardiovascular event including myocardial infarction
  - History (within 6 months) of ischaemic stroke or transient ischaemic attack
  - Haemodynamically significant valvular heart disease such as mitral valve regurgitation, mitral valve stenosis, aortic valve stenosis, or aortic valve regurgitation
  - New York Heart Association (NYHA) Class III-IV heart failure of any aetiology
• History of substance use disorder, including alcohol
• Coadministration with nasal corticosteroid or nasal decongestant
• Coadministration with food and liquids
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Women of reproductive potential
• Moderate to severe hepatic impairment
• Elderly
• Japanese ancestry 
• Clinically significant or unstable cardiovascular or respiratory conditions
  -  Significant pulmonary insufficiency, including chronic obstructive pulmonary disease (COPD)
  -  Sleep apnoea with morbid obesity (body mass index [BMI] ≥35)
  -  Uncontrolled brady- or tachyarrhythmias that lead to haemodynamic instability
  -  History of myocardial infarction
  -  Haemodynamically significant valvular heart disease or heart failure (NYHA Class III-IV)
• High blood pressure
• Prolonged use of ketamine
• History of suicide-related events
• Significant degree of suicidal ideation
• Suicidal behaviour or thoughts
• Unusual changes in behaviour 
• History of drug abuse or dependence
• Presence or history of psychosis
• Presence or history of mania or bipolar disorder
• Hyperthyroidism that has not been sufficiently treated
• History of brain injury, hypertensive encephalopathy, intrathecal therapy with ventricular shunts, or any other condition associated with increased intracranial pressure
• Coadministration with nasal corticosteroid or nasal decongestant
• Coadministration with food and liquids
• May impair ability to drive and operate machinery

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

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Treatment-resistant depression (TRD) (Additional agent required)
- In combination with an oral antidepressant (selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI)) in those who have not responded adequately to treatment with at least two different antidepressants of adequate dose and duration to treat the current depressive episode

• Nasal (nas): See table

Induction Phase	Maintenance Phase
Weeks 1-4 (two treatment sessions/week): Starting Day 1 dose: 56mg Subsequent doses: 56mg or 84mg Evidence of therapeutic benefit should be evaluated at the end of induction phase to determine need for continued treatment	Weeks 5-8:  56mg or 84mg once weekly From Week 9: 56mg or 84mg every 2 weeks or once weekly Individualised to the lowest frequency to maintain remission/response

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For nasal use only. Single-use device that delivers a total of 28mg of esketamine in two sprays (one spray per nostril)

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Device should not be primed before use. Use 1 device (for 28mg dose), 2 devices (for 56mg dose) or 3 devices (for 84mg dose), with a 5-minute rest between use of each device to allow medication to absorb

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A treatment session consists of nasal administration by the patient and post-administration observation under the supervision of a healthcare professional

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After depressive symptoms improve, treatment is recommended for at least 6 months. Periodically re-examine the need for continued treatment

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Since some patients may experience nausea and vomiting after administration, patients should be advised not to eat for at least 2 hours before administration and not to drink liquids at least 30 minutes prior to administration

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Patients who require nasal corticosteroid or nasal decongestant on a dosing day should be advised not to administer these medications within 1 hour before administration

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See additional prescribing points for blood pressure assessment

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International manufacturer recommendations

Treatment-resistant major depressive disorder (MDD) -  moderate to severe (Additional agent required)
- In combination with an SSRI or SNRI in those who have not responded to at least two different treatments with antidepressants in the current depressive episode

• Nasal (nas): See table

Induction Phase	Maintenance Phase
Weeks 1-4: Starting Day 1 dose: 56mg Subsequent doses: 56mg or 84mg twice a week Evidence of therapeutic benefit should be evaluated at the end of induction phase to determine need for continued treatment Recommended to maintain the dose received at the end of induction phase in the maintenance phase. Dose adjustments should be made based on efficacy and tolerability to the previous dose	Weeks 5-8: 56mg or 84mg once weekly From Week 9: 56mg or 84mg every 2 weeks or once weekly Individualised to the lowest frequency to maintain remission/response

Major depressive disorder episodes - moderate to severe
- In combination with oral antidepressant therapy, as acute short-term treatment, for the rapid reduction of depressive symptoms, which according to clinical judgement constitute a psychiatric emergency

• Nasal (nas): Initial: 84mg, twice weekly; Maintenance: 56-84mg, twice weekly; Duration:4 weeks

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The decision to prescribe esketamine should be determined by a psychiatrist

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For nasal use only. Single-use device that delivers a total of 28mg of esketamine in two sprays (one spray per nostril)

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Device should not be primed before use. Use 1 device (for 28mg dose), 2 devices (for 56mg dose) or 3 devices (for 84mg dose), with a 5-minute rest between use of each device

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Intended to be self-administered by the patient under the direct supervision of a healthcare professional

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A treatment session consists of nasal administration and post-administration observation in an appropriate clinical setting (See additional prescribing points)

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For treatment-resistant MDD , treatment is recommended for at least 6 months after depressive symptoms improve. Periodically re-examine the need for continued treatment. For acute short-term treatment,  the antidepressant therapy should be continued, per clinical judgement, after 4 weeks of treatment with esketamine. Treatment with esketamine should be part of the comprehensive clinical care plan

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Since some patients may experience nausea and vomiting after administration, patients should be advised not to eat for at least 2 hours before administration and not to drink liquids at least 30 minutes prior to administration

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Patients who require nasal corticosteroid or nasal decongestant on a dosing day should be advised not to administer these medications within 1 hour before administration

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See additional prescribing points for blood pressure assessment

Not established for use in children below 18 years

Pregnancy 

South African manufacturer recommendations

• Caution; not recommended
• Risks during pregnancy have not been studied. Human data in pregnant women during clinical trials with esketamine exposure are too limited to be conclusive
• Animal studies with ketamine, the racemic mixture of arketamine and esketamine, show evidence of developmental neurotoxicity. The potential for esketamine to have neurotoxic effects on foetuses cannot be excluded
• If a woman becomes pregnant while being treated, treatment should be discontinued and the patient should be counselled about the potential risk to the foetus and clinical/therapeutic options as soon as possible
• Women of reproductive potential should be advised to use highly effective contraception during and up to 6 weeks after the last treatment with esketamine

International manufacturer recommendation

• Caution; not recommended 
• There are no or limited data on use in pregnant women
• Animal studies have shown that ketamine, the racemic mixture of arketamine and esketamine, induces neurotoxicity in developing foetuses. A similar risk with esketamine cannot be excluded
• If a woman becomes pregnant while being treated, treatment should be discontinued, and the patient should be counselled about the potential risk to the foetus and clinical/therapeutic options as soon as possible
• Not recommended in women of childbearing potential not using contraception

Breastfeeding

South African manufacturer recommendations

• Caution; not recommended 
• Esketamine is present in human milk. There are no data on the effects on the breastfed infant or on milk production
• Published studies with ketamine in juvenile animals report neurotoxicity. Because of the potential for neurotoxicity, advise patients that breastfeeding is not recommended

International manufacturer recommendation

• Caution 
• Unknown whether esketamine is excreted in human milk
• Data in animals have shown excretion of esketamine in milk. A risk to the breastfeeding child cannot be excluded
• A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from esketamine therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

South African manufacturer recommendations

• In a fertility and early embryonic development study in rats, oestrous cycle irregularities were observed at an intranasal esketamine dose of 45mg/kg/day and a delay in mating was observed ≥15mg/kg/day. Due to the lack of overall changes to mating and fertility indices, the no-observed-adverse-effect level (NOAEL) was considered 45mg/kg/day which produce area under the curve (AUC) exposure that was 0,6 times the AUC exposure at the maximum recommended human dose (MRHD)

International manufacturer recommendation

• Animal studies showed that fertility and reproductive capacities were not adversely affected by esketamine

Renal Impairment

South African manufacturer recommendations

• Caution; no dose adjustment recommended 

International manufacturer recommendation

• No dose adjustment recommended 

Hepatic Impairment 

South African manufacturer recommendations

• Mild to moderate (Child-Pugh class A and B): No dose adjustment recommended 
• Severe (Child-Pugh class C): Caution; not recommended 

International manufacturer recommendation

• Mild (Child-Pugh class A): No dose adjustment recommended 
• Moderate: (Child-Pugh class B): Caution; no dose adjustment recommended  
  Dose of 84mg should be used with caution 
• Severe (Child-Pugh class C): Caution; not recommended 

Elderly

South African manufacturer recommendations

• Caution; dose adjustment recommended 
  - Initial dose: 28mg; subsequent doses should be increased in increments of 28mg up to 56mg or 84mg, based on efficacy and tolerability 

International manufacturer recommendation

• Treatment-resistant major depressive disorder (MDD): Caution; dose adjustment recommended 
  - See table

  Induction Phase	Maintenance Phase
  Weeks 1-4 Starting day 1 dose: 28mg Subsequent doses: 28mg, 56mg or 84mg, twice a week, all dose changes should be in 28mg increments Evidence of therapeutic benefit should be evaluated at the end of induction phase to determine need for continued treatment	Weeks 5-8:  28mg, 56mg or 84mg once weekly, all dose changes should be in 28mg increments From Week 9: 28mg, 56mg or 84mg, every 2 weeks or once weekly, all dose changes should be in 28mg increments The need for continued treatment should be reexamined periodically

• Acute short-term treatment of psychiatric emergency due to MDD: Caution; no information available 

Porphyria Information

• Possibly porphyrinogenic (PSP) 

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Dissociation
  - Derealisation
  - Depersonalisation
  - Illusions
  - Altered time perception
• Anxiety
• Euphoric mood
• Confusional state
• Irritability
• Hallucination
  - Visual hallucination
• Agitation
• Panic attack
• Psychomotor retardation
• Emotional distress
• Dysphoria
• Dizziness
• Headache
• Somnolence
• Hypoaesthesia
• Paraesthesia
• Sedation
• Tremor
• Mental impairment
• Lethargy
• Dysarthria
• Attention disturbance
• Nystagmus
• Psychomotor hyperactivity
• Asthenia
• Gait disturbance

Cardiovascular Disorders

• Tachycardia
• Hypertension
• Increased blood pressure 

Respiratory Disorders

• Nasal discomfort
• Throat irritation
• Oropharyngeal pain
• Nasal dryness
  - Nasal crusting
• Nasal pruritus

Gastrointestinal Disorders

• Nausea and vomiting
• Oral hypoaesthesia
• Dry mouth
• Salivary hypersecretion

Genitourinary Disorders

• Lower urinary tract symptoms
  - Pollakiuria
  - Dysuria
  - Micturition urgency
  - Nocturia
  - Cystitis

Skin and Subcutaneous Tissue Disorders

• Hyperhidrosis
• Cold sweat

Sensory Disorders

• Dysgeusia
• Blurred vision 
• Vertigo
• Tinnitus
• Hyperacusis

Others

• Feeling abnormal
• Feeling drunk
• Crying
• Feeling of body temperature change

• Central nervous system depressants
• Benzodiazepines
• Opioids
• Psychostimulants
• Amphetamines
• Methylphenidate
• Modafinil
• Armodafinil
• Medicinal agents that may increase blood pressure
• Xanthine derivatives
• Ergometrine
• Thyroid hormones
• Vasopressin
• Monoamine oxidase inhibitors
• Tranylcypromine
• Selegiline
• Phenelzine

Other interactions

• Alcohol

• Blood pressure (See additional prescribing points)

Specific cases may require

• Respiratory depression 

Additional observations

• Sedation (with concomitant use of central nervous system depressants)
• Adverse effects (for at least 2 hours following administration)
• Suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased)
• Assess risk for
  - Abuse or misuse
  - Psychosis
  - Cardiovascular and cerebrovascular conditions
• Clinical worsening of depression and emergence of suicidal thoughts and behaviours (especially during the initial few months of therapy and at times of dosage change)
• Evidence of therapeutic benefit at the end of the induction phase to determine need for continued treatment
• Signs/symptoms of abuse and misuse (during therapy)
• Urinary tract or bladder symptoms 

Blood pressure 

• Esketamine can cause transient increases in systolic and/or diastolic blood pressure which peak at approximately 40 minutes after administration and last approximately 1-2 hours
• Assess blood pressure prior to dosing. If baseline blood pressure is elevated, consider the risks of short term increases in blood pressure and benefit of treatment 
• After dosing, blood pressure must be reassessed approximately 40 minutes after dosing and subsequently as clinically warranted
• Because of the possibility of sedation, dissociation and elevated blood pressure, patients must be monitored by a healthcare professional until the patient is considered clinically stable and ready to leave the healthcare setting
• If blood pressure has normalised and the patient appears clinically stable, both physically and mentally for at least two hours, the patient may be discharged at the end of the post-dose monitoring period; if not, continue to monitor
• Closely monitor blood pressure with concomitant use with psychostimulants or other medicinal agents that may increase blood pressure (e.g. monoamine oxidase inhibitors)
• Adjust lifestyle and/or pharmacologic therapies to reduce blood pressure before starting treatment

Missed treatment session(s)

South African manufacturer recommendations

• In case one or two treatment sessions are missed, schedule the next session when the next dosage session was scheduled to occur based on current treatment frequency
• If more than 2 treatment sessions have been missed, per clinical judgment, adjustment of the dose or frequency may be clinically appropriate

International manufacturer recommendations

• Patients who have missed treatment session(s) during the first 4 weeks of treatment should continue with their current dosing schedule
• For patients with treatment-resistant major depressive disorder who miss treatment session(s) during maintenance phase and have worsening of depression symptoms, per clinical judgement, consider returning to the previous dosing schedule

Esketamine is the S-enantiomer of racemic ketamine. It is a non-selective, non-competitive, antagonist of the N-methyl- D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. Through NMDA receptor antagonism, esketamine produces a transient increase in glutamate release leading to increases in α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptor (AMPAR) stimulation and subsequently to increases in neurotrophic signalling which may contribute to the restoration of synaptic function in these brain regions involved with the regulation of mood and emotional behaviour. Restoration of dopaminergic neurotransmission in brain regions involved in the reward and motivation, and decreased stimulation of brain regions involved in anhedonia, may contribute to the rapid response.

Nasal spray (per spray device) 28mg 

• Spravato (Janssen) originator